Pharm- ALL DRUGS 1ST SEMESTER

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Ezetimibe

*ACTION:* -Cholesterol Absorption Inhibitor *-Blocks intestinal absorption of cholesterol by blocking Niemann-Pick C1-Like 1 (NPC1L1) protein in jejunal enterocytes* -Inhibits cholesterol absorption by ~55% -Reduces LDL (~ 18%) [only inhibits cholesterol absorption through the gut; not inhibiting synthesis and most of the cholesterol in the body is synthetic] *INDICATION:* *-Often given in combination therapy with Niacin or Statins* *ADVERSE:* -Fatigue -GI (diarrhea/abdominal pain) -Rhabdomyolysis (rare)

LITHIUM CARBONATE

*ACTION:* - precise mechanism unknown (see above) *CLINIC:* - primarily BP disorder: prophylactically for treating maniac-depressive patients and in the treatment of manic episodes - Also used as an adjuvant with antidepressants for major depression - Also used as an adjuvant with antipsychotics for schizophrenia *ADVERSE:* -*narrow therapeutic index* *TOXIC IN HIGH DOSES* --> can compete with Na+ and interfere with rxns in body - *hypothyroidism* (effects iodine accumulation for biosynthesis of thyroid hormone) (regular monitoring required) - *renal toxicity* (regular monitoring required) - GI disturbance - ataxia, confusion, convulsions, tremors, - dry mouth, polydipsia, polyuria, leukocytosis *CONTRAINDICATIONS:* - *pregnancy--> teratogenic!* *ADVANTAGE:* - Not a sedative, euphoriant, or depressant *PK:* *ROUTE:* oral *DISTRIBUTION:* rapidly absorbed, and widely distributed -No metabolism (it is an element!) - has no effect on normal individuals (but toxic at high doses; see above) - lots of Na intake can inhibit lithium action

Quinidine Gluconate

*ADVERSE:* - cardiotoxic - hypotension - hypoglycemia - prolonged QTc interval *ROUTE:* IV

Atovaquone/Proguanil

*ATOVAQUONE* *MECHANISM:* selective mitochondrial inhibitor (parasite cytochrome bc1 complex) *PROGUANIL:* *MECHANISM:* enhances collapse of mito membrane potential and its metabolite (cycloguanil) is a DHFR inhibitor (inhibits the folate pathway) *RESISTANCE:* Not yet (drug combo) *INDICATION:* - malaria prophylaxis and treatment -also alternative treatments for Toxoplasma protozoa and Pneumocystis fungi *ADVERSE:* well tolerated *CONTRAINDICATED in patients with severe renal impairment *PK:* *Route oral: *Distribution: majority bound to plasma proteins *Metabolism: minimal *Excretion: bile, feces

Doxepin

*Action:* *Low doses:* selective histamine (H1) antagonist *Higher doses:* tricyclic antidepressant: (increase 5HT and NE at synaptic cleft) and anticholinergic effects *Clinical Use:* *Low doses: insomnia (particularly to help with sleep maintenance)* - doesn't help insomnia very well *Higher doses: depression, anxiety* *Problems:* *Minimal at low doses* *Higher doses:* -black-box warning: potential for increased suicidal ideations (w/ all antidepressants) -Withdrawal (so taper dose upon discontinuation). CONTRAINDICATIONS*Do not use in patients who have taken MAOIs within previous 2 weeks*

Ramelteon

*Action:* -Agonist at melatonin receptors and thus modulate circadian rhythms involved in sleep-wake cycle. *NO direct effect on GABA receptors.* *Clinical Use:* -Treatment of insomnia characterized by difficulty with sleep onset *NOT approved in Europe because of concerns regarding therapeutic effect* *Problems:* Minor *Advantages:* -Minimal potential for abuse no rebound insomnia -No withdrawal. *Only approved sedative-hypnotic that is not scheduled*

Flumazenil

*Action:* -Antagonist at benzodiazepine site of the GABAA receptor *Clinical Use:* -Benzodiazepine overdose -Shorten recovery following anesthesia with benzodiazepines *Problems:* -Seizures, agitation, confusion, dizziness, nausea -Can precipitate benzodiazepine withdrawal symptoms

PHENELZINE

*CLASS: * MAOIs *ACTION:* IRREVERSIBLY -Inhibit irreversibly both MAO-A and MAO-B - *Inhibition lasts 2-3 weeks after stopping drug due to irreversible blockade* (until new MAO molecules are synthesized and replace the irreversible bound ones) *CLINIC:* - treatment of atypical depression with phobia or psychotic features - other antidepressants are more frequently used because they have fewer side effects -elevates mood (2-6 weeks) *ADVERSE:* - **hypertensive crisis** if patient ingests tyramine ("wine and cheese syndrome") - CNS stimulate (amphetamine-like effects) - suppresses REM - orthostatic hypotension, dry mouth, blurred vision, weight gain -hepatotoxicity -may precipitate mania in bipolar patients *CONTRAINDICATIONS:* *use is limited due to complicated dietary restrictions* *PK:* - All are well absorbed, hydrophobic, readily cross BBB - effects persist for 2-3 wks after stopping due to irreversible inhibition until new MAOs are synthesized - complicated diet restrictions: nothing with tyramine

VENLAFAXINE

*CLASS: * SNRIs- Serotonin/Norepinephrine Re-uptake Inhibitors *ACTION:* -potent inhibitor of 5HT reuptake at all doses - only inhibits NE reuptake at HIGHER doses - mild inhibitor of dopamine re-uptake *CLINIC:* - depression - often effective in relieving neuropathic pain associated with depression - may be effective in the cases where SSRIs are ineffective *ADVERSE:* -nausea, dizziness, insomnia, sedation, sexual dysfunction, constipation; - at higher doses - an increase in blood pressure *PK:* - minimal inhibitory action on cytochrome P-450 enzymes

DULOXETINE (cymbalta)

*CLASS: * SNRIs- Serotonin/Norepinephrine Re-uptake Inhibitors *ACTION:* inhibits NE and 5HT re-uptake at ALL doses *CLINIC:* - depression - often effective in relieving neuropathic pain associated with depression - may be effective in the cases where SSRIs are ineffective *ADVERSE:* -nausea, dry mouth, constipation, diarrhea and vomiting,insomnia, dizziness, somnolence, sweating, sexual dysfunction *CONTRAINDICATIONS:* - hepatic insufficiency (metabolized in the liver to numerous metabolites) - End-stage renal disease metabolites are excreted in the urine) *PK:* SRD - food delays absorbtion - highly bound to plasma proteins

FLUOXETINE (Prozac)

*CLASS: * SSRI- Selective Serotonin Re-uptake Inhibitors *ACTION:* potent inhibition of serotonin re-uptake - NO significant effects on NE or DA reuptake *CLINIC:* - depression - OCD *ADVERSE:* in general SSRIs have fewer side effects than other classes of antidepressants -nausea, diarrhea, -nervousness, insomnia, -dizziness, -sexual dysfunction (impotence, decreased libido, delayed or absent orgasm in 70% of patients) - may precipitate mania in bipolar patients *CONTRAINDICATIONS:* - don't use with other MAOIs: can cause serotonin syndrome (hyperthermia, muscle rigidity, myoclonus, rapid changes in mental status) - careful in pts with liver probs *DRUG INTERACTIONS:* -metabolized by cytochrome P-450 system -*potent cytochrome P-450 inhibitor* - watch drug levels ---> *decreased dosage in patients with liver problems* *ADVANTAGE:* -Not much affinity for other peripheral receptors; hence no TCAs side effects -No weight gain *PK:* *ROUTE:* oral *t1/2:* 24 hrs (once a day dosing) *DISTRIBUTION:* hydrophobic, crosses BBB *EXCRETION:* renal - met by P450--> active metabolites

Amitriptyline

*CLASS: * TCAs Tricyclic Antidepressants *ACTION:* - increase NE and 5HT at cleft by blocking neuronal reuptake [act on the NE reuptake channel and 5HT reuptake channel on presynaptic membranes] - also inhibit muscarinic, histamine, alpha1 adrenergic receptors (secondary) --> "Dirty" drugs - downregulates MA receptors - i/a with ion channels (causes side effects) *Many of the TCAs have active metabolites that are potent antidepressants* -imipramine ---> desipramine -amitriptyline ---> nortriptyline *INDICATIONS:* - mood and panic disorders -Anxiety disorders (GAD, PTSD,OCD) - enuresis in children (wetting bed) (imipramine) -neuropathic pain -adjuvant for inflammatory pain -Not usually used for depression because now there are better drugs without side effects *ADVERSE:* *narrow TI --> can use for suicide OD* *Most common agents used in suicide* *Prescribe in small quantities to avoid overdose* -Potential for suicidal thinking/behavior in children/young adults (boxed warning) - anticholinergic: nausea, vomiting, anorexia, blurred vision, hot dry skin, constipation, confusion, urinary retention, tachycardia - antiadrenergic: orthostatic hypotension, drowsiness, dizziness - *influence Na channels --> leads to ECG changes: widening of QRS complex, ARRHYTHMIAS* (cardiovascular toxicities with high doses) - weight gain and sedation due to histamine blockade - possible lowering of seizure threshold -may precipitate mania in bipolar patients *CONTRAINDICATIONS:* - do NOT give with MAOIs (serotonin syndrome) *PK:* *ROUTE:* oral (well absorbed) *DISTRIBUTION:* penetrate CNS - *SIGNIFICANT AND VARIABLE first pass metabolism in the liver* - binds plasma proteins (because they are hydrophobic) -t1/2 : 20 - 60 hrs *EXCRETION:* *metabolized by CYPs* - metabolites can be potent active antidepressants (see above) *Conjugated with glucuronic acid and excreted by kidneys*

Imipramine

VALPROIC ACID

*CLASS: * anticonvulsant *ACTION:* *1.prolongs the inactivated state of Na+ channels 2.suppresses Ca2+ influx through T-type calcium channels* 1+2 - reduce excitation of neurons - may increase GABA concentrations in the brain *CLINIC:* - BP disorder -Epilepsy *ADVERSE:* -nausea, vomiting, tremor, sedation, weight gain, liver toxicity *CONTRAINDICATIONS:* *pregnancy (teratogen)* *PK:* *ROUTE:* oral (well abs) - 90% bound to plasma proteins - metabolized in liver by P450

CARBAMAZEPINE

*CLASS: * anticonvulsant *ACTION:* -prolongs inactive state of Na channels *CLINIC:* -*reduces symptoms during manic and depressive episodes* -*The drug of choice for treating seizures, trigeminal neuralgia* *ADVERSE:* -*acute intoxication can lead to respiratory depression, stupor, or coma* - *severe liver toxicity, requires frequent liver function tests* - *aplastic anemia (requires complete blood counts including platelets)* - *agranulocytosis* (BM dysfunction) - drowsiness, ataxia, nystagmus, vomiting *P[K:* *ROUTE:* oral (slow abs) *METABOLISM:*Metabolized by the cytochrome P-450 system; *induces P-450 enzymes, accelerates its own metabolism* (in contrast to other antidepressants) *EXCRETION:* - metabolized by p450 and induces these enzymes (accelerates own metabolism)

TRAZADONE

*CLASS: * atypical antidepressants *Heterocyclic antidepressant / 5-HT antagonist- trazodone* *ACTION:* -*therapeutic effect is related to blockade of 5-HT1 presynaptic autoreceptors--> increases serotonin release* -weak inhibitor of serotonin re-uptake, useful in treating insomnia - also blocks postsynaptic 5-HT2 receptor --Histamine receptor antagonist *CLINIC:* - depression -off-label: insomnia *ADVERSE:* - sedation, orthostatic hypotension, nausea, headache, dizziness, agitation *NOTE* *Most widely prescribed sleep aid in US* Not FDA-approved for insomnia (use is "off-label") Few Randomized control trials Generally regarded as fairly safe drug but daytime sleepiness and motor/cognitive impairments have not been well studied Problems: -Lack of randomized, controlled trials to assess efficacy for insomnia (particularly in patients without affective disorders and at lower doses) EFFICACY UNKNOWN -Tolerance to sedating effect -Daytime drowsiness -Discontinuation syndrome Advantage: -Lack of abuse potential -Shorter half-life than TCAs (less daytime sedation) -Less antimuscarinic activity than TCAs

MITRAZAPINE

*CLASS: * atypical antidepressants *Heterocyclic antidepressant* *ACTION:* *blocks presynaptic α2-adrenergic autoreceptors --> increases NE neurotransmission* (prevents stimulation of biosynthesis of NE) -blocks postsynaptic 5-HT2 and 5-HT3 receptors *potent antihistamine activity--> sedative action* *CLINIC:* -depression *ADVERSE:* - sedation, increased appetite, and weight gain *ADVANTAGE:* -*does not cause antimuscarinic side effects as TCAs do* -does not interfere with sexual functioning as the SSRIs do

BUPROPRION

*CLASS: * atypical antidepressants *Heterocyclic antidepressant* *ACTION:* act at unidentified site - minimal effect on monoamine R *CLINIC:* - depression -*decreases craving for nicotine in tobacco abusers * *ADVERSE:* -headache, nausea, tachycardia, restlessness, dry mouth,sweating, tremor, seizures at high doses -relatively short t1/2 (~20 h), may require more than once-a-day dosing *ADVANTAGE:no side effects related to sexual dysfunction such as those that occur with SSRIs*

ST. JOHN'S WORT

*CLASS: * herbal antidepressant -Contains a variety of compounds that may contribute to its pharmacological activity -Used as a dried hydroalcoholic extract of flowers *ACTION:* 1. *hypericin: high concentrations inhibits MAO-A and -B* -does not inhibit any of re-uptake systems 2. *hyperforin: inhibits 5HT, NE, and DA reuptake* *CLINIC:* - Might be effective for mild to moderate depressions but not for more severe depression *ADVERSE:* nothing serious, but can cause: - dizziness, skin rash - photosensitization (hypersensitivity to sun light) - hypomania - autonomic arousal *DRUG INTERACTIONS:* - simultaneous administration of drugs with similar action should be used cautiously or avoided due to risk of *serotonin syndrome*

Testosterone and androgens

*CLASS:* *MECHANISM OF ACTION*: -Testosterone is highly lipophilic (crosses membranes) -Bind to androgen receptors--> translocate to nucleus and receptor complex interacts with co-factors to alter regulation of target genes [can have different effects in different tissues] *INDICATIONS:* -Androgen replacement therapy *for hypogonadism* in adolescence {*note*: replacement therapy in mature men is probably overprescribed} -Catabolic or muscle-wasting conditions (helps *AIDS-related muscle wasting*) -*Stimulation of erythropoiesis* [Effective in selected anemias- *danazol* might be used if erythropoietin not effective] -*Hereditary angioedema* (due to inadequate activity of a protein called C1 inhibitor --> effects blood vessels) -->*Androgens can stimulate production of C1 inhibitor protein* -*Breast Cancer* -*Endometriosis (Danazol)* *ADVERSE:* -Increased prostate specific androgen -Enlarged prostate (men may have to pee more often during the night) -Emotional lability (can effect mood) -*Hypertension and other cardiovascular-related adverse events* -*Liver toxicity* (metabolized by liver) *PK* *Route:* -Inactive by oral route -Can be given by gel, patch, IM -*Testosterone:* Transdermal formulations available - patch or gel -*Esters*-Often administered intramuscularly in oil as a depot preparation *ADVANTAGE:* slower absorption *Metabolism:* -Rapidly metabolized by liver -*Inactive by oral route - first pass effect* (just like estrogen and progesterone) *Distribution:* -Highly bound to plasma proteins -*Transformed to dihydrotestosterone (DHT) in certain target tissues by 5 a-reductase* *Note:* DHT creates different complexes and regulates different sets of genes from testosterone *MORE:* -*Testosterone is the immediate precursor of estradiol*, small amounts of which are normally produced in males either in the testis or in peripheral tissues by aromatization of circulating testosterone -The adrenal cortex is an additional source of small amounts of androgenic steroids (as well as the corpus luteum in women)

Levodopa/Carbidopa

*CLASS:* *MECHANISM OF ACTION:* *Levodopa:* converted to DA via the dopa decarboxylase (aka amino acid decarboxylase) *Carbidopa:* peripheral inhibitor of amino acid decarboxylase (does not cross BBB)- increases levodopa delivery to the brain *INDICATION:* -Symptoms of Parkinson's disease, particularly bradykinesia *ADVERSE:* -Decreased effectiveness with time (less than 5 effective years) *Effectiveness of levodopa limited to jut a few years* -"On-off phenomena": patients cycle (few minutes to few hours of hypokinesia) between normal and Parkinsonian states due to short half-life of the drug "On" = when drug is effective and working "Off" = when the drug stops working As the dx progresses pts have less ability to store and release DA so they are more dependent on the plasma conc. of levodopa In more advanced dx: levodopa is converted to DA but pts not able to store DA - there are ineffective tx between doses of levodopa -Competition at transporter by amino acids, *effectiveness may be reduced with high protein meal* [competition at the aa transporter and decreased transport of L-dopa in the CNS; also decreased absorption of L-dopa in the SI due to competition with other proteins] -Effectiveness may also be reduced by transition metals (Fe, Zn, Cu, Manganese, Chromium, Molybdenum, Nickel, and Vanadium) - found in some vitamins (reduces the F of levodopa) -GI: nausea --> production of DA peripherally and DA accesses the postrema [w/ the vomiting center] -Postural hypotension for some patients [due to presynaptic inhibition of certain sympathetic fibers] -Behavioral: agitation, confusion, hallucinations, depression -*Dyskinesias* most commonly choreoathetosis of the face and distal extremities ---->Develop within 2 years of starting levodopa therapy, appear in at least half of all patients within 5 years of starting drug ---->Occur at time of peak therapeutic effect (in advanced PD) See graphs on slide 31

Baclofen

*CLASS:* *MECHANISM OF ACTION:* -*Agonist at GABA-B receptors* -GABA-B receptors are located presynaptically on interneurons and postsynaptically on the motor neuron itself -*Presynaptically:* GABA-B receptors are linked to Gi --> close voltage gates Ca++ channels --> leading to reduction in Ca++ influx in response to an AP --> leading to less neurotransmitter release -*Postsynaptically:* opening of K+ channels and hyperpolarization (making it harder to fire the motor neuron:* *INDICATION:* -Spasticity *ADVERSE:* -Tolerance and withdrawal -Some sedation (although tolerance will occur sedative effects) -Some muscle weakness *ADVANTAGES:* -Less sedation than diazepam -Less reduction in muscle strength than dantrolene

Dantrolene

*CLASS:* *MECHANISM OF ACTION:* -*NOT CENTRALLY ACTING!* - doesn't act at spinal cord; acts at the muscle itself -Binds to ryanodine receptor and blocks its opening thus decreasing release of calcium from sarcoplasmic reticulum in the muscle fiber *INDICATION:* -Spasticity -Malignant hyperthermia *ADVERSE:* -Generalized muscle weakness -Sedation -*Potential serious hepatotoxicity* (black box warning) *ADVANTAGES:* -Less sedation than diazepam or baclofen

Penicillamine

*CLASS:* *MECHANISM OF ACTION:* -Copper chelation -*NOT* effective as antibiotic *INDICATION:* -Wilson's disease -On World Health Organization's List of Essential Medicines *ADVERSE:* -Early sensitivity reaction (fever, thrombocytopenia, cutaneous eruptions) -Nephrotic syndrome -Worsening of neurological symptoms

Apomorphine

*CLASS:* *MECHANISM OF ACTION:* -Dopamine receptor agonist *INDICATION:* -Parkinson's disease "rescue therapy" -Temporary relief from sudden off periods experienced by pts on levodopa *ADVERSE:* -Only temporary relief (1-2 hrs) -GI: severe nausea *Begin treatment with an anti-emetic at least 3 days prior to apomorphine* -Postural hypotension for some patients -Behavioral: drowsiness, hallucinations -Dyskinesias *ADVANTAGES:* -Subcutaneous injection can provide rapid (within 10 minutes) relief of "off periods" of akinesia associated with levodopa therapy

Entacapone

*CLASS:* *MECHANISM OF ACTION:* -Inhibition of COMT thus decreasing degradation of dopamine/levodopa [usually not used as a monotherapy; usually used with levodopa or levodopa/carbidopa] *-Entacapone acts in periphery only* (doesn't cross BBB* -*Increase the "on-time" associated with levodopa* *INDICATION:* -Parkinson's disease *ADVERSE:* -Minimal use as monotherapy -GI: nausea -Postural hypotension for some patients -Behavioral: agitation, hallucinations -Dyskinesias -*Discolored urine: alkaline urine may become dark yellow or have a reddish brown tinge* *CONTRAINDICATIONS:* *-Contraindicated with nonselective MAOIs* - blocks COMT (blocks a pathway for NE and E to be degraded);' If also blocking MAOIs now blocking the peripheral metabolism of NE and E --> could result in hypertensive crisis *ADVANTAGES:* -Entacapone is more commonly used due to hepatotoxicity of talcapone (sometimes a fatal hepatotoxicity with talcapone)

Tetrabenazine

*CLASS:* *MECHANISM OF ACTION:* Reversible inhibitor of VMAT2 thus decreasing vesicular storage of DA *VMAT2 = in brain* (Remember: Reserpine: irreversible inhibitor of VMAT1 and 2) *INDICATION:* -Chorea associated with Huntington's disease -Tourette's syndrome *ADVERSE:* -*May increase risk of depression or suicidal ideation* -Extrapyramidal symptoms -Sedation -Expensive - nearly $40,000/year *PK:* *Metabolism:* CYP2D6 -Manufacturer recommends genotyping patients -Beware of slow or extensive metabolizers -Beware when using with strong CYP2D6 inhibitors such as fluoxetine (antidepressant)

Chlorphenitamine

*CLASS:* *1st generation H1 Receptor Antagonists* *INDICATION:* -*Produce drowsiness and sedation:* found in some OTC sleep aids [somnolence] -Acute allergic rxns (rhinitis, conjunctivitis, urticaria) -Reduce itching -*Diminish symptoms of cold and flu* *ADVERSE:* -*Major side effect = sedation* -Dizziness, lassitude, fatigue, nervousness, insomnia, tremor [can occur in if medication is given to children or the elderly] -Loss of appetite, N/V -Hypersensitivity rxns (allergic dermatitis, fever photosensitivity) -Exhibit some *antimuscarinic activity*: dry mouth, blurred vision, urinary retention [These anticholinergic actions can be a real problem in the elderly] *PK:* *Absorption:* -*Highly lipid soluble* -Well absorbed from GI tract *Distribution:* -*Widely distributed in body, including CNS* *Metabolism:* Extensively metabolized

Pyrilamine

Diphenhydramine

*CLASS:* *1st generation H1 Receptor Antagonists* *INDICATION:* -Prophylaxis and tx of *motion sickness* -*Reduce early Parkinson's symptoms* (bradykinesia) -Somnolence (sleep aid) *ADVERSE:* -*Major side effect = sedation* -Dizziness, lassitude, fatigue, nervousness, insomnia, tremor [can occur in if medication is given to children or the elderly] -Loss of appetite, N/V -Hypersensitivity rxns (allergic dermatitis, fever photosensitivity) -Exhibit some *antimuscarinic activity*: dry mouth, blurred vision, urinary retention [These anticholinergic actions can be a real problem in the elderly] -*long half-life so may cause sedation next day (more concerning in this drug than in others)* *Routine use of diphenhydramine to treat insomnia is NOT recommended* *PK:* *Absorption:* -*Highly lipid soluble* -Well absorbed from GI tract *Distribution:* -*Widely distributed in body, including CNS* *Metabolism:* Extensively metabolized

Promethazine

*CLASS:* *1st generation H1 Receptor Antagonists* *INDICATION:* -Prophylaxis and tx of *motion sickness* -Treat *nausea and vomiting* -Somnolence (sleep aid) *ADVERSE:* -*Major side effect = sedation* -Dizziness, lassitude, fatigue, nervousness, insomnia, tremor [can occur in if medication is given to children or the elderly] -Loss of appetite, N/V -Hypersensitivity rxns (allergic dermatitis, fever photosensitivity) -Exhibit some *antimuscarinic activity*: dry mouth, blurred vision, urinary retention [These anticholinergic actions can be a real problem in the elderly] *PK:* *Absorption:* -*Highly lipid soluble* -Well absorbed from GI tract *Distribution:* -*Widely distributed in body, including CNS* *Metabolism:* Extensively metabolized

Desloratadine

*CLASS:* *2nd generation H1 Receptor Antagonists* *INDICATION:* -Allergies -Acute allergic rxns (rhinitis, conjunctivitis, urticaria) -Reduce itching (Hydroxyzine = given for itch) -*Diminish symptoms of cold and flu* *ADVANTAGES:* -No anticholinergic side effects (dry mouth, urinary retention, etc) -Produce *MINIMAL sedation and drowsiness* *PK:* *Absorption:* Well absorbed *Distribution:* -Do NOT readily penetrate the CNS since they *are ionized at pH 7.4 (blood pH) and highly bound to albumin* [highly ionized drugs and drugs that are highly bound to plasma proteins don't penetrate BBB easily] *Metabolism:* -Metabolized by P450 and thus i/a w/ other drugs metabolized by the same pathway

Fexofenadine (Allegra)

Loratadine (Claritin)

Finasteride

*CLASS:* *5 alpha reductase inhibitor* *MECHANISM OF ACTION*: -5 alpha reductase inhibitor -*Blocks conversion of testosterone to DHT* *INDICATIONS:* -*Benign prostatic hyperplasia (BPH)* -Male pattern baldness [*note:* In adolescence DHT increase body and facial hair; later in life DHT is toxic to hair follicles and kills them] *ADVERSE:* -Decreased libido -Erectile dysfunction -Swelling in hands or feet -Gynecomastia -Finasteride reduced the incidence of prostate cancer, but individuals who did get prostate cancer tended to be higher grade (i.e., more malignant) *CONTRAINDICATIONS* -Women who are or may become pregnant (bad for sexual development of the fetus) -Liver impairment *PK* *Route:* Oral *Metabolism:* Hepatic *Half-life:* 5-7 hrs

Melphalan

*CLASS:* *Alkylating agents- Nitrogen mustard analogues* *MECHANISM OF ACTION:* -Attaches the alkyl group to the *N7 position of guanine*. It cross links DNA and RNA. *INDICATION:* -*Multiple myeloma* -*Breast cancer* -*Ovarian cancer* *Note:* Blood and solid tumors *ADVERSE:* N/V and mucositis Myelosuppression (bone marrow suppression), including: -Decreased WBC count causing increased risk of infection -Decreased platelet count causing increased risk of bleeding -Can cause a secondary malignancy (e.g. leukemia) *PK:* *Route:* Oral or IV

Cyclophosphamide

*CLASS:* *Alkylating agents- Nitrogen mustard analogues* *MECHANISM OF ACTION:* -One of the most widely used alkylating agents -Bis-alkylate the DNA, inducing crosslinks in the DNA-intrastrand (within strand) and interstrand crosslinks (in between 2 strands) *Pro-drug* *INDICATION:* -*Breast cancer* -*Autoimmune diseases: severe rheumatoid arthritis, multiple sclerosis* *ADVERSE:* General toxicity: N/V *Unique toxicity:* -Its metabolite, acrolein, can cause severe cystitis, *fancoli-like syndrome in kidneys* -CNS toxicity manifest by confusion, drowsiness, hallucinations *PK:* *Route:* Oral (high oral F) and IV *Metabolism: Bioactivation pathway: (see image) -Is inactive in its parent form -Must be activated to cytotoxic forms by liver microsomal enzymes. -The cytochrome P450 mixed-function oxidase system converts cyclophosphamide to active metabolites

Oxaliplatin

*CLASS:* *Alkylating-like agents- Platinum analogs* *ADVERSE:* -*Marked peripheral neuropathy*

Carboplatin

*CLASS:* *Alkylating-like agents- Platinum analogs* *Note:* A second-generation platinum analog *INDICATION:* -*Has broad-spectrum activity against a wide range of solid tumors* -Widely used in transplant regimens to treat refractory hematologic-malignancies. *ADVERSE:* -Acute toxicity: N/V -Delayed toxicity: *Myelosuppression- STRONG [dose-limiting]*; rarely peripheral neuropathy, renal toxicity, hepatic dysfunction *ADVANTAGES:* -Vigorous intravenous hydration is *NOT* required for carboplatin therapy -Viewed as an easier agent to administer to patients -*In contrast to cisplatin, it exhibits significantly less renal toxicity and gastrointestinal toxicity* -*Has replaced cisplatin in various combination chemotherapy regimens*

Cisplatin

*CLASS:* *Alkylating-like agents- Platinum analogs* *Note:*Cisplatin (cis-diamminedichloroplatinum II, CDDP) is an inorganic metal complex. *INDICATION:* -*A broad range of solid tumors* *ADVERSE:* -Acute toxicity: N/V -Delayed toxicity: *Nephrotoxicity common*, peripheral sensory neuropathy, ototoxicity, nerve dysfunction *PK:* *Route:*IV *The patient is typically given saline solution intraveneously before, during and after the drug is injected and advised to maintain adequate water consumption for a day.* [nephrotoxicity] *Elimination:* Renal -Dose modification is required in patients with renal dysfunction.

Methotrexate (MTX)

*CLASS:* *Antimetabolites- Folate analogs (antifolates)* *MECHANISM OF ACTION:* -MTX binds to the active catalytic site of *dihydrofolate reductase (DHFR)* and inhibits its activity -Inhibits the synthesis of tetrahydrofolate (THF) -THF is the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate (transformation of dUMP to dTMP) -MTX depletes dTMP *INDICATION:* *Breast cancer* *Non-cancers: Rheumatoid arthritis, psoriasis* *ADVERSE:* -Mucositis -Diarrhea -Myelosuppression with neutropenia and thrombocytopenia -GI epithelial damage -Alopecia -Defective oogenesis or spermatogenesis *Distinctive adverse effect:* *-Nephrotoxicity (encourage adequate hydration to prevent crystallization in renal tubules)* -Teratogenic *PK:* *Route:* IV, intrathecal, oral *Metabolism:* -MTX undergoes *conversion to series of polyglutamates (MTX-PGs)* (with the addition of up to 5-7 glutamate residues) -Formation of MTX-PG is critically important for the therapeutic action of MTX -PGs process is catalyzed by the enzyme *folylpolyglutamate synthase (FPGS)* -Adding PGs prevents MTX egressing the cell (migrating out of the cell) -MTX-PGs display increased inhibitory effect for thymidylate synthethase (TS) [Adding PGs keeps MTX in the cell --> enhances its activity] *Elimination:* Renal -Dose modification is required in the setting of renal dysfunction -Care must also be taken when used in the presence of drugs such as aspirin, nonsteroidal anti-inflammatory agents, penicillin, and cephalosporins, as these agents inhibit the renal excretion of MTX

6-mercaptopurine (6-MP)

*CLASS:* *Antimetabolites- Purine analogs* 6-Thiopurine analogs *MECHANISM OF ACTION:* -Functions as analog of the natural purines hypoxanthine (H) -Is catalyzed by *hypoxanthine-guanine phosphoribosyltransferase (HGPRT) yielding 6-MP riboside -5'phosphate or T-IMP, which can be incorporated into DNA* -*T-IMP leads to inhibition of glutamine-5-phosphoribosylpyrophosphate (PRPP) amidotransferase (first step in de novo synthesis)* [Most important effect for 6-MP] -TIMP incorporation into DNA also cause DNA damage *MECHANISM OF DRUG RESISTANCE:* -*Deficiency or lack of HGPRT* -Decreased drug transport -Alteration in inhibition of PRPP amidotransferase *INDICATION:* -*Acute myelogenous leukemia (AML)* *ADVERSE:* -Myelosuppression -Hepatotoxicity *PK:* *Route:* Oral and IV *Metabolism:* First-pass metabolism by xanthine oxidase in the liver (F= 10%-50%) *Elimination:* Hepatic

5-fluorouracil (5-FU)

*CLASS:* *Antimetabolites- Pyrimidine analogs* *MECHANISM OF ACTION:* -*Inhibits thymidylate synthase (TS) (conversion of dUMP to dTMP), leading to thymidine depletion* -Enhances the incorporation of FdUTP into DNA, resulting in inhibition of DNA synthesis and function -Enhances incorporation of FUTP into RNA resulting in alteration in RNA processing *INDICATION:* -*Colorectal cancer* *ADVERSE:* -Nausea, mucositis, diarrhea, bone marrow depression, neurotoxicity -Toxicity is enhanced with leucovorin because 5dUMP binds tightly to TS in the presence of leucovorin. -Can cause significant mucositis and diarrhea particularly if deficient in dihydropyrimidine dehydrogenase (DPD). -*Overdose rescue with thymidine* -*Photosensitivity* -*Potent radiosensitizer* -*Skin hyperpigmentation and rashes are common* These may be lessened with daily administration of pyridoxine (Vitamin B6). *PK:* *Route:* IV *Metabolism:* *Extensively metabolized by the liver, by dihydropyrimidine dehydrogenase (DPD)*

Cytarabine (cytosine arabinoside)

*CLASS:* *Antimetabolites- Pyrimidine analogs* *MECHANISM OF ACTION:* -*MOA is similar to Gemcitabine:* -*Inhibits ribonucleotide reductase (RNR) activity*(conversion of UDP-dUDP and CDP-dCDP). -*Inhibits incorporation of dCTP into DNA by DNA polymerase* *INDICATION:* -*AML* [Ara-C is the most important antimetabolite used in AML therapy] -ALL -CML in blast crisis *ADVERSE:* -*Fever* -*Hand-foot syndrome* -N/V -Myelosuppression with neutropenia and thrombocytopenia -Cerebellar ataxia *PK:* *Route:* IV (because of high levels of cytidine deaminase in GI musosa - drug would lose F if given orally) *Metabolism:* Ara-C must be phosphorylated to triphosphate form for activity [Activated by kinases to Ara-CTP (cytarabine triphosphate)]

Capecitabine

*CLASS:* *Antimetabolites- Pyrimidine analogs* *MECHANISM OF ACTION:* -*oral prodrug of 5-FU* -The expression of *thymidine phosphorylase* has been shown to be significantly higher in solid tumors than in normal tissue, *particularly in breast cancer and colorectal cancer* (converts drug to 5-FU in tumor after it has been metabolized in the liver) *INDICATION:* -*Breast cancer* -*Colorectal cancer* *Because thymidine phosphorylase is particularly active in these tissues* *ADVERSE:* -Hand-foot syndrome -Diarrhea -Myelosuppression -N/V *PK:* *Route:* Oral *Metabolims:* Undergoes extensive metabolism in the liver and tumor to convert into 5-FU (see image)

Gemcitabine

*CLASS:* *Antimetabolites- Pyrimidine analogs* *MECHANISM OF ACTION:* -A deoxycytidine analog that *inhibits ribonucleotide reductase (RNR) activity* (conversion of UDP-dUDP and CDP-dCDP), so that inducing a depletion of cellular pool of deoxynucleotides (dNTP) [Gemcitabine eventually depletes the dNTP to make DNA because it blocks the deoxy process] -*Inhibits incorporation of dCTP into DNA* by DNA polymerase *INDICATION:* *Pancreatic cancer* *ADVERSE:* -N/V -Diarrhea, -Myelosuppression -Flu like syndrome -Pulmonary toxicity -Causes more thrombocytopenia than neutropenia -A potent radiosensitizer *PK:* *Route:* IV only *Metabolism:* -The active form is gemcitabine diphosphate (2',2'-difluoro-2'-deoxycytidine diphosphate, *dFdCDP*) and gemcitabine triphosphate *(dFdCTP)* converted inside cells -*dFdCTP*-mediated inhibition of dCMP deaminase is responsible for the prolonged cellular half-life of the active dFdCTP. Therefore, increases effectiveness!

Hydroxyurea (HU)

*CLASS:* *Antimetabolites- Pyrimidine analogs* *MECHANISM OF ACTION:* -Inhibition of ribonucleotide reductase (RNR) -Blocks synthesis of dUDP and dCDP (this effects DNA synthesis) *INDICATION:* -*Chronic myelogenous leukemia* (largely replaced by imatinib, but still in use for its cost-effectiveness) -*Melanomas* *Non Cancer:* *Sickle-cell disease (breaks down cells that are prone to sickle, as well as increasing fetal hemoglobin content)* *ADVERSE:* -Drowsiness -N/V -Diarrhea -Constipation, -Mucositis -Anorexia -Stomatitis -Bone marrow toxicity -Alopecia (hair loss), skin changes -Abnormal liver enzymes, creatinine and blood urea nitrogen *PK:* *Route:* Oral *Elimination:* Renal -*Consider reducing dose in patients with renal impairment*

Azacitidine

*CLASS:* *Chemical Inhibitors - Epigenetic Pathway Inhibitors: DNMT Inhibitors* *MECHANISM OF ACTION:* -A chemical analogue of cytidine (C), a nucleoside present in DNA and RNA. -Covalently binds between the C6 atom of the cytosine (C) and the DNMTs, inhibiting DNMTs -*Triggers DNA damage signaling resulting in the degradation of trapped DNMTs* -Leading to loss of methylation marks of DNA (hypomethylation of DNA). -*Also, incorporates into RNA, leading to the dissembly of polyribosomes, and inhibition of the production of protein* *INDICATION:* -*myelodysplastic syndrome (MDS)* -*Tx of HIV and HTLV* *ADVERSE:* -Myelosuppression, GI (diarrhea, constipation), skin (pale skin, easy bruising or bleeding) *PK:* *Route:* IV or injection under the skin

Decitabine

*CLASS:* *Chemical Inhibitors - Epigenetic Pathway Inhibitors: DNMT Inhibitors* *MECHANISM OF ACTION:* -A chemical analogue of cytidine (C). -*Deoxy derivative of azacitidine* -*MOA similar to azacitidine* -*Decitabine can only be incorporated into DNA strands while azacitidine can be incorporated into both DNA and RNA chains* *INDICATION:* -*myelodysplastic syndrome (MDS)* *ADVERSE:* -*Same as Azacitidine* -Myelosuppression, GI (diarrhea, constipation), skin (pale skin, easy bruising or bleeding) *PK:* *Route:* IV or injection under the skin

Vorinostat

*CLASS:* *Chemical Inhibitors - Epigenetic Pathway Inhibitors: HDAC inhibitor* Also known as suberanilohydroxamic acid (suberoyl+anilide+ hydroxamic acid abbreviated as *SAHA*) *MECHANISM OF ACTION:* -Binds to the active site of HDACs [HDAC is frequently overactive in tumor cells] -*Acts as a chelator for Zinc ions in the active site of HDACs* -Results in the accumulation of acetylated histones and acetylated proteins. *INDICATION:* -*Cutaneous T cell lymphoma (CTCL)* *ADVERSE:* -*Edema* -Fatigue - GI (diarrhea, constipation) -Proteinuria *PK:* *Route:* Oral

Imatinib (Gleevac)

*CLASS:* *Chemical Inhibitors - Protein Kinase Inhibitors* *MECHANISM OF ACTION:* -*Inhibits Bcr-Abl tyrosine kinase and other receptor tyrosine kinases*, e.g. platelet-derived growth factor receptor (PDGFR), stem cell factor, and c-kit. -Prevents phosphorylation of the kinase substrates by ATP. *INDICATION:* -*CML* -*Philadelphia chromosome-positive ALL, AML* *Note:* Philadelphia (Ph) chromosome is found in >95% of CML; 25-30% of adult ALL (acute lymphoblastic leukemia), 2-10% in pediatric ALL, occasionally in AML (acute myelogenous leukemia) -CML = Chronic myelogenous leukemia = A pluripotent hematopoietic stem cell disorder characterized by the t(9:22) Philadelphia chromosomal translocation. *Philadelphia CreaML cheese* *ADVERSE:* -Acute toxicity: N/V -Delayed toxicity: *Myelosuppression, GI, skin, fluid retention with ankle and periorbital edema*, diarrhea, myalgias, congestive heart failure *PK:* *Route:*Oral *Metabolism:* -Metabolized in the liver, mainly by the CYP3A4 liver microsomal enzyme. *Elimination:* -In feces via the hepatobiliary route (biliary excretion)

Erlotinib

*CLASS:* *Chemical Inhibitors - Protein Kinase Inhibitors* *MECHANISM OF ACTION:* -*Inhibits EGFR tyrosine kinase leading to inhibition of EGFR signaling* *INDICATION:* -*Non-small cell lung cancer* *ADVERSE:* -Acute toxicity: Diarrhea -Delayed toxicity: Skin rash, diarrhea, anorexia, *interstitial lung disease* *PK:* *Route:* Oral *Metabolism:* Metabolized in the liver by the CYP3A4 enzyme system *Caution must be taken when using these agents with drugs that are also metabolized by the liver CYP3A4 system, such as phenytoin and warfarin* *Elimination:* Hepatic, excretion in feces

Crizotinib

*CLASS:* *Chemical Inhibitors - Protein Kinase Inhibitors* *MECHANISM OF ACTION:* -Functions as an *ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor* -Compete for binding within the ATP-binding pocket of target kinases -~ 4% of patients with non-small cell lung carcinoma (NSCLC) have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK, leading to constitutive ALK kinase activity that contributes to carcinogenesis. -Inhibits the fusion ALK kinase activity and the growth, migration, and invasion of malignant cells. *INDICATION:* -*non-small cell lung carcinoma (NSCLC)* *ADVERSE:* -N/V -rash or diarrhea -trail of lights phenomena (Trails' from lights in peripheral vision in low light conditions) *PK:* *Route:*Oral

Bortezomib

*CLASS:* *Chemical Inhibitors- Proteosome Inhibitors* *Note:The first therapeutic proteasome inhibitor to be tested in humans* *MECHANISM OF ACTION:* -*The boron atom in bortezomib binds the catalytic site of the 26S proteasome* -The 26S proteosome plays a role in maintaining the immortal phenotype of myeloma cells, and in solid tumor cancers. *INDICATION:* -*Multiple Myeloma* *ADVERSE:* -*Peripheral neuropathy* -Gastro-intestinal (GI) effects (constipation, nausea)* -Myelosuppression -Neutropenia -Thrombocytopenia -Shingles -Asthenia *PK:* *Route:* IV

Everolimus

*CLASS:* *Chemical Inhibitors- mTOR inhibitors* *MECHANISM OF ACTION:* -*Works as an inhibitor of mammalian target of rapamycin (mTOR)* -*Binds to its protein receptor FKBP12 (FK506 binding protein 12), which directly interacts with mTORC1, inhibiting its downstream signaling* *INDICATION:* -*Renal cell carcinoma* -ER+/HER2- breast cancer -*Immunosuppressant to prevent rejection of organ transplants* *ADVERSE:* -*Lung or breathing problems* -Infections -Kidney failure -Delayed wound healing *PK:* *Route:* Oral *Metabolism:* Metabolized hepatically via CYP450 3A4

Temsirolimus

*CLASS:* *Chemical Inhibitors- mTOR inhibitors* *MECHANISM OF ACTION:* -A mTOR inhibitor and an immunosuppressive agent as well -*SAME MOA AS EVEROLIMUS* -*Works as an inhibitor of mammalian target of rapamycin (mTOR)* -*Binds to its protein receptor FKBP12 (FK506 binding protein 12), which directly interacts with mTORC1, inhibiting its downstream signaling* *INDICATION:* -*Renal cancer* -Breast cancer *ADVERSE:* -fatigue, skin rash, stomatitis, hematologic abnormalities *PK:* *Route:* IV

Daunorubicin

*CLASS:* *Cytotoxic antibiotics- Anthracyclins* -Among the most widely used cytotoxic anticancer drugs. *MECHANISM OF ACTION:* -Inhibition of topoisomerase II. -Binding to DNA through intercalation, leading to blockade of DNA and RNA synthesis, and DNA strand scission. -Generation of semiquinone free radicals and oxygen free radicals through an iron-dependent, enzyme-mediated reductive process. -Binding to cellular membranes to alter fluidity and ion transport. *INDICATION:* -*AML* -*ALL* *Note:* In contrast to doxorubicin, its efficacy in solid tumors is limited. *ADVERSE:* -Acute toxicity: Pericarditis-myocarditis syndrome, nausea, fever, red urine (not hematuria). -Delayed toxicity: *Cardiotoxicity*, alopecia, myelosuppression *PK:* *Route:* IV *Metabolism & Excretion is the same as Doxorubicin* *Metabolism:* -Metabolized to doxorubicinol in the liver -Dose reduction is required in the setting of liver dysfunction *Elimination:* -Renal: *Urine may turn bright red in color* -Feces via biliary excretion

Doxorubicin

*CLASS:* *Cytotoxic antibiotics- Anthracyclins* -Among the most widely used cytotoxic anticancer drugs. *MECHANISM OF ACTION:* -Inhibition of topoisomerase II. -Binding to DNA through intercalation, leading to blockade of DNA and RNA synthesis, and DNA strand scission. -Generation of semiquinone free radicals and oxygen free radicals through an iron-dependent, enzyme-mediated reductive process. -Binding to cellular membranes to alter fluidity and ion transport. *INDICATION:* -Generally used in combination with other anticancer agents (eg, cyclophosphamide, cisplatin, and 5-FU), and clinical activity is improved with combination regimens as opposed to single-agent therapy. -*Breast cancer* *ADVERSE:* -Acute toxicity: Pericarditis-myocarditis syndrome, nausea, red urine (not hematuria) -Delayed toxicity: *Cardiotoxicity*, alopecia, myelosuppression, stomatitis *PK:* *Route:* IV *Metabolism:* -Metabolized to doxorubicinol in the liver -Dose reduction is required in the setting of liver dysfunction *Elimination:* -Renal: *Urine may turn bright red in color* -Feces via biliary excretion

Bleomycin

*CLASS:* *Cytotoxic antibiotics- Antitumor antibiotics* *MECHANISM OF ACTION:* *cell cycle specific! G2-M phase* {EXCEPTION TO CYTOTOXIC ANTIBIOTICS} -A glycopeptide antibiotic produced by the bacterium Streptomyces verticillus. -Contains a DNA-binding region and an iron-binding domain at opposite ends of the molecule. -Binds to DNA, resulting in single- and double-strand breaks due to oxidation of a DNA-bleomycin-Fe(II) complex by free radical formation. -*It is a cell cycle-specific drug that causes accumulation of cells in the G2 phase of the cell cycle* *INDICATION:* -*Hodgkin's and non-Hodgkin's lymphomas* -Blood cancer (written above) and solid cancers *ADVERSE:* -Acute toxicity: Allergic reactions, fever, hypotension -*Delayed toxicity: pulmonary fibrosis, skin toxicity, mucositis, alopecia, Raynaud's phenomenon* -Toxicity may be due to *low expression of bleomycin hydrolase in the lung and skin.* *ADVANTAGES:* -Rarely causes myelosuppression *PK:* *Route:* subcutaneously, IM, or IV *Elimination:* Renal -Dose modification is recommended in patients with renal dysfunction

Dactinomycin (Actinomycin D)

*CLASS:* *Cytotoxic antibiotics- Antitumor antibiotics* *MECHANISM OF ACTION:* -A *polypeptide antibiotic* isolated from soil bacteria of the genus Streptomyces -Inhibits transcription by binding DNA at the transcription initiation complex and preventing elongation of RNA chain by RNA polymerase. [blocks RNA synthesis via static hindrance] -May be metabolized to produce a free-radical generating species which may produce some DNA single-strand breaks. *INDICATION:* -*Wilms' tumor* *ADVERSE:* -Myelosuppression -Fatigue -Hair loss -Mouth ulcer -Loss of appetite -Diarrhea. *PK:* *Route:* IV

All-trans-retinoic acid (ATRA)

*CLASS:* *Differentiation Agents* *MECHANISM OF ACTION:* -*A derivative of vitamin A* -*In most APL (acute promyelocytic leukemia ) cases, RAR-alpha (retinoic acid receptor-alpha) gene on chromosome 17 has a reciprocal translocation with the PML (promyelocytic leukemia) gene on chromosome 15, a translocation denoted as t(15;17)(q22;q21). -The fusion PML-RAR-alpha hybrid protein binds to DNA, blocking transcription and differentiation of granulocytes -ATRA can inhibit the binding of PML-RAR-alpha on DNA, and promote transcription and differentiation of granulocytes *INDICATION:* -*Cancer: Used exclusively in acute promyelocytic leukemia (APL) (AML subtype M3)* -Non Cancer: Dermatology, acne treatment. *ADVERSE:* -*Retinoid acid syndrome:* fever, wt gain, respiratory distress, pleural effusions, pulmonary infiltrates, rapidly increased white blood cell -The etiology of retinoic acid syndrome has been attributed to capillary leak syndrome from cytokine release from the differentiating promyelocytes. *PK:* *Route:* Oral

Flutamide

*CLASS:* *Hormone Therapy - non-steroidal antiandrogen drug* *MECHANISM OF ACTION:* -*An antagonist of the androgen receptor (AR)* -Competing with testosterone and its metabolite, dihydrotestosterone (DHT) for binding to ARs in the prostate gland. -Prevents testosterone from stimulating the prostate cancer cells to grow. *INDICATION:* -*Androgen-dependent Prostate Cancer* *ADVERSE:* -Gynecomastia -Mild liver injury -Gastrointestinal side effects *PK:* *Route:* Oral

Abiraterone

*CLASS:* *Hormone Therapy* *MECHANISM OF ACTION:* -An androgen production inhibitor from non-gonadal source -Formulated as the prodrug abiraterone acetate. -*Inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1)*, an enzyme expressed in testicular, adrenal, and prostatic tumor tissues. *Inhibits two sequential reactions:* -Pregnenolone ->17-α-hydroxy Pregnenolone using *17 α-hydroxylase activity* -Form dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its *C17,20 lyase activity* *INDICATION:* -*Castration-resistant (formerly hormone-resistant or hormone-refractory) prostate cancer* -*Androgen-independent prostate cancer* *ADVERSE:* -UTI -Hypokalaemia -Hypertension -Diarrhea -Peripheral edema *PK:* *Route:* Oral w/ food *Metabolism:* -Prodrug Abiraterone acetate is cleaved to release free Abiraterone by plasma esterases in the bloodstream

Leuprolide

*CLASS:* *Hormone Therapy- GnRH and LH-RH analog* *MECHANISM OF ACTION:* -*Acts as an agonist at pituitary GnRH receptors* -Indirectly downregulates the secretion of gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). -Leading to reduction in estradiol and testosterone levels in both sexes. *INDICATION:* -Hormone response cancers: *breast cancer and prostate cancer* -Estrogen-dependent conditions (such as endometriosis or uterine fibroids), to treat precocious puberty, and to control ovarian stimulation in In Vitro Fertilization (IVF) -*Non cancer: chronic adrenal disease* *ADVERSE:* -bone pain -gynecomastia -hematuria -impotence -testicular atrophy *PK:* *Route:* Slow release implant or subcutaneous/IM injection

Tamoxifen

*CLASS:* *Hormone Therapy- SERMs* (selective estrogen-response modulators) *MECHANISM OF ACTION:* -*An antagonist of the estrogen receptor* -Metabolized into compound (4-hydroxytamoxifen) that also binds to the estrogen receptor but do not activate it. -Preventing estrogen from binding to its receptor. Hence breast cancer cell growth is blocked. *INDICATION:* -*Breast Cancer [nearly all pre-menopausal women with hormone receptor-positive (ER+) breast cancer)* -McCune-Albright syndrome -Infertility -Gynecomastia -Bipolar disorder *Hormone therapy for breast cancer* in post-menopausal, selected pre-menopausal women and all men -Also effective for *long-term prevention of recurrence of breast cancer* *ADVERSE:* -*Increase the risk of endometrial cancer* -Blood clots -CNS: reduced cognition -Risk of cataracts *CONTRAINDICATIONS:* -Family history of endometrial carcinoma *ADVANTAGES:* Beneficial "side effects": -Prevents bone loss [INCREASES bone density in post-menopausal women] -Enhances serum lipid profiles (Lowers circulating cholesterol levels by inhibiting cholesterol synthesis) *PK:* *Route:* Oral *Metabolism:* -*A prodrug*, having relatively little affinity for its target protein, the estrogen receptor -Metabolized in the liver by the cytochrome P450 isoform CYP2D6 and CYP3A4 into active metabolites which have 30-100 times more affinity with the estrogen receptor than tamoxifen itself

Bicalutamide

*CLASS:* *Hormone Therapy- non-steroidal antiandrogen* *INDICATION:* -*Androgen-dependent Prostate Cancer* *ADVANTAGES:* -*Less side effects compared to Flutamide* (often used instead of Flutamide *PK:* *Route:* Oral

Anastrozole

*CLASS:* *Hormone therapy- non-steroidal aromatase inhibitor* *MECHANISM OF ACTION:* -*Binds reversibly to the aromatase enzyme through competitive inhibition* -Inhibits the conversion of androgens to estrogens in peripheral tissues (extra-gonadal), thus *inhibits the synthesis of estrogen* *INDICATION:* -*Only postmenopausal women with localized ER+ breast cancer* *ADVERSE:* -*Arthralgias (joint pain)* *ADVANTAGES:* -*This class of drugs is more effective than previous drugs such as tamoxifen and crucially, it has fewer side effects"* -bone weakness -dyspnea -peripheral edema -nausea -diarrhea -hot flushes *PK:* *Route:* Oral

Interferon alpha

*CLASS:* *Immunotherapy- Cytokine Therapy* *MECHANISM OF ACTION:* -Interferons (IFNs) are cytokines produced by the immune system. (Involved in anti-viral response, but also have use in the treatment of cancer.) -Three groups of IFNs: *type I (IFNα and IFNβ)*, type II (IFNγ) and the relatively newly discovered type III (IFNλ). -Although both type I and II IFNs promote the anti-tumor effects of the immune system, *only type I IFNs have been shown to be clinically effective in cancer treatment.* -Promotes the anti-tumor effects of the immune system by increasing major histocompatibility complex (MHC) expression and increasing immune effector T and natural killer cells. *INDICATION:* -*hairy-cell leukemia* *ADVERSE:* -malaise, fatigue, fever, "flu-like symptoms", immunosupression *PK:* *Route:* IM or injection under the skin

Interleukin 2

*CLASS:* *Immunotherapy- Cytokine Therapy* *MECHANISM OF ACTION:* -Interleukin-2 (IL-2) is a member of a group of specific immune system signaling cytokines called interleukins (ILs). -ILs send chemical messages between leukocytes -*IL-2 functions in the proliferation of cytotoxic T-cells* as an immune response to an antigen reaching a T-cell receptor on a leukocyte. -These cytotoxic T-cells have the function of destroying infected, diseased, or tumor-characterized cells. -*IL-2 enhances T-cell response against cancerous cells.* (T cells secrete IL2, which is necessary for the proliferation of T cells) *INDICATION:* -Renal cell carcinoma -Melanoma *ADVERSE:* -May lead to capillary leak syndrome, fevers, renal and liver failure *PK:* *Route:* IV or inject under skin

Trastuzumab (Herceptin)

*CLASS:* *Immunotherapy- Naked monoclonal antibodies* *MECHANISM OF ACTION:* -*A monoclonal antibody against HER2/neu receptor* -*Binds to domain IV of the extracellular segment of the HER2 receptor, blocking EGF (Epidermal growth factor) pathway* *SELECTIVE TOXICITY:* -In cancer cells, the HER2 protein can be expressed up to 100 times more than in normal cells (2 million versus 20,000 per cell). *INDICATION:* -*HER2-positive breast cancer* *ADVERSE:* -Unique toxicity: *Infusion-related reactions*, flu-like symptoms (such as fever, chills and mild pain), nausea and diarrhea -Significant complications: Trastuzumab is *associated with cardiac dysfunction* in 2-7% of cases. As a result, regular cardiac screening is commonly undertaken during the trastuzumab treatment period. [Trastuzumab downregulates neuregulin-1 (NRG-1), which is essential for the activation of cell survival pathways in cardiomyocytes and the maintenance of cardiac function. These are all significant for the function and structure of cardiomyocytes.] *PK:* *Route:* IV

Bevacizumab

*CLASS:* *Immunotherapy- Naked monoclonal antibodies* *MECHANISM OF ACTION:* -*Binds to and prevents VEGF-A from interacting with VEGF receptors* -Leads to inhibition of VEGF signaling; inhibits tumor vasculature. -This inhibits tumor growth and reduced tumor size *INDICATION:* -*Colorectal cancer* *ADVERSE:* -Acute toxicity: Hypertension, infusion reaction -Delayed toxicity: *Arterial thromboembolic events (transient ischemic attack, stroke, angina, and myocardial infarction)*, gastrointestinal perforations, wound healing complications, proteinuria *PK:* *Route:* IV

Rituximab

*CLASS:* *Immunotherapy- Naked monoclonal antibodies* *MECHANISM OF ACTION:* -A chimeric *monoclonal antibody against the protein CD20* -Binds to CD20. (CD20 is widely expressed on B cells, from early pre-B cells to later in differentiation). -Sticks to one side of cancerous B cells, forming a cap and drawing proteins over to that side (asymmetric protein cluster). -The cap enhances the effectiveness of natural killer (NK) cells in destroying these diseased cells. (When an NK cell latched onto the cap, it had an 80% success rate at killing the B cell). [Ab binding all the CD20 to form a large patch that can be killed by the NK cells] *INDICATION:* -*Hematological cancers: leukemias and lymphomas, including Hodgkin's lymphoma.* -*Autoimmune diseases: rheumatoid arthritis.* -*Anti-rejection treatment for organ transplants* *ADVERSE:* -*Severe infusion reaction*, cardiac arrest, cytokine release syndrome, immune toxicity, pulmonary toxicity, bowel obstruction and perforation. *PK:* *Route:* IV

Cetuximab

*CLASS:* *Immunotherapy- Naked monoclonal antibodies* *MECHANISM OF ACTION:* -A chimeric monoclonal antibody *against the extracellular domain of the EGFR* -Binds to EGFR and inhibits downstream EGFR signaling; enhances response to chemotherapy and radiotherapy. *INDICATION:* -*Its efficacy is restricted to only those patients whose tumors express wild-type KRAS* -Colorectal cancer -Head and neck cancer (used in combination with radiotherapy) -Non-small cell lung cancer *ADVERSE:* -Acute toxicity: Infusion reaction -Delayed toxicity: Skin rash, hypomagnesemia, fatigue, interstitial lung disease *PK:* *Route:* IV

Ipilumimab

*CLASS:* *Immunotherapy- Naked monoclonal antibodies* *MECHANISM OF ACTION:* -A human *antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4)* -Binds and activates the immune system by targeting CTLA-4 (CTLA-4 is a protein receptor that downregulates the immune system) -Cancer cell antigens (antigens that are produced by cancer cells), can be recognized by dendritic cells, which present the antigens to CTLs (cytotoxic T lymphocytes). -CTLA-4 inhibits the CTLs activation -*Ipilimumab blocks the CTLA-4 inhibitory signal, and allows the CTLs to destroy the cancer cells* *INDICATION:* -*Melanoma* *ADVERSE:* -Immune related side effects such as: fever, colitis, rash *PK:* *Route:* IV

T-DM1 (Trastuzumab Emtansine)

*CLASS:* *Immunotherapy- conjugated monoclonal antibodies* *MECHANISM OF ACTION:* -links HER2 antibody to cytotoxic cross-linking agent -Targets the HER2 protein, attached to a chemo drug called DM1 (DM1: Derivative of Maytansine, a microtubule destablizing agent) Same as Trastumuzab, except for carrying a chemo drug DM1 *INDICATION:* -*Advanced HER2 positive breast cancer* *ADVERSE:* -Fever, chills, weakness, headache, nausea, vomiting, diarrhea, rashes *PK:* *Route:* IV

Paclitaxel

*CLASS:* *Microtubule Inhibitors - Taxanes* *MECHANISM OF ACTION:* -*Functions as a mitotic spindle poison through binding to microtubules with ENHANCEMENT of tubulin polymerization.* -Results in inhibition of mitosis and cell division. *INDICATION:* -*A broad range of solid tumors, including breast cancer* *ADVERSE:* -Acute toxicity: N/V, hypotension, arrhythmias, *hypersensitivity* (allergy- hypersensitivity rxns upon infusion)- incidence is significantly reduced by premedication with dexamethasone, diphenhydramine, and an H2 blocker. -Delayed toxicity: *Peripheral sensory neuropathy, myalgia (muscle pain)/arthalgia (joint pain), hand-foot syndrome*, myelosuppression *PK:* *Metabolism:* Metabolized extensively by the liver P450 system *Elimination:* Feces via the hepatobiliary route. -*Dose reduction is required in patients with liver dysfunction*

Docetaxel

*CLASS:* *Microtubule Inhibitors - Taxanes* *MECHANISM OF ACTION:* -*Same as paclitaxel* -*Functions as a mitotic spindle poison through binding to microtubules with ENHANCEMENT of tubulin polymerization.* -Results in inhibition of mitosis and cell division. *INDICATION:* -*Breast cancer* *ADVERSE:* -Acute toxicity: Hypersensitivity -Delayed toxicity: *Neurotoxicity* (myalgia/arthralgia, hand-foot syndrome), hand-foot syndrome, fluid retention, myelosuppression with neutropenia *PK:* *Metabolism & Excretion are the same as Paclitaxel* *Metabolism:* Metabolized extensively by the liver P450 system *Elimination:* Feces via the hepatobiliary route. -*Dose reduction is required in patients with liver dysfunction*

Abraxane

*CLASS:* *Microtubule Inhibitors - Taxanes* *MECHANISM OF ACTION:* -A novel albumin-bound paclitaxel formulation *INDICATION:* -*Metastatic breast cancer* *ADVANTAGES:* -*In contrast to paclitaxel, Abraxane is not associated with hypersensitivity reactions, and premedication to prevent such reactions is not required.* -Abraxane has significantly reduced myelosuppressive effects compared with paclitaxel. -The neurotoxicity caused by Abraxane is more readily reversible than is observed with paclitaxel.

Vincristine

*CLASS:* *Microtubule Inhibitors - Vinca alkaloids* *MECHANISM OF ACTION:* -*Inhibition of tubulin polymerization by disrupting assembly of microtubules (an important part of the cytoskeleton and the mitotic spindle)* -Causes mitotic arrest in metaphase (M phase), brings cell division to a halt, then leads to cell death. *INDICATION:* -*ALL* (blood tumor) *ADVERSE:* -No acute toxicities -Delayed toxicity: *Neurotoxicity with peripheral neuropathy*, *vesicant*, paralytic ileus, myelosuppression, alopecia, SIADH *PK:* *Metabolism:* Metabolized by the liver P450 system. *Elimination:* Feces via the hepatobiliary system. -*Dose modification is required in the setting of liver dysfunction*

Vinblastine

*CLASS:* *Microtubule Inhibitors - Vinca alkaloids* *MECHANISM OF ACTION:* -*Same as Vincristine* -*Inhibition of tubulin polymerization by disrupting assembly of microtubules (an important part of the cytoskeleton and the mitotic spindle)* -Causes mitotic arrest in metaphase (M phase), brings cell division to a halt, then leads to cell death. *INDICATION:* -*Hodgkin's and non-Hodgkin's lymphoma* -Blood and solid tumors *ADVERSE:* - Acute toxicity: N/V -Delayed toxicity: Neurotoxicity, vesicant, *myelosuppression*, mucositis, alopecia, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), vascular events. *PK:* *Metabolism & Excretion are the same as Vincristine* *Metabolism:* Metabolized by the liver P450 system. *Elimination:* Feces via the hepatobiliary system. -*Dose modification is required in the setting of liver dysfunction*

Pembrolizumab

*CLASS:* *PD 1 Inhibitors* *MECHANISM OF ACTION:* -PD-1L present on the surface of some tumor cells -PD-1 present on T-cells -PD-1L/PD-1interaction blocks action of T-cell on tumor cell -PD-1 inhibition results in T-cell activation against tumor cell -*Tumor cells can inhibit the body's immune response by binding proteins, such as PD-1 (explained above) on the surface of T cells. Antibody therapies that block this binding reactivate the immune response* *INDICATION:* *Melanoma* *ADVERSE:* -Largely T-cell mediated: such as flu-like symptoms, diarrhea, pneumonitis, etc.

Leucovorin (5-formyltetrahydrofolate)

*CLASS:* *Rescue Therapy* *MECHANISM OF ACTION:* -Leucovorin is a reduced form of folic acid (5-CHO-THF) -*Leucovorin bypasses DHFR step in folic acid synthesis* [provides the product] -Administration of leucovorin or by l-leucovorin can reverse the biologic effects of MTX *INDICATION:* -Leucovorin rescue is used in conjunction with high-dose (>1,000 mg/m2) MTX therapy to rescue normal cells from undue toxicity, and it has also been used in cases of accidental drug overdose

Mesna

*CLASS:* *Rescue Therapy* *MECHANISM OF ACTION:* -*Cyclophosphamide may be converted to urotoxic metabolites, such as acrolein in vivo.* -Mesna assists to detoxify these metabolites and it also increases urinary excretion of cysteine. {*Detoxification*} *INDICATION:* -Used as an adjuvant in cancer chemotherapy involving cyclophosphamide. -Used therapeutically to reduce the incidence of haemorrhagic cystitis and haematuria when a patient receives cyclophosphamide for cancer chemotherapy Note: MESNA is an acronym for 2-mercaptoethane sulfonate Na

Vitamin K

*CLASS:* *Reversal of warfarin effects* *MECHANISM OF ACTION:* -Reverses the effects of warfarin slowly *INDICATION:* -Warfarin overdose in the absence of acute major bleeding *PK:* *Route:* Oral

Kcentra

*CLASS:* *Reversal of warfarin effects* *INDICATION:* -Acute major bleeding where the effects of warfarin need to be reversed immediately Ex: If a person on warfarin is in a car accident or need emergency surgery *PK:* *Route:* IV

Methimazole

*CLASS:* *Thioamides* *MECHANISM OF ACTION:* -Have antithyroid action through *inhibition of thyroid peroxidase* -Referred to as *goitrogens*: inhibition of thyroid hormone production upregulates TSH in the pituitary gland. Continuous TSH production without the negative feedback from thyroid hormone synthesis results in thyroid gland hypertrophy. -*NOTE:*Clinical effects of tx are observed only after the preformed hormone and stores of iodinated thyroglobulin are depleted. --->*onset of action is about 5 days* (won't see immediate effects with this drug) *INDICATION:* -*The preferred treatment for hyperthyroidism in males and non-pregnant females* -Graves' disease -Hyperthyroidism -Toxic multinodular goiter -To acutely treat hyperthyroidism prior to thyroidectomy or radioactive iodine therapy *DRUG-DRUG I/As* -Thioamides can increase the risk of bleeding when coadministered with oral anticoagulants due to a decrease in prothrombin *CONTRAINDICATIONS:* -Known allergy to antithyroid drugs -*Pregnancy* (causes congenital birth defects) [methimazole crosses the placental barrier and enters breast milk more readily than propylthiouracil] *ADVANTAGES:* -Less toxic and has improved adherence with only a single daily dose

Propylthiouracil

*CLASS:* *Thioamides* *MECHANISM OF ACTION:* -Have antithyroid action through *inhibition of thyroid peroxidase* -Referred to as *goitrogens*: inhibition of thyroid hormone production upregulates TSH in the pituitary gland. Continuous TSH production without the negative feedback from thyroid hormone synthesis results in thyroid gland hypertrophy. -*NOTE:*Clinical effects of tx are observed only after the preformed hormone and stores of iodinated thyroglobulin are depleted. --->*onset of action is about 5 days* (won't see immediate effects with this drug) -*Also inhibits 5' deiodinase to prevent the peripheral conversion of T4 to T3* *INDICATION:* -*The preferred treatment for hyperthyroidism in pregnant females* -Graves' disease -Hyperthyroidism -Toxic multinodular goiter -To acutely treat hyperthyroidism prior to thyroidectomy or radioactive iodine therapy *ADVERSE:* -*Severe liver injury and acute liver failure* --->Presenting symptoms include: anorexia, nausea, vomiting, fatigue, pruritus, dark colored urine, or jaundice *DRUG-DRUG I/As* -Thioamides can increase the risk of bleeding when coadministered with oral anticoagulants due to a decrease in prothrombin *CONTRAINDICATIONS:* -Known allergy to antithyroid drugs

Irinotecan

*CLASS:* *Topoisomerase I inhibitors: Camptothecins* *MECHANISM OF ACTION:* -*Inhibit the activity of topoisomerase I, the key enzyme responsible for cutting and religating single DNA strands (SS)*. -Inhibition of TopoI results in DNA damage. *INDICATION:* -*Colorectal cancer (first-line therapy when used in combination with 5-FU and leucovorin)* *ADVERSE:* -Acute toxicity: Diarrhea, N/V, cholinergic reaction (facial flushing, abdominal cramping) -Early form of diarrhea: occurs within 24 hours after treatment, and is thought to be a cholinergic event effectively treated with atropine. -Delayed toxicity: *Myelosuppression and diarrhea* -Late form of diarrhea: usually *occurs 2-10 days after treatment, which can be severe, leading to significant electrolyte imbalance and dehydration in some cases* *PK:* *Route:* IV *Metabolism:* -A prodrug that is converted mainly in the liver by the carboxylesterase enzyme to the SN-38 metabolite. -*SN-38 metabolite is 1000-fold more potent as an inhibitor of topoisomerase I than the parent compound.* *Elimination:* In biles and feces -*Dose reduction is required in the setting of liver dysfunction*

Etoposide

*CLASS:* *Topoisomerase II inhibitors: Epipodophyllotoxins* *MECHANISM OF ACTION:* -*Acts on the G2-S phase of the cell cycle* -*Inhibits the DNA enzyme topoisomerase II, the key enzyme responsible for cutting and religating double DNA strands (DS)* -Inhibition of this enzyme results in DNA damage. *INDICATION:* -*Non-small cell and small cell lung cancer* -*It is effective in high-dose regimens in the transplant setting for breast cancer and lymphomas* (myelosuppression) *ADVERSE:* -Acute toxicity: N/V, hypotension -Delayed toxicity: *Myelosuppression*, alopecia -*Unique complication of this class: Secondary malignancies* *PK:* *Route:* IV and oral (Oral F = 50%; oral dose must be twice the IV dose) *Elimination:* Renal -Dose reduction is required in the setting of renal dysfunction

Fluconazole

*CLASS:* AZOLES *MECHANISM:* interfere with ergosterol synthesis - block lanosterol-14a-demethylase= a CYP450 enzyme (enzyme in the biosynthesis of ergosterol) *Could also have cross reactivity with P450 enzyme system *SELECTIVE TOX:* ergosterol only in fungi *RESISTANCE:* - C. albicans via: mutant drug target, drug efflux pump, increased expression of drug target *CONTRAINDICATIONS:* - Avoid azoles in pregnancy (unless its topical) *INDICATION:* superficial and systemic fungal infections - candidiasus (except: C. krusei and C. glabrata) - cryptococcal meningitis in AIDS - *NOT aspergillosis* *ADVERSE:* well tolerated - GI distress, headache, rash *DRUG INTERACTIONS:* -Inhibits human CYP3A4--> *MANY* drug i/as *PK:* *Route: oral & IV *Distribution: well distributed to most tissues *INCLUDING to CSF* (meningitis) *Metabolism: hepatic (also inhibits human CYP3A4- drug i/as) *Elimination = primarily renal* ; adjust dose if renally impaired

Terbinafine (*LAMI*sil)

*CLASS:* Ally*LAMI*ines (like *LAMI*sil) *MECHANISM:* inhibits ergosterol synthesis enzyme SQUALENE EPOXIDASE - decreases membrane fluidity/integrity by decreasing ergosterol in the membrane *SELECTIVE TOX:* ergosterol only in fungi *INDICATION:* dermatophytes (ex: Tineas) - nail fungus, jock itch, althlete's foot, scalp ringworm *ADVERSE:*Oral form: well tolerated; avoid if pregnant/nursing; or if liver/kidneys impaired (Does NOT apply to topical forms *ROUTE:* oral or topical *PK:* *Route: -Oral: high lipophilic; accumulates in skin, nails and fatty tissues -Lamasil Granules (oral) approved for scalp ringworm (T.capitis) in children age 4+ -Take oral granules with non-acidic food

Tizanidine

*CLASS:* Alpha2 agonist *MECHANISM OF ACTION:* - Alpha 2 receptor linked to Gi protein -Alpha 2 receptors are located presynaptically and postsynaptically on the motor neuron dendrite *INDICATION:* -Spasticity -Certain types of headaches (unlabeled) *ADVERSE:* -Drowsiness -Hypotension -Dry mouth -Hepatotoxicity *ADVANTAGES:* -Fewer cardiovascular effects than clonidine -Less muscle weakness than diazepam, baclofen, dantrolene

Oxandrolone

*CLASS:* Androgenic Steroids *MECHANISM OF ACTION:* -Synthetic androgen (derivative of dihydrotestosterone) -Agonist at androgen receptors *INDICATIONS:* -Alcoholic hepatitis -Turner's syndrome -Weight loss caused by HIV -Hereditary angioedema *ADVERSE:* -*Liver toxicity* -*Increased LDL and decreased HDL* - CV disease -Swelling of the arms or legs -Frequent or persistent erections, or breast tenderness or enlargement -Decreased fertility (male patients) -Voice changes (hoarseness, deepening) -Hair loss -Facial hair growth -Clitoral enlargement -Menstrual irregularities *ADVANTAGES:* -*not readily aromatized to estrogen* *PK* *Route:* Oral *Metabolism:* Hepatic

Ivermectin

*CLASS:* Anthelmintics *MECHANISM:* - kills larvae in host; not effective against adult worm (use SURAMIN) - induces paralysis via glutamate-gated Cl- channels found only in invertebrates *SELECTIVE TOX:* glutamate-gated Cl- channels found only in invertebrates *INDICATION:* Broad spectrum antiparasitic - Nematode - esp. for filariae causing onchocerciasis (river blindness)- transmitted by black fly (Africa/S. America/Mexico) *ADVERSE:* well tolerated *CONTRAINDICATED when BBB is impaired because it can effect mammalian GABA receptors *PK:* *Route: -oral, one dose/yr; concentrates in liver and fat, little in brain (stays in body a long time) Excretion: long terminal half-life of ~60 hrs

Pyrantel Pamoate

*CLASS:* Anthelmintics *MECHANISM:* Depolarizing neuromuscular blocking agent --> results in spastic paralysis --> can't suck nutrients out of gut; starves and dies *INDICATION:* alternative to MBZ - nematodes round worms - esp Ascaris, hookworm, pinworm *PK:* *ADVERSE:* well tolerated *Route: oral - poorly absorbed - good because it stays in gut where the worms are

Praziquantel

*CLASS:* Anthelmintics *MECHANISM:* causes spastic paralysis and tegument (skin) damage (exposes antigens and so immune system can attack it) *INDICATION:* - Flatworms and cestodes - esp. schistosomes and tapeworms *ADVERSE:* well tolerated - GI distress - CNS effects *CONTRAINDICATIONS:* *- ocular cysticercosis (tapeworm larvae in eye) --> host response to dead worm damages eye* *- ophthalmologic surgery is recommended instead* *PK*: *Route: oral

Fosphenytoin

*CLASS:* Antiepileptics *MECHANISM OF ACTION:* -*A more soluble pro-drug of Phenytoin* *INDICATION:* -Status epilepticus *ADVERSE:* *ADVANTAGES:* -More soluble than Phenytoin - given IV or IM -Faster rate of action than Phenytoin -Fewer adverse rxns than Phenytoin *PK:* *Route:*Can be given faster; *IV or IM* *Metabolism:* Fully converted to phenytoin in 20-30 min -Dosed in phenytoin equivalents (PE)

Zonisamide

*CLASS:* Antiepileptics *MECHANISM OF ACTION:* *Similar to those of Topiramate* -Direct potentiating actions on the GABA receptor at a unique site (i.e. not alcohol or barbiturate sites) -Inactivates voltage-gated sodium channels -Prevents calcium influx *INDICATION:* -Adjuvant treatment for localization-related epilepsies (not enough evidence to say it can be used for monotherapy) *ADVERSE:* *Similar to those of Topiramate* -Psychomotor slowing -Fatigue -Nausea -Parasthesias -Weight loss -Kidney stones *PK:* *Metabolism:* Renal

Tiagabine

*CLASS:* Antiepileptics *MECHANISM OF ACTION:* - Inhibits the reuptake of GABA - Raises GABA level in the synapse, enhances natural GABAergic activity *INDICATION:* -Localization-related epilepsies (focal) *ADVERSE:* -Tremor (can effect cerebellar networks - makes sense- GABA) -Dizziness -Nervousness -Difficulty concentrating, -Somnolence *PK:* *Metabolism:* Liver

Ethosuximide

*CLASS:* Antiepileptics *MECHANISM OF ACTION:* -*Blocks T-type calcium channels* -T-type channels are highly expressed in the thalamus and are involved in the 3Hz synchronized reciprocal thalamus and neocortex that can be measured on EEG that seems to underlie absence seizures -Targeting the T-type Ca++ channels in the thalamus reduces 3 Hz synchronization and reduces absence seizures *INDICATION:* -Absence epilepsy -Etho*sux*imide - *S*ucks to have *S*ilent (absence) *S*eizures *ADVERSE:* -Nausea -Hiccups, -Anorexia -Rash, Lupus syndrome *PK:* *Metabolism:* Liver

Carbamazepine

*CLASS:* Antiepileptics *MECHANISM OF ACTION:* -*Stabilize voltage-gated sodium channels in the fast inactivated conformation* -decrease voltage-gated calcium conductance *INDICATION:* -*Localization-related epilepsies* -*Trigeminal neuralgia* *ADVERSE:* -Double vision -Dizziness -Nausea -Headache -Hyponatremia -Leukopenia -Aplastic anemia in 1/200,000 pts -Rash -*Fetal neural tube defects* *PK:* *Metabolism:* P450 enzymes *Induces hepatic enzymes- can alter metabolism of other drugs; can decrease the efficacy of oral contraceptives* *Half-life:* Short

Gabapentin

*CLASS:* Antiepileptics *MECHANISM OF ACTION:* -Binds to calcium channels -Enhances GABA synthesis *INDICATION:* -*Adjunctive therapy in localization-related epilepsies* -*Post-herpetic neuralgia* -*Chronic pain/Fibromyalgia* *ADVERSE:* -Mild nausea -Somnolence -Lightheadedness *I/A W/ OTHER AEDS:* -Minimal *PK:* *Elimination:* excreted unmetabolized in the urine

Pregabalin

*CLASS:* Antiepileptics *MECHANISM OF ACTION:* -Binds to calcium channels -Enhances GABA transport *INDICATION:* -*Adjunctive therapy in localization-related epilepsies* -*Post-herpetic neuralgia* -*Diabetic neuropathy pain* -*Chronic pain/Fibromyalgia* *ADVERSE:* -Mild nausea -Somnolence -Lightheadedness *I/A W/ OTHER AEDS:* -Minimal *PK:* *Elimination:* excreted unmetabolized in the urine

Topiramate

*CLASS:* Antiepileptics *MECHANISM OF ACTION:* -Direct potentiating actions on the GABA receptor at a unique site (i.e. not alcohol or barbiturate sites) -Inactivates voltage-gated sodium channels -Prevents calcium influx *INDICATION:* -*Treatment for localization-related epilepsies* -Tx of generalized epilepsies -*Migraine headache prevention* (Not good for txing absence seizures) *ADVERSE:* -Psychomotor slowing -Fatigue -Nausea -Parasthesias -Weight loss -Kidney stones *PK:* *Elimination:* Renal

Levetiracetam

*CLASS:* Antiepileptics *MECHANISM OF ACTION:* -Inhibits calcium channels (reduces excitatory NT release) -Interaction with a unique synaptic vesicle protein (SV2A) to decrease seizure activity *INDICATION:* -Adjuvant in the treatment of localization-related and generalized epilepsies (can be helpful in difficult cases) *ADVERSE:* -Somnolence -Weakness -Headache -Behavioral difficulties -*Anti-epileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior.* Patients should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual mood or behavior changes. *PK:* *Elimination:* excreted unmetabolized in the urine

Valproate

*CLASS:* Antiepileptics *MECHANISM OF ACTION:* -Inhibits the metabolism and promotes the synthesis of GABA -Inactivates voltage-gated sodium channels in a unique manner -Blocks T-type calcium channels -May modulate K+ channels (K+ channel agonists would decrease hyperexcitability in the brain) *INDICATION:* -Localization-related epilepsies -Generalized epilepsies -Absence epilepsy -*Migraine headache prevention* *ADVERSE:* -Weight gain -Hair loss -Tremor -Liver failure -Pancreatitis -Thrombocytopenia -*Neural tube defects* *PK:* *Metabolism:* Liver *Enzyme inhibitor*

Lacosamide

*CLASS:* Antiepileptics *MECHANISM OF ACTION:* -Stabilizes voltage-gated sodium channels in the inactivated state -Binds cell proteins (CRMPs) that play a role in ion channel trafficking and neuronal sprouting *INDICATION:* -*Used in combination with other drugs for localization-related epilepsy* *ADVERSE:* -Prolongs the PR interval leading to atrial ventricular block -Mild dizziness, ataxia, nausea/vomiting, and diplopia (double vision) *PK:* *Metabolism:* Liver *Elimination:* 40% excreted unmetabolized in the urine

Lamotrigine

*CLASS:* Antiepileptics *MECHANISM OF ACTION:* -Stabilizes voltage-gated sodium channels in the inactivated state -Inhibits glutamate release -Inhibits T-type calcium currents *INDICATION:* -Used alone and in combination with other drugs for multiple types of epilepsy -Focal epilepsy (inhibits Na+ currents) -Absence epilepsy (T-type Ca++ currents) *ADVERSE:* -Severe and life-threatening rash -Dizziness, ataxia, nausea *PK:* *Metabolism:* Liver

Bivalirudin

*CLASS:* Antiplatelet Drugs *AND* Anticoagulant Drugs - *Direct Thrombin Inhibitors* (DTI) i.e. hirudins *MECHANISM OF ACTION:* (originally isolated from the salivary glands of the medicinal leech) -*Inhibit thrombin by binding directly to the active site of the enzyme and inhibiting activity* -Inactivate thrombin --> prevents it from binding the protease activated receptor and then causing platelet activation -*Binds directly to thrombin regardless if the thrombin is bound or unbound to fibrin* -If the thrombin is bound to fibrin heparin-antithrombin complex can no longer work because it can't fit into the active site --> why it can treat HIT *Direct thrombin inhibitors act by blocking the active site of thrombin to prevent cleavage of fibrinogen and crosslinking of fibrin* *Therapeutic Effect:* : increase of aPTT(activated partial thromboplastin time; increase of ECT (ecarin clotting time assay) *INDICATION:* -*Heparin-induced thrombocytopenia* -*Percutaneous coronary intervention (PIC) for patients at risk of HIT* (heparin induced thrombocytopenia) -*Unstable angina/non-ST-elevation MI* -Prophylactic administration for prevention of postoperative venous thromboembolism -Hip replacement surgery -Knee replacement surgery *ADVERSE:* -*Bleeding* *CONTRAINDICATIONS:* -*Patients with major overt bleeding* *Advantages:* -*Since DTIs bind directly to thrombin, they do not require a cofactor such as antithrombin to exert their effect. This absence of protein binding produces a more predictable anticoagulant effect compared with heparins* -*Antiplatelet effects* -*Absence of immune-mediated thrombocytopenia* -*DTIs can inhibit both soluble thrombin and fibrin-bound thrombin* *PK:* *Route:*IV or subQ injection

Dipyridamole

*CLASS:* Antiplatelet Drugs - "cAMP altering drugs* *MECHANISM OF ACTION:* *Antiplatelet action through inhibition of phosphodiesterase, inhibition of adenosine reuptake, and inhibition of adenosine breakdown* -Inhibit phosphodiesterase (PDE), prevents degradation of cAMP into AMP (↑cAMP) -Inhibits adenosine reuptake into the platelets (↑cAMP) -Inhibits adenosine metabolism by inhibiting adenosine deaminase (↑cAMP) *Dipyridamole acts by ↑ cAMP levels in the platelets* -*In platelets, an increase in the concentration of intracellular cAMP leads to a decrease in intracellular calcium and subsequent decreases in platelet activation and aggregation* *INDICATION:* -*To reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis* *ADVERSE:* -HA -*Bleeding* *CONTRAINDICATIONS:* -Same as aspirin *PK:* *Route:* Oral *Dipyridamole is administered in combination with aspirin therapy*

Clopidogrel

*CLASS:* Antiplatelet Drugs - *ADP Receptor Pathway Inhibitor* *MECHANISM OF ACTION:* *Antiplatelet action through irreversible inhibition of the P2Y12 (ADP) receptor* (binds to the active site) *Inhibit platelet activation by blocking the purinergic P2Y12 (ADP) receptors - inhibit ADP activation of the P2Y12 receptor* -Enhances cAMP levels -Decrease Beta-gamma activation (this normally causes granule secretion and platelet activation) *INDICATION:* -Prevention of MI and/or stroke in patients who cannot tolerate aspirin or who have failed aspirin therapy (Oral) -Adjunct to PCI to prevent MI and stent thrombosis in patients w/o GPIIb/IIIa inhibition (IV) *ADVERSE:* -*Bleeding* *Prasugrel = More potent- increased risk of bleeding* -Neutropenia/agranulocytosis -GI disturbances *CONTRAINDICATIONS:* -*Active pathological bleeding* (peptic ulcer, intracranial hemorrhage, coronary artery bypass graft surgery) -*Prior TIA or stroke* -*Do NOT use in patients >75 or in patients likely to undergo coronary artery bypass graft* **Discontinue prasugrel >7d before surgery** *DRUG-DRUG I/AS:* -*Clopidogrel is metabolized by CYP2C19 so there is some variability between patients* *PK:* *Route:* Oral and IV *Metabolism:* Hepatic; *Pro-Drugs*- therefore they are metabolized by the liver to active metabolites

Prasugrel

Aspirin

*CLASS:* Antiplatelet Drugs - *COX Inhibitors* *MECHANISM OF ACTION:* *Antiplatelet action through inhibition of cyclooxygenase* *Aspirin IRREVERSIBLY* inhibits cyclooxygenase (COX) by covalent acetylation of a serine residue near the active site of COX -At low doses (baby aspirin- 81 mg): Aspirin inhibits COX I and therefore decreases the production of TXA2 in a subsequent step *Prevents TXA2 mediated platelet activation and adhesion* -At higher doses: Aspirin inhibits COX II and therfore decreases synthesis of prostacyclin (PGI2) and prostaglandins (PGE2, PGF2) in subsequent steps (this is why it is effective as an anti-inflammatory at higher doses) *INDICATION:* -*Primary prevention of cardiovascular events (ischemic stroke, TIA, acute MI, prevention of recurrent MI, unstable angina and chronic stable angina)* *ADVERSE:* -Long-term use in high doses can lead to *GI ulceration, nephrotoxicity, and hepatic injury* -*Bleeding* *CONTRAINDICATIONS:* Two unique toxicities: -Allergy: patients with asthma, rhinitis, and nasal polyps: (aspirin can cause urticaria, angioedema or bronchospasm) -Reye's syndrome in children <19 years old (especially with viral illnesses) *PK:* *Route:* Oral *Dose:* Oral dose of 81 mg/ day is sufficient for antiplatelet activity *baby aspirin- small dose --> makes aspirin selective for inhibition of COX I over COX II* (see mechanism of action)

Dabigatran

*CLASS:* Antiplatelet Drugs - *Direct Thrombin Inhibitors* (DTI) i.e. hirudins *MECHANISM OF ACTION:* (originally isolated from the salivary glands of the medicinal leech) -*Inhibit thrombin by binding directly to the active site of the enzyme and inhibiting activity* -Inactivate thrombin --> prevents it from binding the protease activated receptor and then causing platelet activation -*Binds directly to thrombin regardless if the thrombin is bound or unbound to fibrin* -If the thrombin is bound to fibrin heparin-antithrombin complex can no longer work because it can't fit into the active site --> why it can treat HIT *Direct thrombin inhibitors act by blocking the active site of thrombin to prevent cleavage of fibrinogen and crosslinking of fibrin* *Therapeutic Effect:* : increase of aPTT(activated partial thromboplastin time; increase of ECT (ecarin clotting time assay) *INDICATION:* -*Heparin-induced thrombocytopenia* -*Percutaneous coronary intervention (PIC) for patients at risk of HIT* (heparin induced thrombocytopenia) -*Unstable angina/non-ST-elevation MI* -*Stroke prevention in patients with nonvalvular atrial fibrillation* -Prophylactic administration for prevention of postoperative venous thromboembolism -Hip replacement surgery -Knee replacement surgery *ADVERSE:* -*Bleeding* *CONTRAINDICATIONS:* -*Patients with major overt bleeding* *Advantages:* -*Since DTIs bind directly to thrombin, they do not require a cofactor such as antithrombin to exert their effect. This absence of protein binding produces a more predictable anticoagulant effect compared with heparins* -*Antiplatelet effects* -*Absence of immune-mediated thrombocytopenia* -*DTIs can inhibit both soluble thrombin and fibrin-bound thrombin* *PK:* *Route:* Oral- *the only orally available DTI* *Note:* FDA just approved Idarucizumab- the first reversal agent for the anticoagulant dabigitran -Ab that binds to dabigitran to inhibit dabigitran binding to the thrombin

Abciximab

*CLASS:* Antiplatelet Drugs -*GPIIb/IIIa receptor inhibitors* *MECHANISM OF ACTION:* *Antiplatelet action through inhibition of the fibrinogen receptor* *GPIIb-IIIa receptor inhibition* -GPIIb-IIIa = Receptor for fibrinogen (Anchors platelets to foreign surfaces and to each other; Activated by thromboxane A2, thrombin, collagen) *Abciximab* = a chimeric mouse-human monoclonal antibody directed against the human GPIIb-IIIa --> prevents fibrinogen from binding the receptor *Eptifibitide*= a synthetic peptide which selectively blocks GPIIb-IIIa in a reversible manner--> prevents fibrinogen from binding the receptor *Abciximab and eptifibitide act by inhibiting fibrinogen crosslinking of platelets* *INDICATION:* -Acute coronary syndrome (UA/NSTEMI), including those undergoing stenting or angioplasty -PCI (Percutaneous Coronary Intervention) -coronary angioplasty (balloon to stretch open a narrowed or blocked artery) (Used more in acute setting) *ADVERSE:* *Bleeding* *CONTRAINDICATIONS:* -Patients with active abnormal bleeding <30 days prior to treatment -Severe hypertension -Major sx <6 months prior to treatment Stroke within 30 days of tx -Patients with renal dysfunction (Eptifibatide) *PK:* *Route:* IV dosing in combo with aspirin therapy, clopidogrel, and/or heparin *Half-life:* *Short* plasma half life and the *antiplatelet action only persists 4-24 hrs*

Eptifibatide

Amantadine

*CLASS:* Antiviral *MECHANISM OF ACTION:* -targets viral M2 proton channel inhibits uncoating -Mechanism for the tx of PD is unclear *INDICATION:* -Influenza A treatment and prophylaxis -Parkinson's disease Selective Toxicity: targets viral M2 proton channel Mechanisms of Resistance: mutation in M2 proton channel *spreads rapidly* *ADVERSE:* -Only temporary relief (few weeks) -Generally well tolerated -CNS (ataxia, insomnia, confusion, seizures)- low percent of patients (<5%) -Drug interactions: generally well tolerated: antihistammines, anticholinergics, alcohol--> increase CNS effects *PK:* -Absorption: oral, rapid, and complete absorption -Distribution: penetrates nasal and lung secretions -Elimination: >90% excreted unchanged in the urine half-life of 12-18 hrs young adults --> 2x that in elderly; more in renal impairment (therefore reduce dose for elderly and renal impaired)

Anastrozole

*CLASS:* Aromatase inhibitors- *Non-steroidal* *MECHANISM OF ACTION*: -Selectively inhibit aromatase(the final step in estrogen synthesis) -Effectively *lower estrogen levels*, thus reducing hormonal stimulation *INDICATIONS:* -Useful in *adjuvant therapy of breast cancer with tamoxifen* AND as *first-line treatment in post-menopausal women* [Used or with Tamoxifen to treat breast cancer] *ADVERSE:* -Hot flashes [Main complaint] -Increased risk of osteoporosis compared to tamoxifen -Increased risk of cardiac events compared to tamoxifen tx -Hypercholesterolemia -Joint pain *ADVANTAGES:* -Unlike tamoxifen, *not associated with an increased risk of thromboembolism or uterine cancer* -Lower incidence of vaginal bleeding *PK* *Route:* Oral *Metabolism:* Hepatic

Letrozole

Exemestane

*CLASS:* Aromatase inhibitors- *Steroidal* *MECHANISM OF ACTION*: -Selectively inhibit aromatase(the final step in estrogen synthesis) -Effectively *lower estrogen levels*, thus reducing hormonal stimulation *INDICATIONS:* -Useful in *adjuvant therapy of breast cancer with tamoxifen* AND as *first-line treatment in post-menopausal women* [Used or with Tamoxifen to treat breast cancer] *ADVERSE:* -Hot flashes [Main complaint] -Increased risk of osteoporosis compared to tamoxifen -Increased risk of cardiac events compared to tamoxifen tx -Hypercholesterolemia -Joint pain *ADVANTAGES:* -Unlike tamoxifen, *not associated with an increased risk of thromboembolism or uterine cancer* -Lower incidence of vaginal bleeding *PK* *Route:* Oral *Metabolism:* Hepatic

Aripiprazole (Abilify)

*CLASS:* Atypical antipsychotics *MECHANISM:* - partial D2 agonist -5-HT2 receptor antagonist -partial agonist at 5-HT1A receptors *ADVERSE:* Milder anticholinergic actions *PK:* - long T1/2 --> 75 hrs *New- used a lot*

Ziprasidone

*CLASS:* Atypical antipsychotics *MECHANISM:* -Antagonist at D2 and 5-HT2 receptors -Modest selective serotonin reuptake inhibitor (SSRI)-like activity *ADVERSE:* -Prolongs QT intervals -Does not cause weight gain *PK:* -t1/2 is approximately 2.5 (IM) -7 (PO) hours

Quetiapine

*CLASS:* Atypical antipsychotics *MECHANISM:* -Antagonist at D2 and 5-HT2 receptors -Potent actions at α-adrenergic receptors *ADVERSE:* -Tachycardia -Weight gain *Abuse potential - usually crushed and snorted, intravenous co- administration with cocaine, "quell" or "Susie-Q"* *PK:* -t1/2 is approximately 6 hours

Risperidone

*CLASS:* Atypical antipsychotics *MECHANISM:* -Antagonist at D2 and 5-HT2 receptors[*Very high affinity*] *ADVERSE:* -Little to no anticholinergic actions -*Higher incidence of extrapyramidal symptoms at higher doses, but low incidence at low daily doses (i.e. 6 mg or less)* -Prolongs QT intervals -Can cause weight gain -More profound increases in prolactin than other agents *gynecomastia* *PK:* -t1/2 is about 20 hours

Olanzapine

*CLASS:* Atypical antipsychotics *MECHANISM:* -More potent antagonist of 5-HT2 receptors than dopamine receptors *ADVERSE:* -Significant weight gain -*Can induce hyperglycemia and diabetes* -Sedation -Orthostatic hypotension -Anticholinergic effects *PK:* - t1/2 is about 21-54 hours *Hard to put in frame for DA hypothesis* -other mechanisms probably attribute to schizoprenia

Clozapine

*CLASS:* Atypical antipsychotics *MECHANISM:* predominantly blocks D1 & D2 -Less D2 antagonism than typical antipsychotics; -Potent antagonist at some serotonin receptors *INDICATION:* tx of negative sx of schizophrenia - MOST effective drug for schizophrenia but is reserved for patients who have not responded to SAFER drugs [can cause agranulocytosis] *ADVERSE:* - *agranulocytosis* (Bone marrow problem) [1-2% of patients; death 1 in 5000] - *severe neutropenia* - dangerously low levels of neutrophils; can be life-threatening -seizures (3%) - myocarditis - D2: Extrapyramidal effects are UNCOMMON [TD has not been reported] -5-HT: weight gain -Histamine: sedation -a1: orthostatic hypotension - Ach: moderate: dry mouth, blurred vision, urinary retention, constipation, tachycardia *DRUG INTERATIONS:* Because of possible agranulocytosis *CONTRAINDICATED WITH drugs that can suppress bone marrow function (anticancer drugs)* *PK:* *Route: oral - rapid absorption - *95% bound to plasma proteins* - extensive metabolism *Excretion: feces and urine

Itraconazole

*CLASS:* Azoles *MECHANISM:* interfere with ergosterol synthesis - block lanosterol-14a-demethylase= a CYP450 enzyme (enzyme in the biosynthesis of ergosterol) *Could also have cross reactivity with P450 enzyme system *SELECTIVE TOX:* ergosterol only in fungi *RESISTANCE:* - C. albicans via: mutant drug target, drug efflux pump, increased expression of drug target *CONTRAINDICATIONS:* - Avoid azoles in pregnancy (unless its topical) *INDICATION:* broad spectrum antifungal - *aspergillosis* - candidiasis (except C.krusei; C. glabrata) - cryptococcus - histoplasmosis - blastomyces - onychomycosis *ADVERSE:* well tolerated - GI distress = common with the oral form - *hepatotoxicty* -*CONTRAINDICATED* in patients with congestive heart failure (mechanisms not understood) *DRUG INTERACTIONS:* -Inhibits human CYP3A4--> *MANY* drug i/as *PK:* *Route: oral, IV *Distribution: well distribute in most tissues *not CSF* *Metabolism: hepatic (also inhibits human CYP3A4- drug i/as)

Clobazam

*CLASS:* Benzodiazepines *MECHANISM OF ACTION:* -*Enhance binding of GABA to receptors* -*Enhanced inhibitory tone* *INDICATION:* -*Status Epilepticus* -Generalized Epilepsies -*Short term-use* *ADVERSE:* -Sedation -Respiratory depression -Tolerance, Dependence , Withdrawal Issues *Addictive and cause respiratory depression; therefore not good for long-term use and not usually the first choice for seizure prevention* *I/A W/ OTHER AEDS:* -Minimal *PK:*

Propranolol

*CLASS:* Beta-adrenergic blockers *MECHANISM OF ACTION:* *Inhibits 5'-deiodinase causing decreased peripheral conversion of T4 to T3 and increased concentration of rT3* *INDICATION:* -Useful therapies for treating symptoms of hyperthyroidism--many effects of high thyroid hormone levels resemble nonspecific beta-adrenergic stimulation (e.g. sweating, tremor, tachycardia) --> *therefore helpful in tx of thyroid storm*

Alendronate

*CLASS:* Bisphosphonates *MECHANISM OF ACTION:* -*Inhibit osteoclast function by perturbing the mevalonate pathway of cholesterol synthesis* [inhibits the ability for the osteoclast to move --> blocks bone resorption] -This inhibition blocks bone resorption and decreases [Ca2+] plasma *Details:* -Bisphosphonates attach to hydroxyapatite binding sites on bony surfaces, especially surfaces undergoing active resorption -Osteoclasts resorb bone impregnated with bisphosphonates -Bisphosphonates inhibit a step in the mevalonate pathway, which inhibits posttranslational lipid modifications of proteins -*Inhibition of the mevalonate pathway inhibits numerous osteoclast functions (formation of a ruffled border, adherence to the bony surface, and proton generation for bone resorption) and also leads to osteoclast apoptosis* *INDICATION:* -Treatment and prevention of *postmenopausal osteoporosis* -Treatment to increase bone mass in *men with osteoporosis* -Treatment and prevention of *glucocorticoid-induced osteoporosis* -*Paget's Disease* -Heterotopic ossification following total hip replacement or spinal cord injury (etidronate) -*Hypercalcemia secondary to malignancy (zoledronate)* *ADVERSE:* -At *high doses* bisphosphonates can also: *Inhibit formation and growth of bone mineralization→atypical femur fractures, osteonecrosis of the jaw, and esophageal cancer* -*Esophageal and gastric irritation* -*Note:* Because of these adverse effects it is not recommended to keep patients on bisphosphonates long term; better to cycle them on and off the drug; continuation of tx should be based on individual assessment of risks, benefits, and preferences of patients and their physicians -[Until further data are available, the data suggests patients at low risk for fracture (eg, younger patients without a fracture history and bone mineral density [BMD] approaching normal) may be good candidates for discontinuation of therapy after 3-5 years. Patients at increased risk, such as older patients with a history of fracture and a BMD in the osteoporotic range, may benefit from continued therapy] *CONTRAINDICATION:* -*Esophageal abnormalities (potential for esophageal erosion with oral administration)* -Hypocalcemia (zoledronate) -DO NOT coadminister with calcium, antacids or oral medications containing divalent cations --> *this will interfere with the absorption of bisphosphonates* *PK:* *Route:* -Alendronate - Oral *Need to sit upright for 30 mins after taking the drug* --->causes esophageal and gastric irritation -Zoledronate- IV

Zoledronate

Calcium gluconate

*CLASS:* Calcium *MECHANISM OF ACTION:* *Increases plasma calcium levels and subsequently decreases PTH secretion* *INDICATION:* -Hypocalcemia secondary to hypoparathyroidism -Hypocalcemia secondary to rapid growth or pregnancy -Adjunct treatment of rickets or osteomalacia -Dietary calcium deficiencies (oral supplements) *ADVERSE:* - Nausea, constipation, stomach upset *CONTRAINDICATIONS:* -Patients with ventricular fibrillation or hypercalcemia *PK:* *Route:* -IV: 10% calcium gluconate solution (0.93% Ca2+ administered slowly <200mg/minute for a total dose of 500mg-2g) -Oral: Calcium citrate supplements <600mg

Danazol

*CLASS:* Drugs Affecting FSH and LH *MECHANISM OF ACTION*: -Synthetic androgen with weak androgenic activity *-Inhibits production of FSH/LH (negative feedback)* *-Anti-estrogenic effects: blocks enzymes essential for production of estrogen and progesterone in ovaries* *INDICATIONS:* -Used to treat *endometriosis* by atrophying ectopic endometrial tissue (Estrogens induce the growth of endometrial tissue; Danazol has anti-estrogenic effects) -*Hereditary angioedema* -*Stimulation of erythropoiesis* *ADVERSE:* -Hot flashes, weight gain, bloating, fluid retention, acne, increased LDL, smaller breasts, increase in muscle mass, increased facial and body hair, muscle cramps, mood swings, voice deepening and clitoral enlargement -Gastrointestinal upset -Depression -Liver disease *PK* *Metabolism:* Hepatic

Human chorionic gonadotropin (hCG)

*CLASS:* Drugs related to FSH & LH *Collected from urine of pregnant women* *Action similar to LH* *After "priming" with menotropins, inject hCG to induce ovulation (mimics "LH surge")* *Illegal use by athletes: hCG mimics LH --> LH boosts the production of androgens* *INDICATIONS:* -Infertility treatment in males and females [mainly used for infertility; can be used for other things with off label use] (Can be used to treat infertility caused by failure of the pituitary to produce appropriate amounts of FSH and LH) -hCG: mimic LH surge, increase androgen production, treat prepubertal cryptorchidism (absence of one or both testes from scrotum) -Gonadotropins also used in Assisted Reproductive Technologies (ART), including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) *ADVERSE:* -Ovarian stimulation can cause: *Ovarian hyperstimulation syndrome* *Multiple births* *PK* *Route*: -Metotropins given for the first 14 days of a woman's cycle *IV* -*Followed by a single injection of human chorionic gonadotropin (hCG) to mimic the LH surge* *Metabolism:* Excreted in the urine! *NOTE:* *-Gonadotropin therapy use has been plagued with unpredictable multiple births, morbidity of OHSS, and high costs when compared to most other infertility medications* -The only current use for gonadotropin therapy before IVF is in anovulatory patients either resistant to clomiphene or for whom clomiphene is not effective (i.e., hypothalamic patients). -Even when used with IVF, gonadotropins provide a high cost, added stress of treatments, and risks of OHSS.

Menotropins- FSH & LH (human menopausal gonadotropins - HMGs)

*CLASS:* Drugs related to FSH & LH *a purified preparation of FSH and LH recovered from urine of menopausal women* -Estrogen and progesterone levels drop in menopause --> decreases negative feedback --> increase production of LH and FSH --> LH and FSH excreted in the urine of menopausal women *INDICATIONS:* -Infertility treatment in males and females [mainly used for infertility; can be used for other things with off label use] (Can be used to treat infertility caused by failure of the pituitary to produce appropriate amounts of FSH and LH) -hCG: mimic LH surge, increase androgen production, treat prepubertal cryptorchidism (absence of one or both testes from scrotum) -Gonadotropins also used in Assisted Reproductive Technologies (ART), including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) *ADVERSE:* -Ovarian stimulation can cause: *Ovarian hyperstimulation syndrome* *Multiple births* *PK* *Route*: -Metotropins given for the first 14 days of a woman's cycle *IV* -*Followed by a single injection of human chorionic gonadotropin (hCG) to mimic the LH surge* *Metabolism:* Excreted in the urine! *NOTE:* *-Gonadotropin therapy use has been plagued with unpredictable multiple births, morbidity of OHSS, and high costs when compared to most other infertility medications* -The only current use for gonadotropin therapy before IVF is in anovulatory patients either resistant to clomiphene or for whom clomiphene is not effective (i.e., hypothalamic patients). -Even when used with IVF, gonadotropins provide a high cost, added stress of treatments, and risks of OHSS.

Urofollitropin

*CLASS:* Drugs related to FSH & LH *purified FSH ONLY from urine* *INDICATIONS:* -Infertility treatment in males and females [mainly used for infertility; can be used for other things with off label use] (Can be used to treat infertility caused by failure of the pituitary to produce appropriate amounts of FSH and LH) -hCG: mimic LH surge, increase androgen production, treat prepubertal cryptorchidism (absence of one or both testes from scrotum) -Gonadotropins also used in Assisted Reproductive Technologies (ART), including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) *ADVERSE:* -Ovarian stimulation can cause: *Ovarian hyperstimulation syndrome* *Multiple births* *PK* *Route*: -Metotropins given for the first 14 days of a woman's cycle *IV* -*Followed by a single injection of human chorionic gonadotropin (hCG) to mimic the LH surge* *Metabolism:* Excreted in the urine! *NOTE:* *-Gonadotropin therapy use has been plagued with unpredictable multiple births, morbidity of OHSS, and high costs when compared to most other infertility medications* -The only current use for gonadotropin therapy before IVF is in anovulatory patients either resistant to clomiphene or for whom clomiphene is not effective (i.e., hypothalamic patients). -Even when used with IVF, gonadotropins provide a high cost, added stress of treatments, and risks of OHSS.

Follitropin

*CLASS:* Drugs related to FSH & LH rFSH *recombinant FSH* -Produces follicular stimulation *INDICATIONS:* -Infertility treatment in males and females [mainly used for infertility; can be used for other things with off label use] (Can be used to treat infertility caused by failure of the pituitary to produce appropriate amounts of FSH and LH) -hCG: mimic LH surge, increase androgen production, treat prepubertal cryptorchidism (absence of one or both testes from scrotum) -Gonadotropins also used in Assisted Reproductive Technologies (ART), including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) *ADVERSE:* -Ovarian stimulation can cause: *Ovarian hyperstimulation syndrome* *Multiple births* *PK* *Route*: -Metotropins given for the first 14 days of a woman's cycle *IV* -*Followed by a single injection of human chorionic gonadotropin (hCG) to mimic the LH surge* *Metabolism:* Excreted in the urine! *NOTE:* *-Gonadotropin therapy use has been plagued with unpredictable multiple births, morbidity of OHSS, and high costs when compared to most other infertility medications* -The only current use for gonadotropin therapy before IVF is in anovulatory patients either resistant to clomiphene or for whom clomiphene is not effective (i.e., hypothalamic patients). -Even when used with IVF, gonadotropins provide a high cost, added stress of treatments, and risks of OHSS.

Caspofungin

*CLASS:* Echinocandins *MECHANISM:* blocks cell wall synthesis - inhibits 1,3 beta glucan synthase in glucan synthesis pathway -glucans = major component of cell walls *SELECTIVE TOXICITY:* glucans are fungal only *INDICATION:* - *invasive candidiasis - aspergillosis *ADVERSE:* very well tolerated *DRUG INTERACTIONS:* - May cause hepatotoxicity with immunosuppressants (cyclosporine) *PK:* *Route: IV only *Distribution: high in tissues; poor CNS penetration *Elimination: hepatic*

Dihydroergotamine

*CLASS:* Ergot Alkaloids *MECHANISM OF ACTION:* -Don't know mechanistically how they work (effect a lot of different receptors - 5-HT, DA, NE) -Either agonists or antagonists at multiple receptors -*Mechanism for treatment of migraine attributed to agonist action at 5HT receptors* -*Methysergide used for prophylaxis presumably because it is an antagonist at 5HT2A/2C receptors* *INDICATION:* -*Methysergide is the only drug that is used prophylactically for migraine* *ADVERSE:* -Nausea (CNS action), -Vasoconstriction with ischemia -Leg weakness -Muscle pain *NOTE: After long term methysergide, patients may develop retroperitoneal, cardiac, or lung fibrosis, so drug should not be administered for longer than 6 months* *CONTRAINDICATIONS:* -*Fertile or Pregnant women* since they stimulate uterine smooth muscle contraction and restrict uterine blood flow -Coronary artery disease -Peripheral vascular disease -Hypertension -Hepatic or Renal Impairment

Ergotamine

Methysergide

Bromocriptine

*CLASS:* Ergot Derivative *MECHANISM OF ACTION:* - Agonist at D2 receptor -Partial agonist at D1 receptor *INDICATION:* -Parkinson's disease -Acromegaly -Hyperprolactinemia (DA inhibits release of PRL at the hypo-pit axis) *ADVERSE:* -*Less favored than the non-ergot DA agonists* because the adverse effects are more extreme at the beginning -GI: nausea -Postural hypotension for some patients -Behavioral: agitation, hallucinations *ADVANTAGES:* -Less association with "on-off phenomenon" than levodopa

Aminocaproic acid

*CLASS:* Fibrinolytics- *Tissue plasminogen activators* = *CLOT- BUSTERS* *MECHANISM OF ACTION:* -*A derivative and analogue of the amino acid lysine, which makes it an effective inhibitor for plasmin* *INDICATION:* -Used to treat overdose and/or toxic effects of streptokinase and alteplase.

Alteplase (Recombinant t-PA)

*CLASS:* Fibrinolytics- *Tissue plasminogen activators* = *CLOT- BUSTERS* *MECHANISM OF ACTION:* -*Help to dissolve existing clots* -*Homeostasis of the fibrinolytic system is rigidly maintained with a fine balance of inhibitors and activators of plasminogen*- therefore there is a big risk to using fibrinolytics -*TPA binds to a fresh thrombus, undergoes conformational change and activates plasminogen to plasmin* -Plasmin chews up the fibrin in clots --> dissociates fibrin bound clots -*Poor activator of plasminogen in the absence of fibrin-binding* -only activates plasminogen that is bound to the fibrin! *T-PA and Alteplase act by increasing the conversion of plasminogen to plasmin* *INDICATION:* -*Treatment of myocardial infarction* -*Treatment of acute ischemic stroke* -*Treatment of acute pulmonary embolism* *ADVERSE:* -Thrombolytic therapy overwhelms homeostatic inhibitory controls and can cause massive fibrinolysis -*Bleeding, especially cerebral hemorrhage* *CONTRAINDICATIONS:* -*Suspicion of intracranial or intraspinal hemorrhage (confirmed by head CT/MRI)* -Hypertension -Internal bleeding -*Current use of oral anticoagulants* -*Recent heparin tx* *ADVANTAGES:* -Anticoagulants and antiplatelet drugs are effective in preventing the formation and propagation of thrombi; however they are inactive against pre-existing clots. Fibrinolytics help to dissolve existing clots. *PK:* *Route:* IV as soon as symptoms are apparent (preferably within 3 hours)

TMP-SMX Trimethoprim-Sulfamethoxazole

*CLASS:* Folate Synthesis Inhibitor *MECHANISM:* inhibits folate synthesis at 2 locations: dihydropteroate synthase (DHPS) {Sulfamethoxazole} and dihydrofolae reductase (DHFR){Trimethoprim} *SELECTIVE TOXCITY*: -Mammals don't have DHPS -Mammals have DHFR; but TMP-SMX binds to fungal/bacterial enzyme w/ a greater affinity *INDICATION:* *Pneumocystis jiroveci pneumonia (PCP)* *ADVERSE:* - similar to when used as an antibacterial -More pronounced in AIDS patients -rash, hepatitis, neutropenia, azotemia, thrombocytopenia

Gonadorelin - synthetic GnRH

*CLASS:* GnRH -GnRH = a small peptide hormone *MECHANISM OF ACTION*: -Stimulate GnRH receptors in pituitary -GnRH in pulsitile fashion stimulate production and release of FSH&LH -*Sustained action desensitizes GnRH receptors, results in downregulation of receptors and reduces FSH&LH* *INDICATIONS:* OPPOSITE EFFECTS POSSIBLE DEPENDING UPON TREATMENT REGIMEN -Fertility treatment (pulsatile gonadorelin) ---->Treatment of INFERTILITY resulting from hypothalamic amenorrhea: *Intermittent administration results in sustained release of FSH and LH* RESULT = OVULATION -Theoretical use as a CONTRACEPTIVE: More frequent administration causes desensitization of GnRH receptors on anterior pituitary gonadotrophs leading to suppression of FSH and LH release RESULT = INFERTILITY *GnRH receptors are subject to desensitization when overstimulated* -Therefore GnRH must be given in a pulsatile fashion to mimic endogenous release to treat infertility *ADVERSE:* -Side effects related to suppression of sex hormones for prolonged stimulation: mood disturbances, eventually osteoporosis *PK* *Route:* Given by IV infusion to mimic pulsatile pattern. *Half-life:* 2-4 min (very short)

Abarelix

*CLASS:* GnRH antagonists *MECHANISM OF ACTION*: -Competitive antagonist of GnRH at receptors in pituitary --> induces rapid inhibition of LH&FSH without initial surges *INDICATIONS:* *Prevent premature LH surge (Ganirelix)* -Delays the LH surge to treat infertility caused by premature ovulation *ADVERSE:* -Primarily due to sex hormone suppression: ---> Mimics menopause in women: hot flashes, osteoporosis, thinning of skin ---> In men: reduced muscle, impotence (reduced effect of testosterone on muscle) *ADVANTAGE:* -GnRH used for tx of prostate cancer causes an initial surge of LH and FSH than may not be ideal --> therefore could be better to use a GnRH antagonist *PK* *Metabolism:* Excreted in feces and urine

Ganirelix

Degarelix

*CLASS:* GnRH antagonists *MECHANISM OF ACTION*: -Competitive antagonist of GnRH at receptors in pituitary --> induces rapid inhibition of LH&FSH without initial surges *INDICATIONS:* *Prostate cancer (Degarelix)* *ADVERSE:* -Primarily due to sex hormone suppression: ---> Mimics menopause in women: hot flashes, osteoporosis, thinning of skin ---> In men: reduced muscle, impotence (reduced effect of testosterone on muscle) *ADVANTAGE:* -GnRH used for tx of prostate cancer causes an initial surge of LH and FSH than may not be ideal --> therefore could be better to use a GnRH antagonist *PK* *Metabolism:* Excreted in feces and urine

Protamine sulfate

*CLASS:* Heparin Antagonist *MECHANISM OF ACTION:* -A low molecular weight polycationic protein which forms a stable complex with the negatively charged heparin through multiple electrostatic interactions (a non-specific binder of heparin) -Decreases the amount of heparin in the blood *INDICATION:* -To reverse rapidly the effects of heparins in situations of life-threatening hemorrhage or great heparin excess (Does not reverse effects of fondaparinux-synthetic heparin) -NOT a tx for HIT (heparin-induced thrombocytopenia) *PK:* *Route:* IV

Sitagliptin

*CLASS:* Incretins: *DPP-4 Inhibitor* *MECHANISM:* -Inhibits DPP-4, an enzyme which breaks down GLP-1 and GIP --> increases the concentration of endogenous incretins which can enhance insulin release from pancreatic beta cells. *Increases insulin sensitivity in peripheral tissues and increases insulin release from beta cells* *INDICATION:* -Adjunct to diet and exercise to improve glycemic control in T2DM *ADVERSE:* -Gastrointestinal disturbances (dyspepsia, nausea, vomiting, and diarrhea) -Pancreatitis -May cause pancreatic cancer (pancreatic duct metaplasia) secondary to tx (watch for this) *CONTRAINDICATIONS:* -Type 1 DM -Diabetic ketoacidosis -Severe GI disease -Breastfeeding *ADVANTAGE:* *-Low risk of hypoglycemia* *PK:* *ROUTE:*Subcutaneous Injection or Oral

Exenatide

*CLASS:* Incretins: *Glucagon-like peptide 1 (GLP-1) receptor agonist* *MECHANISM:* -Control hyperglycemia by potentiating glucose-mediated insulin secretion and suppressing postprandial glucagon release *Increases insulin sensitivity in peripheral tissues and increases insulin release from beta cells* *INDICATION:* -Adjunct to diet and exercise to improve glycemic control in T2DM *ADVERSE:* -Gastrointestinal disturbances (dyspepsia, nausea, vomiting, and diarrhea) -Pancreatitis -May cause pancreatic cancer (pancreatic duct metaplasia) secondary to tx (watch for this) *CONTRAINDICATIONS:* -Type 1 DM -Diabetic ketoacidosis *-Renal impairment* [different compared to Sitagliptin] -Severe GI disease -Breastfeeding *ADVANTAGE:* *-Low risk of hypoglycemia* *PK:* *ROUTE:* Subcutaneous Injection

Flucytosine

*CLASS:* Inhibitors of DNA/RNA Synthesis *MECHANISM:* Cytosine nucleoside analogue; -Sensitive fungi convert Flucytosine to 5-fluorouracil by CYTOSINE DEAMINASE -5-fluorouracil is then acted on by another enzyme (UPRTase) and converted to 5-FUMP -5-FUMP is toxic and inhibits RNA synthesis and is a poison to nucleic acids in the cell *SELECTIVE TOX:* Cytosine deaminase is not present in humans *RESISTANCE* -Resistance occurs through several mechanisms: --->uptake can be inhibited --->cytosine deaminase can be mutated of lost --->UPRTase can be modified *Needs to be given in combination therapy* - *INDICATION:* systemic fungal infections - candida - cryptococcus *Used with Amphotericin B to treat cryptococcal meningitis* *ADVERSE:* - *Bone marrow suppression* - elevated liver enzymes - GI distress *CONTRAINDICATED during pregnancy* *PK:* *Route: oral *Distribution: High in tissues and fluids, including CSF *Elimination: renal; adjust dose if renally impaired

Warfarin

*CLASS:* Inhibitors of clotting factor synthesis *MECHANISM OF ACTION:* *Interferes with the normal post-translational modification of clotting factors in the liver, a process that depends on an adequate supply of reduced vitamin K* - Vitamin K oxidation is coupled to gamma-carboxylation of glutamate residues on clotting factor proteins, which is necessary for Ca2+ binding leading to full biological activity -Warfarin blocks the vitamin K reductase step [Vitamin K reductase normally recycles Vitamin K to the reduced form] *Warfarin acts by inhibiting the synthesis of clotting factors II, VII, IX, and X* *INDICATION:* -*Prophylaxis and/or treatment of:* -Deep venous thrombosis -Pulmonary embolism -Prevention of systemic embolization in patients with acute MI, prosthetic heart valves, or chronic atrial fibrillation. -After MI, to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization *ADVERSE:* *Warfarin overdose*-The effects of warfarin can be reversed by the administration of exogenous vitamin K *Warfarin necrosis* - Some patients have a deficiency of protein C -Protein C is an *innate anticoagulant* that requires vitamin K-dependent carboxylation for its activity -Since warfarin initially decreases protein C levels faster than the coagulation factors, it can paradoxically increase the blood's tendency to coagulate when treatment is first begun *(many patients when starting on warfarin are given heparin in parallel to combat this-BRIDGE WITH HEPARIN)* -*Increase in coagulation can lead to massive thrombosis with skin necrosis and gangrene of limbs* = warfarin necrosis -A deficiency in protein S would lead to the same necrosis *Hemorrhage* - requires close monitoring when starting treatment and during heparin coadministration *CONTRAINDICATIONS:* -*PREGNANCY* (can cross the placenta and cause hemorrhage disorders in fetus; teratogen - causes facial deformities) -Situations where the risk of hemorrhage is greater than the potential clinical benefits of therapy such as uncontrolled alcohol or drug abuse or unsupervised dementia/psychosis *DRUG-DRUG I/AS:* -99% of warfarin is bound to plasma albumin (long half-life) -hydroxylated by cytochrome P450 system -*co-administration with albumin-bound drugs or drugs that affect P450 metabolism can influence the plasma concentrations of both drugs* *Drugs that DIMINISH Warfarin's Anticoagulant Effect:* -Vitamin K (reduced) [found in kale, spinach]: Bypasses warfarin-induced epoxidise reductase inhibition -*shouldn't eat if on warfarin* *Drugs that ENHANCE Warfarin's Anticoagulant Effect:* -Broad-Spectrum Antibiotics: Reduce availability of vitamin K in the GI tract -*if on antibiotics modify the warfarin dose* *PK:* *Route:* Oral or IV *Half-Life:* *Long* (~36 hours) [99% of warfarin is bound to plasma albumin] *Note:* Warfarin has a delayed onset of action because we have a stock pile of functional zymogens -The delayed onset of warfarin's effect actually reflects the half-lives of these modified clotting factors (shortest, Factor VII 6h; longest, Factor II 40-60h) *Dosing:* variable, based on patient history and genetics *Genetic variability alters warfarin dosing requirements* - The P450 enzyme, *CYP2C9*, is the major enzyme responsible for converting the S-enantiomer warfarin to its inactive metabolites *Approximately 10% of patients require less than 1.5 mg per day of warfarin to achieve an INR of 2 to 3. These patients are more likely to possess one or two variant CYP2C9 alleles* -The variant alleles are more prevalent in Caucasians (10-20%), compared to African-Americans or Asians (<5%) -*Can also have polymorphisms in the Vitamin K reductase that can alter the dosing requirements of warfarin*

Heparin

*CLASS:* Inhibitors of clotting factors - *Direct-Acting Anticoagulants* *MECHANISM OF ACTION:* -*Heparins, in combination with antithrombin III, irreversibly inactivate thrombin and several other factors, particularly factor Xa* *Heparin acts by accelerating ATIII reactions to inactivate thrombin and factor Xa* -Heparin binding to antithrombin III changes the conformation of the protein and allows the formation of a ternary complex (heparin-antithrombin-target factor) -Heparin binding to ATIII and the subsequent conformational change increases the interaction of ATIII with the target factors -The ratio of antithrombin III activity is typically 3:1 (thrombin:factor Xa) -Inhibiting thrombin and Factor Xa --> really shutting down the coagulation cascade *INDICATION:* *High doses of standard heparin - treat abnormal thrombi* -Deep venous thrombosis (DVT) -Pulmonary embolism -Acute arterial occlusion (such as acute myocardial infarction) -Prevention of thromboses (but not in ischemic stroke/TIA) -Surgery with extracorporeal circulation -Hemodialysis *Low doses of standard heparin- prevents production of abnormal thrombi* -Prophylaxis of DVT -Prophylaxis of pulmonary embolism -Venous thromboembolism -Maintenance of open venous catheters *ADVERSE:* -*Bleeding* -*Thrombocytopenia* -Allergy hazard (heparin is a highly negatively charged glycosaminoglycan found in mast cells of porcine intestinal mucosa and bovine lung) *CONTRAINDICATIONS:* -*Patients with a high risk of bleeding* -*Previous incidence of heparin-induced thrombocytopenia* -*Requires close monitoring* *PK:* *Route:* Continuous IV infusion or intermittant injections (i.v. or deep s.c.) to achieve1.5-2.5 times increase of the aPTT

Enoxaparin (LMWH)

*CLASS:* Inhibitors of clotting factors - *Direct-Acting Anticoagulants* Low molecular weight heparins (Enoxaparin: depolymerized heparin) *MECHANISM OF ACTION:* -*Heparins, in combination with antithrombin III, irreversibly inactivate thrombin and several other factors, particularly factor Xa* -*Low molecular weight heparins (LMWH) are too small to bind antithrombin and thrombin, and thus have greater specificity for inhibition of factor Xa* -*Just binding to and inhibiting Factor Xa and not thrombin!* *INDICATION:* -Prophylaxis of DVT for hip/knee replacement, abdominal surgery, or bariatric sx -Treatment of DVT -Treatment of MI *ADVERSE:* -*Bleeding* -*Thrombocytopenia* *CONTRAINDICATIONS:* -*Patients with a high risk of bleeding* -*Previous incidence of heparin-induced thrombocytopenia* -*Requires close monitoring* *ADVANTAGES:* -Yields "better" control of the coagulation cascade than unfractionated heparin (only binds to and inhibits Factor Xa and not thrombin!) - less severe effects than unfractionated heparin on the coagulation cascade -Induces HIT to a lesser extent than unfractionated heparin -Allergies not seen with LMWHs *PK:* *Route:* Continuous IV infusion or intermittant injections (i.v. or deep s.c.) to achieve1.5-2.5 times increase of the aPTT *Half-Life:* *about 5 hrs*

Rivaroxaban

*CLASS:* Inhibitors of clotting factors- *Direct factor Xa inhibitor* *MECHANISM OF ACTION:* *Inhibits platelet activation and fibrin clot formation via direct, selective and reversible inhibition of factor Xa* -*This inhibition results in decreased conversion of prothrombin to thrombin and thus decreases platelet activation and the conversion of fibrinogen to fibrin* *INDICATION:* -Treatment of DVT or PE -Prophylactic administration for prevention of postoperative venous thromboembolism -Hip replacement surgery -Knee replacement surgery -Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism) *ADVERSE:* -*Bleeding* -*Epidural or spinal hematomas* -*Premature discontinuation of factor Xa inhibitors increases the risks of thrombotic events* [need another anticoagulation mechanism in place or pts will have thrombotic events] *CONTRAINDICATIONS:* -Active pathological bleeding *PK:* *Route:* Oral

Insulin formulations Aspart Glulisine Lispro Regular NPH Detemir Glargine

*CLASS:* Insulin *MECHANISM:* -Activates insulin receptors on target tissues to clear glucose from the blood and to increase anabolic activity in the liver, adipose tissue and skeletal muscle *-Covers basal and prandial insulin needs* *INDICATION:* -Type 1 DM and Type 2 DM *ADVERSE:* *-Hypoglycemia* -Hypokalemia -Localized fat accumulation or atrophy at the site of injection -Allergic reactions (less of a problem now because of the use of recombinant insulin formulations) *CONTRAINDICATIONS:* -Hypersensitivity to insulin *PK:* *ROUTE:* -Subcutaneous or IV administration -Subcutaneous continuous pumps- rapid/short acting ONLY [get a small dose of insulin every 1/2 hr or hr to yield a basal level of insulin; then can give yourself a bolus dose of insulin for prandial after a meal] -Inhalation insulins: love/hate relationship with FDA (very $$$$) *NOTES:* There are no variations of insulin molecules other than how the pharmacokinetics are modulated *Absorption:* Once injected, the rate-limiting step for capillary absorption of insulin is the subcutaneous dissociation into dimers and then monomers [some insulin dissolves very quickly once it hits the bloodstream; other insulin takes a long time to dissolve] -Insulin preparations can be formulated to differ in their peaks and durations of action on the basis of factors which alter the dissociation of the administered insulin. *The modifications only change pharmacokinetics; insulin analogs all bind to and activate the insulin receptor with the same affinity.* (ONLY CHANGES PK NOT PD)

Repaglinide

*CLASS:* Insulin Secretagogues: Meglitinides *MECHANISM:* -Induce release of insulin by inhibiting potassium conductance through ATP-sensitive K+ channels in the membrane of the pancreatic β-cells --->K+ channel closure depolarizes the cell and triggers insulin release from beta cells *Act similarly to sulfonylureas but bind to distinct region of SUR1-a protein that associates with the K+ channel* (sulfonylureas bind an extracellular site of the K+ channel) *INDICATION:* -Adjunct to diet and exercise to improve glycemic control in adults with T2DM *Controls postprandial hyperglycemia without risk of long-lasting hypoglycemia* *ADVERSE:*Same as sulfonylureas *-Hypoglycemia* -Weight gain (because of the potential for weight gain, these drugs are most appropriate for non- or mildly obese patients), -Disulfiram-like reactions [contain sulfur cmpds --> can cause flushing] -GI disturbances (N/V, diarrhea, anorexia, hunger) *CONTRAINDICATIONS:* -Type 1 DM -Diabetic ketoacidosis with or without coma -Administration of the endothelin receptor antagonist, bosentan (glyburide) -Morbidly obese pts (causes weight gain) -Pregnancy or breastfeeding, surgery, severe infections, severe stress or trauma, and severe hepatic or renal failure: *insulin should be used in all of these cases* *Concurrent gemfibrozil therapy* *PK:* *ROUTE:* Oral <30 min before a meal -RAPID onset and short duration of action [*good drug to cover prandial insulin in T2DM]

Glipizide

*CLASS:* Insulin Secretagogues: Sulfonylureas *MECHANISM:* -*Induce release of insulin* by inhibiting potassium conductance through ATP-sensitive K+ channels in the membrane of the pancreatic β-cells --->K+ channel closure depolarizes the cell and triggers insulin release from beta cells -The potency of sulfonylureas correlates with the binding affinity of the drug for ATP-sensitive K+ channel proteins *INDICATION:* -Adjunct to diet and exercise to improve glycemic control in adults with T2DM *This class of drugs is most effective when β cell function has not been severely compromised* because they lower blood glucose by increasing the secretion of insulin from pancreatic β-cells *ADVERSE:* Same as Meglitinides *-Hypoglycemia* -Weight gain (because of the potential for weight gain, these drugs are most appropriate for non- or mildly obese patients), -Disulfiram-like reactions [contain sulfur cmpds --> can cause flushing] -GI disturbances (N/V, diarrhea, anorexia, hunger) *CONTRAINDICATIONS:* -Type 1 DM -Diabetic ketoacidosis with or without coma -Administration of the endothelin receptor antagonist, bosentan (glyburide) -Morbidly obese pts (causes weight gain) -Pregnancy or breastfeeding, surgery, severe infections, severe stress or trauma, and severe hepatic or renal failure: *insulin should be used in all of these cases* *DRUG-DRUG I/As:* -Be careful of this: Sulfonylureas i/a with other proteins -I/As with other drugs can enhance hypoglycemic effects or decrease the effect of the sulfonylureas *PK:* *ROUTE:* Oral 1x daily *Distribution:* bind plasma proteins

Metformin

*CLASS:* Insulin Sensitizers: *Biguanides* *MECHANISM:* -Mechanism not thoroughly understood: All mechanisms are suspected to be mediated through *activation of AMP-activated protein kinase (AMPK)* ----> *Suppresses gluconeogenesis in the liver and increases insulin-dependent peripheral glucose utilization (esp. in smooth muscle)* *Together, these actions increase liver insulin sensitivity, and decrease plasma glucose and triglyceride load to improve hyperglycemia* *INDICATION:* *First-line treatment for T2DM* -Adjunct to diet and exercise to improve glycemic control in T2DM *ADVERSE:* *-Lactic acidosis* -GI upset -Skeletal weakness -Upper respiratory tract infection *CONTRAINDICATIONS:* -*Renal disease/dysfunction* (serum creatinine ≥1.5mg/dL in males or ≥1.4mg/dL in females; abnormal creatinine clearance from any cause-- shock, acute MI, septicemia) *If metformin is administered to someone who has kidney disease there is a high chance of lactic acidosis therefore it is only given to pts with adequate renal function* -Discontinue metformin (temporarily) 48 prior to *radiologic studies with intravascular iodinated contrast materials* due to possible renal failure -Acute or chronic metabolic acidosis -Diabetic ketoacidosis with or without coma -Conditions associated with hypoxemia (cardiorespriratory insufficiency, cardiovascular collapse, congestive heart failure, acute MI) -Pregnancy or breastfeeding, surgery, severe infections, severe stress or trauma, and severe hepatic or renal failure: *insulin should be used in all of these cases* *ADVANTAGE:* -Metformin does not elicit the release of insulin therefore it still has efficacy in patients with dysfunctional beta cells and there is a *very low risk of hypoglycemia* *PK:* *Clearance:* *Renal*

Pioglitazone

*CLASS:* Insulin Sensitizers: *Thiazolidinediones* *MECHANISM:* -Activate the nuclear peroxisome proliferator activated receptor-gamma (PPAR-gamma) -*Activation of PPAR-gamma alters lipid metabolism and glucose metabolism, increasing the insulin sensitivity at the target tissues* *INDICATION:* -Adjunct to diet and exercise to improve glycemic control in T2DM *ADVERSE:* -*Increase HDL, LDL and total cholesterol→slight increase in adverse ischemic events (MI and angina)* -Dose related weight gain -Fluid retention -Bladder cancer {Pioglitazone} *CONTRAINDICATIONS:* *-Class III/IV heart failure* [therefore not very useful because people with diabetes are at risk for a CV event] -Hepatic disease/dysfunction (metabolized by p450 enzymes). -Pregnancy or breastfeeding, surgery, severe infections, severe stress or trauma, and severe hepatic or renal failure: *insulin should be used in all of these cases* *ADVANTAGE:* *-Very low risk of hypoglycemia* because these drugs improve hyperglycemia by increasing liver insulin sensitivity without increasing insulin secretion

Rosiglitazone

Iodide salts/Potassium Iodide -Lugol's solution: potassium iodide and iodine; saturated potassium iodide

*CLASS:* Iodide salts *MECHANISM OF ACTION:* -Iodide limits it's own transport through the sodium iodine symporter -Wolff Chaikoff effect: acute and transient inhibition of iodination and conjugation -High I- plasma levels inhibit the release of T3 and T4 from the follicular cells [*increased levels of iodine inhibits thyroid peroxidase --> results in less T3 and T4 being released] -*Have an antithyroid action through inhibition of iodide uptake, inhibition of iodination and organification (Wolff-Chaikoff effect) and inhibition of thyroid hormone release* *Effects are transient:* -If you have a downregulated symporter you will eventually deplete the massive quantity of iodide in cells --> regular iodine level ---> relieve inhibition of thyroid peroxidase --> normal release of T3 and T4 (symporter goes back to normal as well) *INDICATION:* -*Emergency treatment for thyroid storm* -*Thyroid protection during medical treatment*; reduces size and vascularity of the thyroid gland often administered before thyroid gland surgery -*Thyroid protection due to nuclear accidents and emergencies* [administer clean iodine so pts can't uptake the radioactive iodine they are exposed to] *ADVERSE:* -Hypothyroidism, may worsen toxic goiter symptoms [tansient hypothyroidism with tx] *CONTRAINDICATIONS:* -Known hypersensitivity to iodide or to organic preparations that contain iodine when administered via IV *PK:* *Route:* Oral - as an iodine solution -Iodine is reduced to iodide in the intestine before absorption or intravenously administered *Onset and duration of action:* -*Rapid onset of action with observable decrease in thyroid hormone by 24 hrs* [Why it is used for thyroid storm] -Peak effects are observed in 10-15 days --> These effects are reversible and transient, thus *iodide treatment is not optimal for long-term management of hyperthyroidism*

Suramin

*CLASS:* Kinetoplastid Drugs *MECHANISM:* UNKNOWN - may target pyruvate kinase *INDICATION:* African "sleeping sickness" (T. brucei) - hemolymphatic stage *ADVERSE:* minimal -malaise, nausea, fatigue headache *PK:* *Route: slow IV *Distribution: binds tightly to plasma proteins *Excretion: renal (caution in renal impaired)

Nifurtimox

*CLASS:* Kinetoplastid Drugs *MECHANISM:* metabolized to toxic free radicals *INDICATION:* - American "Chagas' disease" (T. cruzi) - African "sleeping sickness" (T. brucei) *chronic stage*: *WITH EFLORNITHINE* *ADVERSE:* anorexia, emesis, memory loss, convulsions *Less pronounced with new generation drug *PK:* *Route: oral

Eflornithine

*CLASS:* Kinetoplastid Drugs *MECHANISM:* ornithine decarboxylase inhibitor (prevents synthesis of polyamines) - inhibit formation of precursors --> kills cells *RESISTANCE:*Occurs quickly, rapidly spreading -resistance = due to a single point mutation -given only as a combo with NIFURTIMOX *INDICATION:* African "sleeping sickness" (T. brucei) - hemolymphatic stage - *chronic stage*: *WITH NIFURTIMOX * *PK:* *Route: inconvenient - IV every 6 hrs for 2 wks; expensive *Distribution: well distributed, *penetrates into CSF- therefore active against chronic stage* *Elimination: Largely renal

Melarsoprol

*CLASS:* Kinetoplastid Drugs *Mel B "arsenic in antifreeze"* -Fire in veins" -Devastating to patient *RESISTANCE:* reported and spreading *INDICATION:* Chronic stage of T. brucei; LAST RESORT *ADVERSE:* -Kills ~10% of patients *PK:* *Route: IV injection only

Statins *Lovastatin* *Atorvastatin - Lipitor* *Rosuvastatin*

*CLASS:* Lipid-Lowering Agents: Statins *ACTION:* *Competitively inhibit HMG-CoA reductase* (3-Hydroxy-3-methylglutaryl-CoA reductase) - that catalyzse the rate limiting step in cholesterol synthesis --> therefore they block cholesterol synthesis *Reduce LDL levels by increasing hepatic uptake of LDL, VLDL remnants* *Also reduce susceptibility of LDL to oxidation* *INDICATION:* *-Reduce incidence of recurrent myocardial infarction and total mortality by reducing LDL levels* *ADVERSE:* -*Myopathy/Rhabdomyolysis* (muscle soreness --> muscle atrophy) - occurs in 10-15% of pts taking statins [*Note:* Niacins don't cause this on their own but they can exacerbate it in combination with statins] -*Hepatotoxicity* (monitor liver enzymes-transaminase, bilirubin- in serum) -Neuropathy (particularly chemo brain) -Mild GI symptoms, headache, rash, muscle cramps, insomnia *CONTRAINDICATIONS:* -Hepatotoxicity -Pregnancy and nursing mothers (safety not established) *DRUG-DRUG INTERACTIONS:* *CYP P450 3A4* -Grapefruit juice = contraindicated -Increase coumarin levels (ex: Coumadin) -OATP2 inhibitors (gemfibrozil) --> increased circulating statin levels *PK* *ROUTE:* Oral -During the night cholesterol synthesis increases *Give statins at night* -Lovastatin: take w/meals in evening -Atorvastatin & Rosuvastatin: take w/ or w/out food any time of day *Potency* -Rosuvastatin > Atorvastatin >Lovastatin (least potent)

Cholestyramine

*CLASS:* Lipid-lowering agents- Bile Acid Resins *ACTION:* -They are catonic polymers that are NOT ABSORBED -Bind anionic bile acids in the intestinal lumen *-Resin-bile acid complex cannot be absorbed (block 95% of bile acid reabsorption) and is excreted into the stool* ---> therefore more cholesterol needs to be diverted into the production of bile for digestion -Shunting: pull cholesterol out of the liver and into the gut to form bile --> this lowers overall cholesterol levels in the body *-Useful only where LDL is elevated* -Reduce LDL cholesterol - 10-20% -No significant effect on HDL levels *INDICATION:* *-Often given in combination therapy with Niacin or Statins* -Reduce major coronary events -Reduce coronary heart disease mortality *ADVERSE:* -May increase TG due to unknown feedback mechanism -*GI distress/constipation, bloating* --> will often cause patients to stop taking this therapy *CONTRAINDICATIONS:* -Patients with hypertriglyceridemia (high TG without elevated LDL) *DRUG-DRUG INTERACTIONS:* -Decreased absorption of other drugs: *take these medications 1 hr before or 3 hrs after taking the resin* *PK* *ROUTE:* -Oral -Typically given multiple times a day -Need large quantities

Colesevelam

Fenofibrate

*CLASS:* Lipid-lowering agents-Fibrates *ACTION:* - Increase FA oxidation in muscle and liver and lipogenesis in the live *Agonist of PPAR alpha* (proxisome proliferating antigen receptor) ----> increase HDL proteins (ApoA1 and ApoAll) at the level of gene expression ----> Decrease VLDL proteins (ApoCIII) at the level of gene expression *Effects cell signaling in lipid cell in a manner that shifts the production of Apo proteins in a pro HDL and anti VLDL direction -Lower TG's 20-50%, -Raise HDL-Ch 6-15%, -Lower LDL-Ch 5-20% (with normal TG), *INDICATION:* *-Often given in combination therapy with Niacin or Statins* *ADVERSE:* *-Myalgias* *-Rhabdomyolysis* -Increased gallstones (1-2%) -Increased transaminases (ALT/AST) [indicated liver damage] -GI distress -May raise LDL-Ch (with high TG) *PK:* -*Absorpion:* >90% absorbed (less efficient on empty stomach) -*Distribution:* >95% protein bound (albumin)

Gemfibrozil

Rasagiline

*CLASS:* MAO-B Inhibitor *MECHANISM OF ACTION:* -Selective inhibition of MAO-B thus decreasing degradation of dopamine/levodopa -Good adjunct with levodopa *INDICATION:* -Parkinson's disease *ADVERSE:* -Minimal use as monotherapy -GI: nausea -Postural hypotension for some patients -Dyskinesias *ADVANTAGES:* -Serotonin syndrome and hypertensive crisis are less likely than with inhibitors of MAO-A

Ropinirole

*CLASS:* Non-ergot Derivative *MECHANISM OF ACTION:* -Agonist at D2 receptor *INDICATION:* -Parkinson's disease -Restless legs syndrome *ADVERSE:* -GI: nausea -Postural hypotension for some patients -Not as associated with dyskinesias as levodopa -Behavioral: agitation, hallucinations; *sudden sleep onset* *ADVANTAGES:* -Less association with "on-off phenomenon" than levodopa -*Favored over ergot DA agonists*

Pramipexole

*CLASS:* Non-ergot Derivative *MECHANISM OF ACTION:* -Agonist at D2 receptor and D3 receptor *INDICATION:* -Parkinson's disease -Restless legs syndrome *ADVERSE:* -GI: nausea -Postural hypotension for some patients -Behavioral: agitation, hallucinations; *sudden sleep onset* *ADVANTAGES:* -Less association with "on-off phenomenon" than levodopa -Not as associated with dyskinesias as levodopa -*Favored over ergot DA agonists*

Amphotericin B

*CLASS:* Polyenes *MECHANISM:* binds ergosterol and forms pores in membrane --> dysregulation in fungal cell membrane *SELECTIVE TOX:* ergosterol only in fungi; binds ergosterol 500x greater than cholesterol *INDICATION:* - broad spectrum serious infections, some protozoa - *drug of choice for cryptococcal meningitis* *ADVERSE:* AMPHOTERRIBLE - IV related rxns: fever, chills hypotension [happens immediately after infusion] - nephrotoxicity (80%) *RENAL IMPAIRMENT = CAUTION IN USE* - arrhythmias *Liposomes formulations = less toxic* *DRUG INTERACTIONS:* -Caution with other nephrotoxic drugs *PK:* *Route: IV; oral, topical preps for oral or cutanous candidiasis (NOT TOXIC - No adverse effects) -Different formulation developed to reducy, toxicity, but doasge varies/cost rises *Distribution: Highly insoluble (poorly absorbed in GI); poor CNS penetration (intrathecal delivery for fungal meningitis); highly tissue bound (t1/2 = 15 days)

Progestins: Drospirenone

*CLASS:* Progesterone *MECHANISM OF ACTION*: *Progestin receptor-mediated:* -maintenance of pregnancy (suppresses menstruation and uterine contractility) -development of secretory endometrium, proliferation of acini in mammary glands, thermogenic effect in CNS, blunting of estrogenic effects *"Crossover effects" at androgen receptors* *INDICATIONS:* Available in combination-type oral contraceptives (used in Yasmin) *ADVERSE:* -Anti-androgenic and anti-mineralocorticoid activity -May double the risk of nonfatal blood clots when compared to levonorgestrel

Progestins: Norgestrel

*CLASS:* Progesterone *MECHANISM OF ACTION*: *Progestin receptor-mediated:* -maintenance of pregnancy (suppresses menstruation and uterine contractility) -development of secretory endometrium, proliferation of acini in mammary glands, thermogenic effect in CNS, blunting of estrogenic effects *"Crossover effects" at androgen receptors* *Note:* In order to make them orally effective, some synthetic progestins are substituted at the 19 position. Because of this substitution, these compounds are structurally similar to testosterone and so they also produce effects at androgen receptors. *INDICATIONS:* -Birth Control *ADVERSE:* -Have the least androgenic activity of the synthetic "19-nor" progestins *PK* *Route:* -Oral -Subdermal implant; lasts 5 yrs!

Progestin-Only Contraceptives 1. "minipill" - *daily norethindrone or norgestrel (oral)* 2. *Depot preparations: Slow release* *Norgestrel - subdermal implant; lasts 5 yrs!* *Medroxyprogesterone - IM injection; effective for 3 months* 3. *IUD impregnated with progesterone*

*CLASS:* Progesterone *MECHANISM OF ACTION*: -Inhibit ovulation, and produce direct effects on reproductive tract. -In theory may also interfere with implantation -Decreasing the frequency of GnRH pulses -Decreasing penetration of the cervix by sperm by changing the watery secretions elicited by estrogen to a viscous substance *INDICATIONS:* -Birth control: 99% (theoretical) *NOT as effective as combination* -*Useful for nursing mothers - do not interfere with lactation* *ADVERSE:* -Impaired fertility upon withdrawal (6 months to a year) -More likely to be problematic than after combination OCs -Irregular breakthrough bleeding, edema and weight gain, depression, headache

Quinine Quinidine = stereoisomer-IV form; also antiarrhythmic agent

*CLASS:* Quinolines *MECHANISM:* inhibition of heme polymerization *RESISTANCE:* - spreading, mutations in multidrug-resistance transporter, mdr1 (pumps out drug) *INDICATION:* erythrocytic forms of Plasmodium - prophylaxis & treatment - different mechanism of resistance means it is effective against chloroquine-resistant strains *ADVERSE:* more toxic, less effective --> use in combo therapy - cinchonism - hypoglycemia - hypotension *CONTRAINDICATED in patients w/: - epilepsy - MG - optic neuritis or tinnitus --> will worsen these *Caution in patients with G6PD deficiency (hemolysis could occur- rare) *PK:* *Route: Oral *Excretion: renal

Choloroquine

*CLASS:* Quinolines *MECHANISM:* targets heme metabolism: - binds heme and prevents polymerization to hemozoin --> parasite can't form hemozoin and heme accumulates --> parasite dies in its own waste due to extensive oxidative damage *SELECTIVE TOX:* Parasitized erythrocytes take up 100x more chloroquine than uninfected *RESISTANCE:* - EXTENSIVE; WIDESPREAD -mostly mutations in food vacuole transporter, crt (so drug can't get to where it needs to go) *INDICATION:* erythrocytic forms of Plasmodium - prophylaxis & treatment *ADVERSE:* well tolerated; safest quinoline *CONTRAINDICATED in patients w/: - epilepsy - MG - psoriasis *Caution in patients with G6PD deficiency (hemolysis could occur- rare) *PK:* *Route: Oral *Metabolism: two active metabolites generated by hepatic P450 system *Excretion: renal

Radioiodine 131I-

*CLASS:* Radioactive Iodide 131I *MECHANISM OF ACTION:* -*An antithyroid action through uptake and subsequent destruction of the follicular cells by ionizing radiation (β particles and γ rays) emitted from colloid-containing 131Iodide* -Destroy thyroid and ability to produce THs *INDICATION:* -Graves' disease -Overactive or enlarged thyroid -Thyroid cancer (thyroid ablation and treatment of metastatic disease) *ADVERSE:* -Hypothyroidism (life-long thyroid replacement therapy is essential) -Radiation may induce thyroiditis, which entails release of preformed T3 and T4 into the circulation, worsening ophthalmopathy in Graves' disease (cardiac manifestations are rare) *CONTRAINDICATIONS:* -*Pregnancy* (Radioactive iodide enters the breast milk and can cause serious fetal problems, therefore these drugs should not be used during pregnancy unless the benefit to the mother clearly overweighs the potential risk to the fetus) *PK:* *Route:* Oral as a sodium iodide solution or in capsule form *Half-life:* 8 days *Onset and duration of action:* -*Delayed onset of action* with observable decrease in hyperthyroid symptoms by a few weeks (max at 2-3 months posttx). -Duration of action: if the appropriate dose has been given the hyperthyroid treatment is *permanent*

Clomiphene

*CLASS:* SERM (selective estrogen receptor modulators) *MECHANISM OF ACTION*: -Acts as an *estrogen receptor antagonist* in the hypothalamus/pituitary axis --->Blocks negative feedback of estrogen on hypothalamus and pituitary to stimulate FSH and LH production. *INDICATIONS:* -Used for *anovulatory infertility* (infertility cause by failure of the woman to ovulate) --->Don't use for prolonged periods --->Used for 7 days to kick start the production of FSH, the stimulation of follicles, and start the cycle -Off-label use to treat male infertility (doesn't work well) - Illegal use by body builders and other athletes to *increase testosterone levels in males* (used to kick start the natural cycle for people using illegal androgens *ADVERSE:* -Ovarian hyperstimulation -Increased incidence of multiple births *NEED TO MONITOR* [Multiple births is a significant health risk] -Hot flushes (get menopausal life effects; makes sense because you are blocking estrogen receptors in the CNS) *PK* *Metabolism:* Hepatic

Raloxifene

*CLASS:* SERMs *MECHANISM OF ACTION*: Functional competitive estrogen receptor antagonist decreases estrogenic stimulation of the tumor cells but partial agonist activity in some settings and tissues *INDICATIONS:* *-Treatment and prevention of osteoporosis in postmenopausal women* *-Reduction of risk of invasive breast cancer* [*NOTE:* NOT approved for the treatment of invasive breast cancer- haven't looked at this in clinical trials] *ADVERSE:* -Hot flashes -Leg cramps -Paradoxically it may have a higher incidence of death due to stroke and the FDA has issued a warning for long-QT with it -Increased incidence of thromboembolic events early in therapy [Not clear if blood clotting effect is better or worse than with Tamoxifen] *ADVANTAGES:* -Lower risk of endometrial cancer than tamoxifen and estrogen [NO UTERINE STIMULATION] -Increases bone density (prevention of osteoporosis) -Decreases LDL -Lower incidence of blood clots and cataracts compared to tamoxifen [Not clear if blood clotting effect is better or worse than with Tamoxifen] *PK* *Route:* Oral *Metabolism:* Hepatic *Half-life:*1-3 days (enterohepatic circulation)

Raloxifine

*CLASS:* SERMs *MECHANISM OF ACTION:* -These SERMS inhibit bone resorption through *estrogenic agonist activity in bone to suppress PTH-induced bone resorption* -*Estrogen receptor activation suppresses osteoclast activity/survival and increases the lifespan of osteoblasts and osteocytes.* *INDICATION:* -Treatment and prevention of postmenopausal osteoporosis -*Preferred treatment for osteoporosis in women with breast cancer, with a past history or family history of breast or endometrial cancer* *ADVERSE:* -Hot flashes -Thromboembolism *CONTRAINDICATIONS:* -*Active or past history of venous thromboembolism* -Pregnancy/breastfeeding *ADVANTAGE:* -These SERMS have estrogen receptor antagonist properties in breast and uterus making them less of a risk factor for breast and endometrial cancers than supplementing with estrogen alone. *PK:* *Route:* Oral

Cyproterone acetate

*CLASS:* STEROIDAL ANTIANDROGEN *MECHANISM OF ACTION*: -Weak *partial agonist for androgen receptor* -*May inhibit spermatogenesis and libido*

Levothyroxine

*CLASS:* Thyroid Drugs; Synthetic Hormone *MECHANISM OF ACTION:* -T4 only -about 35% of T4 is converted to T3 *INDICATION:* -As replacement or supplemental therapy in patients with *hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis* -*As pituitary TSH suppressants* (because of the negative feedback on the pituitary), in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto's), multinodular goiter, and in the management of thyroid cancer -As diagnostic agents in suppression tests to differentiate suspected mild hyperthyroidism or thyroid gland autonomy *ADVERSE:* -Weight loss *CONTRAINDICATIONS:* -*Thyroid hormones should not be used during acute myocardial infarction because they could exacerbate this condition* -*Angina pectoris or the elderly*: the development of chest pain or other exacerbation of cardiovascular symptoms will require a decrease in dosage. -Diabetes mellitus -Diabetes insipidus -*Cortical insufficiency*---> Metabolism increases at a faster rate than cortical activity can keep up with --> precipitates adrenal insufficiency (and TH will intensify the symptoms because of enhanced metabolism) *ADVANTAGES:* -Synthetic hormones are more consistent and don't have allergenic potential that is associated with natural hormone preparations *PK:* *Route:* Oral -F bioavailability varies between 48 to 79%, depending on formulation, fasting, malabsorption syndromes and dietary factors (different patients will need different levels) *It is really important to take Levothyroxine on an empty stomach --> Calcium and other foods can effects its absorption* *Half-life:* About 7 days

Almotriptan

*CLASS:* Triptans (5H1 receptor agonists) *MECHANISM OF ACTION:* -Agonists at 5HT1 receptors, especially 5HT1B and 5 HT1D *INDICATION:* -Drugs of choice for *acute treatment of migraine (w/ or w/out aura)* *Note:* Only work AFTER the patient is developing the headache *ADVERSE:* -NOT useful for prophylaxis or long term use -Nausea, malaise, dizziness, weakness -Dry mouth -Paresthesia -Pain at site of injection -Rarely patients can have severe cardiovascular complications including coronary artery spasm, ischemia, and arrhythmias [5-HT can be iontropic, an chronotropic on the heart] *CONTRAINDICATIONS:* -Patients with history of ischemic or vasospastic coronary artery disease -Patients with cerebrovascular or peripheral vascular disease -Patients with uncontrolled hypertension -Patients taking MAO inhibitors -*Naratriptan should not be given to patients with severe renal or hepatic disease* *PK:* *Route:* -Oral -Nasal spray -Injection (subcutaneous) *Absorption:* -Readily absorbed -F = 15-40% -Onset after subcutaneous injection or spray is 10-15 mins (30 or 40 mins for onset after oral preparation)

Naratriptan

Rizatriptan

Sumatriptan

Zolmitriptan

Haloperidol

*CLASS:* Typical antipsychotics - HIGH potency *MECHANISM:* D2 receptor blockade *high affinity DA receptor antagonist *INDICATION* *Antipsychotic action is equivalent to those of chloropromazine* - schizophrenia and other psychotic disorders - Tourette's syndrome -Chorea associated with Huntington's disease *ADVERSE:* -Extrapyramidal effects occur frequently -Risk of Tardive Dyskinesia is high relative to low-potency agents *MONITOR cardiac function in patients- QT prolongation and potential for life-threatening arrhythmias* -Uncommon: Sedation, orthostatic hypotension, and anticholinergic effects -May decrease fine motor coordination and increase rigidity (Reconsider use if parkinsonian features are present) *PK:* *Route: - PO (F=60%) - IM *Extensive hepatic metabolism *Excretion: in urine as parent drug and metabolites

Chlorpromazine

*CLASS:* Typical antipsychotics - LOW potency *MECHANISM* D2 receptor blockade (low potency) - also blocks: NE a1, histamine, and ACh & 5-HT receptors *INDICATION:* - schizophrenia and other psychotic disorders - manic phase of bipolar disorder *ADVERSE:* - prolonged QT - D2: moderate EPS *risk or tardive dyskinesia is relatively low - NE a1: orthostatic hypotension (high) - H1: sedation (high) - Ach: moderate: dry mouth, blurred vision, urinary retention, constipation, tachycardia - 5HT: moderate: weight gain **tardive dyskinesia is low** *DRUG INTERACTIONS:* - Can intensify response to CNS depressants: antihistamines, benzodiazepines, and barbiturates - Can intensify response to anti-cholinergic drugs: antihistamines, TCAs (tricyclic antidepressants) and atropine-like drugs *PK:* *Route: - PO (F = 30%) - IM - IV *High first pass metabolism --> requires high dose *t1/2 is biphasic (intial - 2hrs; terminal-30 hrs) *Excretion: renal (as metabolites)

Misoprostol (Mifeprex)

*CLASS:* Used in Medical Abortion *MECHANISM OF ACTION*: *A prostaglandin that stimulates uterine motility* *INDICATIONS:* -Medical Abortion -Approved to terminate intrauterine pregnancies of up to *49 days gestation (7 weeks)* - 600 mg mifepristone induces decidual breakdown in endometrium followed 2d later with misoprostol to induce contractions *ADVERSE:* -Bleeding, nausea, vomiting, abdominal pain, fatigue (all infrequent) -The rate of sepsis is about 1 in 100,000 uses of the Mifeprex system, comparable to infection risks with surgical abortions and childbirth.

Mifepristone (RU-486)

*CLASS:* Used in Medical Abortion *MECHANISM OF ACTION*: *Competitive antagonist at progesterone and glucocorticoid receptors* *INDICATIONS:* -Medical Abortion -Approved to terminate intrauterine pregnancies of up to *49 days gestation (7 weeks)* - 600 mg mifepristone induces decidual breakdown in endometrium followed 2d later with misoprostol to induce contractions *Also approved for treatment of Cushing's Syndrome.* - antagonist at glucocorticoid receptors *ADVERSE:* -Bleeding, nausea, vomiting, abdominal pain, fatigue (all infrequent) -The rate of sepsis is about 1 in 100,000 uses of the Mifeprex system, comparable to infection risks with surgical abortions and childbirth. *PK* *Route:* Oral *Plasma t1/2* = 20-40 hrs *Metabolism:*

Calcitriol

*CLASS:* Vitamin D analogs *MECHANISM OF ACTION:* -The primary site of action of vitamin D analogs to alter plasma calcium is in the *small intestine- increase the absorption of dietary calcium and phosphate.* -*Also increase bone resorption to increase plasma calcium and phosphate* ***Also effective in reducing plasma PTH levels.*** *INDICATION:* -Secondary hyperparathyroidism with *moderate to severe chronic renal failure* -Hypocalcemia in patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, and pseudohypoparathyroidism -Hypocalcemia in patients undergoing chronic renal dialysis -Psoriasis *ADVERSE:* -Hypercalcemia -Hyperphosphatemia -Hypercalciuria *CONTRAINDICATIONS:* -Hypercalcemia -Hyperphosphatemia -Evidence of vitamin D toxicity

Phenytoin

*CLASS:*Antiepileptics *MECHANISM OF ACTION:* -*Stabilizes voltage-gated sodium channels in the fast inactivated conformation* -inhibits voltage-gated calcium channels -stimulates sodium/potassium ATPase activity *INDICATION:* -Localization-related epilepsies -Tonic-clonic seizures -Status epilepticus *ADVERSE:* -Nystagmus -Ataxia -Gingival hyperplasia -Rash -Blood dyscrasias -Skin necrosis -Cardiac arrhythmia *PK:* *Zero-order or non-linear pharmacokinetics - this increases the toxicity of the drug; therefore it needs to be monitored very carefully- monitor serum levels to get it in 10-20mg/L range (this is where it is clinically effective)* [metabolism = easily saturated] *Metabolism:* *Induces hepatic enzymes- can alter metabolism of other drugs; can decrease the efficacy of oral contraceptives* and is metabolized by hepatic enzymes - this makes it very hard to adjust the dose -*Note:* Very insoluble in water and the dilutant is very toxic

Benztropine

*CLASS:*Antimuscarinic *MECHANISM OF ACTION:* -Targets unopposed ACh action in basal ganglia and restores DA-ACh balance *INDICATION:* -Parkinson's disease especially tremor and rigidity (not much effect on bradykinesia) *ADVERSE:* *Antimuscarinic adverse effects:* -Confusion: may be confused with disease progression -Blurred vision -Urinary retention -Other antimuscarinic (dry mouth) -Usually used in younger patients with milder symptoms (not usually used in older pts because they are more susceptible to confusion side effects) *ADVANTAGES:* -Generally used early in therapy for mild symptoms

Mebendazole (MBZ)

*CLASS:*Benzimidazoles; Anthelmintics *MECHANISM:* inhibits microtubule polymerization/mitotic spindle poison *SELECTIVE TOX:* bind worm b-tubulin with higher affinity than mammalian orthologue *INDICATION:* nematodes/roundworms *Because worms are BENDY- MeBENDazole* *ADVERSE:* well tolerated *PK:* *Route: oral - poorly absorbed - good because it stays in gut where the worms are

Griseofulvin

*CLASS:*Inhibitors of DNA/RNA Synthesis *MECHANISM:* binds microtubules and inhibits mitosis - can't get chromosome separation for cytokinesis to occur *Results in polynucleated fungal cells because they can't complete end stage mitosis *SELECTIVE TOX:* there are subtle differences in fungal tubulin monomers and human tubulin monomers and drug binds with a greater affinity to fungal tubulin *INDICATION:* restricted to dermatophytes - skin,hair nail, infections -ringworm cause by Microporum, Epidermophyton, or Trichophyton *ADVERSE:* relatively well tolerated - blood counts 1/wk for first week to check for adverse effects - Headache; confusion = less frequent - photosensitivity; rash - Carcinogenic in animals at high doses *Avoid during pregnancy* *DRUG INTERACTIONS:* induces CYPs - increased warfarin metabolism - decreased efficacy of low-estrogen birth control *EXCRETION:* - 50% in urine *ROUTE:* - oral - topical powder *PK:* *Route: - oral - topical powder *Distribution: - *deposits in keratin precursor cells (cells that give rise to hair and nails* - very little little distribution in body/fluids - treatment time must be continued until infected tissue is replaced: scalp: 1mo fingernails: 6-9mo toenails: 1yr+

Pentobarbital

*Class:* Barbiturates *Controlled Substance:* C-II *Action:* -Allosteric agonist at GABAA receptor acting to enhance duration of channel opening in response to GABA; -inhibit glutamate receptors *Clinical Use:* -largely limited to induction of anesthesia *Problems:* -Impaired cognitive and motor functioning -small therapeutic index -overdose risk particularly with other depressants-tolerance -abuse

Phenobarbital

*Class:* Barbiturates *Controlled Substance:* C-IV *MECHANISM OF ACTION:* -*Prolongs the length of time that GABA-activated chloride channels remain open* (works on GABA-A receptors) = increases inhibitory tone -Blocks voltage-gated Ca++ channels (decreases excitatory transmission) -Direct inhibitory action on NMDA-type glutamate receptors (decreases excitatory transmission) *INDICATION:* -Used since 1912, effective with multiple epilepsy types (but not absence) -largely limited to induction of anesthesia -also for seizures BUT not the first line for seizures because of its delayed action *ADVERSE:* -Used less now because of adverse effects -Somnolence -Depression -Behavioral problems -Hyperactivity, rash, Lupus syndrome *DRUG-DRUG I/As* -*Enzyme inducer and competitively inhibits the metabolism of other drugs* *PK:* *Metabolism:* **Induces hepatic enzymes- can alter metabolism of other drugs; can decrease the efficacy of oral contraceptives* *Half-life:* 60 - 110 hours

Thiopental

*Class:* Barbiturates *NO LONGER SUPPLIED TO US* -Manufactured in Itla -European Union banned distribution to US unless it is not used for executions (manufacturer can't guarantee this; so banned) *Action:* -Rapid rise in brain concentrations: Rapid onset of anesthesia -Lipid soluble drug: Rapid decrease in brain concentrations and redistribution to compartments that are large but poorly perfused (lean muscle and fat)--> Short duration of action -But if you keep dosing it can build up in lean muscle and fat and then redistribute to the brain --> anesthesia can last longer than you want *THEREFORE used for induction but not maintenance of anesthesia* *Clinical Use:* -largely limited to induction of anesthesia *induction! not maintenance*

Midazolam

*Class:* Benzodiazepines *Controlled Substance:* C-IV *Action:* -Positive allosteric modulator at GABA-A receptor --> acting to enhance frequency of channel opening in response to GABA *resulting in enhanced membrane hyperpolarization* *Clinical Use:* -Anesthesia *Problems:* -Shorter acting = greater withdrawal risk -*psychomotor depression* -residual daytime sedation -tolerance to hypnotic effect -risk of dependence -depression of CNS on own and enhancement of other depressants -amnestic effects -abuse *Avoid:* In patients with *sleep apnea* -drugs decrease muscle tone in airways -CNS depressant depresses the part of the brain that senses apnea *Advantages:* -rapid onset -relatively high therapeutic index -low risk of drug interactions -fairly safe - minimal effects on CV or ANS function (except in presence of other depressants-ETOH) [safe outlook: unless combined with CNS depressants won't see coma and death *PK:* -Short-acting (t1/2<6 hr)

Diazepam (Valium)

*Class:* Benzodiazepines *Controlled Substance:* C-IV *Action:* -Positive allosteric modulator at GABA-A receptor --> acting to enhance frequency of channel opening in response to GABA *resulting in enhanced membrane hyperpolarization* *Clinical Use:* -Anxiety -Spasticity -Sedation -*Status Epilepticus* -Generalized Epilepsies -*Short term-use* *Problems:* -High abuse potential *Problems:* -*psychomotor depression* -residual daytime sedation -tolerance to hypnotic effect -risk of dependence -depression of CNS on own and enhancement of other depressants -amnestic effects *Avoid:* In patients with *sleep apnea* -drugs decrease muscle tone in airways -CNS depressant depresses the part of the brain that senses apnea *Advantages:* -rapid onset -relatively high therapeutic index -low risk of drug interactions -fairly safe - minimal effects on CV or ANS function (except in presence of other depressants-ETOH) [safe outlook: unless combined with CNS depressants won't see coma and death *PK:* -Long-acting (t1/2>20 hours)

Alprazolam (Xanax)

*Class:* Benzodiazepines *Controlled Substance:* C-IV *Action:* -Positive allosteric modulator at GABA-A receptor --> acting to enhance frequency of channel opening in response to GABA *resulting in enhanced membrane hyperpolarization* *Clinical Use:* -Anxiety *Problems:* -High abuse potential (less with alprazolam XR)*Problems:* -*psychomotor depression* -residual daytime sedation -tolerance to hypnotic effect -risk of dependence -depression of CNS on own and enhancement of other depressants -amnestic effects *Avoid:* In patients with *sleep apnea* -drugs decrease muscle tone in airways -CNS depressant depresses the part of the brain that senses apnea *Advantages:* -rapid onset -relatively high therapeutic index -low risk of drug interactions -fairly safe - minimal effects on CV or ANS function (except in presence of other depressants-ETOH) [safe outlook: unless combined with CNS depressants won't see coma and death *PK:* -Intermediate-acting (t1/2 = 6-20 hrs)

Lorazepam

*Class:* Benzodiazepines *Controlled Substance:* C-IV *Action:* -Positive allosteric modulator at GABA-A receptor --> acting to enhance frequency of channel opening in response to GABA *resulting in enhanced membrane hyperpolarization* *Clinical Use:* -Anxiety -*Status Epilepticus* -Generalized Epilepsies -*Short term-use* *Problems:* -High abuse potential *Problems:* -*psychomotor depression* -residual daytime sedation -tolerance to hypnotic effect -risk of dependence -depression of CNS on own and enhancement of other depressants -amnestic effects *Avoid:* In patients with *sleep apnea* -drugs decrease muscle tone in airways -CNS depressant depresses the part of the brain that senses apnea *Advantages:* -rapid onset -relatively high therapeutic index -low risk of drug interactions -fairly safe - minimal effects on CV or ANS function (except in presence of other depressants-ETOH) [safe outlook: unless combined with CNS depressants won't see coma and death *PK:* -Intermediate-acting (t1/2 = 6-20 hrs)

Triazolam

*Class:* Benzodiazepines *Controlled Substance:* C-IV *Banned in UK* *Action:* -Positive allosteric modulator at GABA-A receptor --> acting to enhance frequency of channel opening in response to GABA *resulting in enhanced membrane hyperpolarization* *Clinical Use:* -Insomnia *Problems:* -Shorter acting = greater withdrawal risk -dependence and abuse potential -*psychomotor depression* -residual daytime sedation -tolerance to hypnotic effect -risk of dependence -depression of CNS on own and enhancement of other depressants -amnestic effects *Avoid:* In patients with *sleep apnea* -drugs decrease muscle tone in airways -CNS depressant depresses the part of the brain that senses apnea *Advantages:* -rapid onset -relatively high therapeutic index -low risk of drug interactions -fairly safe - minimal effects on CV or ANS function (except in presence of other depressants-ETOH) [safe outlook: unless combined with CNS depressants won't see coma and death *PK:* -Short-acting (t1/2<6 hr)

Ampicillin Class? Mechanism? Indication? Selective Toxicity? Mechanisms of Resistance? Adverse Effects? Contraindication?

*Class:* Beta-lactam *Indication:* - G+: S. pneumonia, listeria, enterococci - G-: H. influenzea, E. coli, Salmonella, Proteus mirabilis *Adverse* -Colits --> can lead to superinfection with C. diff *Route:* oral, parenteral *PK:* good for gut infection, lower abs by gut *Note: skin rash may not be allergy related

Penicillin G Class? Mechanism? Indication? Selective Toxicity? Mechanisms of Resistance? Adverse Effects? Contraindication?

*Class:* Beta-lactam *Indication:* - G+: S. pneumonia (50% have resistance), bacillus anthracis (anthrax) - G-: Neisseria meningitides: meningococcus -Spirochete: treponema pallidum: syphillis *Route:* IV, parenteral

Piperacillin/Tazobactam Class? Mechanism? Indication? Selective Toxicity? Mechanisms of Resistance? Adverse Effects? Contraindication?

*Class:* Beta-lactam *Indication:* -G- bacteria: Psuedomonas spp. (these are naturally resistant to most penicillins) *Use with a beta-lactamase inhibitor* *Adverse:* - Can inhibit platelet aggregation (potentiates effects of anticoagulants) *Route:* parenteral

Penicillin V Class? Mechanism? Indication? Selective Toxicity? Mechanisms of Resistance? Adverse Effects? Contraindications?

*Class:* Beta-lactam *Mechanism:* inhibition of transpeptidase and subsequent weakening of cell wall *Indication:* - G+ bacteria: S. pneumonia (50% have resistance), S. pyogenes, anthrax *Route:* oral

Penicillin Family (general) Class? Mechanism? Indication? Selective Toxicity? Mechanisms of Resistance? Adverse Effects? Contraindications? Excretion?

*Class:* Beta-lactam *Structure:* Beta-lactam ring fused to five-membered thiazolidine ring and "R" group *Mechanism:* - inhibition of *transpeptidase* weakens cell wall *Drug Interactions:* -*Bacteriostatic antibiotics (chloramphenicol, macrolides, tetracyclines)* interfere with their activity because penicillins work best against actively growing bacteria *Indication:* many G+ bacteria, some G- *Adverse:* -allergy (skin rash in 10%) (anaphylaxis 0.2%) *Contraindiation: anyone with previous allergic reaction to any beta-lactam* -Diarrhea, nausea, vomiting (esp Amoxicillin/clavulanic acid) -Oral candiadiasis = common in prolonged therapy -colitis --> can lead to superinfection with C. diff [most common with Ampicillin or Amoxicillin] *PK:* *Distribution:*: -Renal levels generally high -Diffusion into CNS is low but is facilitated by inflammation of meninges, renal impairment, and high does over prolonged periods *Excretion:* -Primary = renal (except nafcillin--> primary excretion is hepatic)

Cephalosporin Family Class? Mechanism? Indication? Selective Toxicity? Mechanisms of Resistance? Adverse Effects? Contraindication? Excretion?

*Class:* Beta-lactam *Structure:* b-lactam ring fused to six-membered dihydrothiazine ring; *2 "R" groups* *Mechanism:* inhibition of transpeptidase and subsequent weakening of cell wall *Indication:* - later generations have wider spectrum of activity - many G+ and G- *Drug interactions:* -Increased toxicity with Nephrotoxic drugs (e.g. aminoglycosides) *Adverse Effects:* -10% of patients exhibit allergy (skin rash); 0.2% anaphylaxis -Cephalosporin antigen formation more variable than penicillins (no skin test) *CAUTION: previous allergic reaction to any b-lactam antibiotic* *GI:* Diarrhea, nausea, vomiting can occur with any b-lactam Oral candidiasis common in prolonged therapy Colitis - Broad spectrum oral cephalosporins can be severe *Superinfections: ~10% of patients on 3rd gen cephalosporins or IMIPENEM* *Cephalosporins may be directly toxic to renal tubular epithelium* *Excretion:* primarily renal EXCEPT ceftriaxone which is mostly hepatic *ADJUST DOSE IN RENAL INSUFFICIENCY* *Distribution:* CSF levels low (except cefotaxime and ceftriaxone); high in kidney *In general, subsequent generations have wider spectrum*

Cefazolin Class? Mechanism? Indication? Selective Toxicity? Mechanisms of Resistance? Adverse Effects? Contraindication?

*Class:* Beta-lactam *1st generation cephalosporin* *Indication:* - G+: staph and strep - G-: E. colis, proteus mirabilis

Cephalexin Class? Mechanism? Indication? Selective Toxicity? Mechanisms of Resistance? Adverse Effects? Contraindication?

*Class:* Beta-lactam - 1st generation cephalosporin *Indication:* same as cefazolin - G+: staph and strep - G-: E. colis, proteus mirabilis

Ceftriaxone (Rocephin) Class? Mechanism? Indication? Selective Toxicity? Mechanisms of Resistance? Adverse Effects? Contraindication?

*Class:* Beta-lactam - 3rd generation cephalosporin *Indication:* - G-: Enterobacter, Serratia, - *** gonorrhea*** - ***meningitis *** *Adverse Effects:* *Adverse:* *Superinfections: ~10% of patients on 3rd gen cephalosporins or IMIPENEM* Prolonged use ocauses biliary sludging (pain, nausea, vomiting) in up to 43%* *Distribution:* high CSF levels *Excretion:* primary = hepatic

Ceftazidime Class? Mechanism? Indication? Selective Toxicity? Mechanisms of Resistance? Adverse Effects? Contraindication?

*Class:* Beta-lactam - 3rd generation cephalosporin *Indication:* G- - commonly for Pseudomonas *Adverse:* *Superinfections: ~10% of patients on 3rd gen cephalosporins or IMIPENEM*

Cefotaxime Class? Mechanism? Indication? Selective Toxicity? Mechanisms of Resistance? Adverse Effects? Contraindication?

*Class:* Beta-lactam - 3rd generation cephalosporin *Indication:* severe infections similar to ceftriazone *Distribution:* high CSF levels *Adverse:* *Superinfections: ~10% of patients on 3rd gen cephalosporins or IMIPENEM*

Aztreonam Class? Mechanism? Indication? Selective Toxicity? Mechanisms of Resistance? Adverse Effects? Special Use?

*Class:* Beta-lactam *monobactam family* *Structure:* single ring beta-lactam *Indication:* *Gram negative aerobes only* (aerobic forms of Enterobacter, Pseudomonas) *OK for patients with penicillin allergy* --> doesn't have the chemical moiery that can form the haptan in the penicillin allergy *Resistance:* same as cephalosporin and penicillin families but imipenem is naturally resistant to most beta-lactamases *Adverse Effects:* well-tolerated *Special Use:* can be used for patients with penicillin allergy -

Nafcillin Class? Mechanism? Indication? Selective Toxicity? Mechanisms of Resistance? Adverse Effects? Contraindication?

*Class:* Beta-lactam *penicillinase-resistant* *Indication:* S. aureus: MSSA but not MRSA *Route:* parenteral

Amoxicillin Class? Mechanism? Indication? Selective Toxicity? Mechanisms of Resistance? Adverse Effects? Contraindication?

*Class:* Beta-lactam with broader spectrum than penicillin *Resistance:* -Resistance increasing; can try adding a beta-lactamase inhibitor *Indication:* - G+: S. pneumonia(50% have resistance), listeria, enterococci - G-: H. influenzea, E. coli, Salmonella, Proteus mirabilis *Adverse* -Amoxicillin/clavulanic acid:Diarrhea, nausea, vomiting -Colits --> can lead to superinfection with C. diff *Route:* oral *PK:* good gut absorption *better than Ampicillin* -don't want a drug that is absorbed well if you are treating a gut infection *Note: skin rash may not be allergy related

Imipenem/Cilastatin Class? Mechanism? Indication? Selective Toxicity? Mechanisms of Resistance? Adverse Effects? Contraindication? Excretion?

*Class:* Beta-lactam, *carbapenem family* *Structure:* different stereochemistry and "R" group position = broader spectrum *Mechanism:* - imipenem: inhibition of transpeptidase and subsequent weakening of cell wall *Co-administer with cilastatin (IV)*: prevents degradation by renal enzymes (CILASTATIN inhibits kidney dehydropeptidase- which if not inhibited will degrade imipenem) *Indication:* broad spectrum (G+, G-, anaerobes) - *LAST RESERVE TX for resistant strains* *Resistance:* same as cephalosporin and penicillin - *imipenem is naturally resistant to most beta-lactamases* *Adverse:* *Superinfections: ~10% of patients on 3rd gen cephalosporins or IMIPENEM*

Eszopiclone (Lunesta)

Zolpidem

*Class:* Non-benzodiazepines *Controlled Substance:* C-IV *Action:* - Allosteric agonist at GABAA receptor acting to enhance frequency of channel opening in response to GABA -Act as Benzodiazepines but don't have the benzodiazepine structure so they are *non* or *atypical* *Clinical Use:* *Onset not maintenance* *XR formulation: also maintenance* *Problems:* -Special alert regarding complex sleep behaviors such as driving car while not fully awake. "FDA recommends that the bedtime dose be lowered because new data show that blood levels in some patients may be high enough the morning after use to impair activities that require alertness, including driving." -Risk factors: Ingestion of other sedating drugs, Higher doses, History of parasomnia, Ingestion at times other than bedtime *Used as Date-Rape Drug* -Depression of CNS on own and enhancement of other depressants *Advantages:* -rapid onset -modest day-after pyschomotor depression -some amnestic effects -low risk of tolerance *PK:* -Longer half-life -Extended release formulation (XR)

Zaleplon

Differences between targeted therapies and classical chemotherapy

*Classical Chemotherapy* -Act on all rapidly dividing normal and cancerous cells -Identified because they kill cells -Cytotoxic (they kill cells) -Waste due to insufficient rx or excessive rx *Targeted Cancer Therapies:* -Act on specific molecular targets that are associated with cancer -Deliberately chosen or designed to interact with their target -Cytostatic (they block tumor cell proliferation) -Currently the focus of much anticancer drug development -Improved effectiveness when compared to some generic therapy

Synthetic Estrogens

*Ethinyl Estradiol* *Mestranol* *Diethylstibesrol*

Intermediate-acting insulin analog

*For basal insulin and overnight coverage* *Neutral protamine Hagedorn (NPH)* -Yields a stretched out insulin peak (see graph in above flashcard or on slide 13)

Treatment of severe malaria

*IV infusion of QUINIDINE GLUCONATE + DOXYCYCLINE or CLINDAMYCIN -IV for 24 hrs -Parasitemia is <1% switch to oral QUININE

Combination oral contraception - synthetic estrogen + progestin

*MANY FORMULATIONS* -Daily dose of estrogen + progestin for 21 days, then withdrawal for 7 days to permit "normal" menses. -Currently, a number of preparations are available in which two or three different doses of one or both components are taken over the 21 day period in an attempt to lower the total dose of hormone(s) given and further reduce incidence of side or adverse effects while still maintaining the contraceptive effect: these are the bi- or tri-phasic combinations *MECHANISM OF ACTION*: *ESTROGEN (either mestranol or, more often, ethinyl estradiol)*- inhibits ovulation *PROGESTIN (one of the synthetics)*- inhibits ovulation and produces effects in endometrium and cervix that prevent fertilization * Primarily responsible for combination contraceptive effect by:* -Suppressing LH and FSH levels -Eliminating the mid-cycle LH surge *INDICATIONS:* *Oral contraception*: Can be 99.9% effective and reversible if used perfectly *ADVERSE:* *ESTROGENS:* - Increased blood pressure (5-10% old style) - Increased risk of breast cancer (low) - *Increased risk of thromboembolic and other cardiovascular disorders, benign hepatoma, gall bladder disease* *PROGESTINS* -Hirsutism (abnormal growth of hair on a person's face and body)- because of androgenic activity of some synthetic progestins *Infrequent/minor effects:* headache [migraine], nausea, edema *NOTE:* -Still *RARE* -*All adverse effects greatly reduced in modern, low-estrogen preparations* *CONTRAINDICATIONS:* -Smoker, over the age of 35 (see potential risk factors flashcard) -*Cardiovascular:* thromboembolic disorders, cerebral vascular disease, myocardial infarction, coronary artery disease, hyperlipidemia -*Hormone-dependent neoplasia* (e.g., known or suspected breast, ovarian, or uterine cancer) -*Liver tumors or liver dysfunction* -*Pregnancy* - there is no reason to give birth control to a pregnant woman NOTE: *Diethylstilbestrol - DES*, an orally active synthetic nonsteroidal estrogen - was prescribed to prevent miscarriages but not effective *Increased risk of clear-cell vaginal and cervical adenocarcinoma after exposure of females to estrogens in utero* -Women who use OCs during early pregnancy have no increased risk for most types of major congenital malformations [But Maternal OC use during the first 3 months of pregnancy was associated with an increased odds ratio for 2 of 32 birth defects: hypoplastic left heart syndrome and gastroschisis] *ADVANTAGES:* -Reduced risk of endometrial and ovarian cancer (when estrogen is paired with progesterone) -Normalization of menstrual irregularities *DRUG-DRUG INTERACTIONS:* - Induction of hepatic enzymes (resulting in increased metabolism of estrogen) by barbiturates, rifampin, and phenytoin results in reduced efficacy of combination OC -Interference with enterohepatic recycling by ampicillin and tetracycline (antibiotics) results in reduced efficacy of combination OC (Risk = low; about 1%) *PK* *Route:* -Oral -Transdermal (Patches = higher systemic estrogen levels and higher risk of clot formation) *Metabolism:* -Estrogens in oral contraceptives (such as ethinyl estradiol and others) undergo enterohepatic recycling. Estrogens undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. Bacteria in the gut may be crucial in the reabsorption. This prolongs the action of the estrogen.

Estrogens -Estradiol, Estrone

*MECHANISM OF ACTION*: -Bind to estrogen receptors, complexes interact with DNA to impact gene transcription in multiple tissues *Estrogen receptors found on many tissues including vascular endothelium, heart, bone, liver, CNS* *ACTIONS:* -Female maturation -Stimulates growth of endometrium in first half of menstrual cycle -Modulates CNS activity -Increased HDL & decreased LDL -Positive effects on bone mass and density *PK:* *Route:* Not orally effective *Metabolism:* *-Strong first pass effect* -Hepatic metabolism *Half-life*: A few minutes

Teriparatide (Recombinant PTH (1-34))

*MECHANISM OF ACTION:* *Activates PTH receptors to acutely stimulate osteoblasts preferentially over osteoclasts, resulting in stimulation of new bone formation and an increase in bone mineral density.* *INDICATION:* -Severe postmenopausal osteoporosis -Severe osteoporosis in males *ADVERSE:* -Hypercalcemia (because there is also stimulation of the kidney effects of PTH) -Hypercalciuria -*Increased risk of osteosarcoma* *CONTRAINDICATIONS:* -Avoid use in patients with an increased risk of OS (Paget's disease, elevated serum alkaline phosphate, open epiphysis or prior radiation therapy of the skeleton) *PK:* *Route:* Subcutaneous injection pen daily; only works for 6 months ---> injection causes small peaks of [PTH] that activates osteoblasts and not osteoclasts to cause bone formation

Cinacalcet

*MECHANISM OF ACTION:* -*Activates the calcium-sensing receptor on the surface of the chief cell, subsequently decreasing the secretion of PTH* *INDICATION:* -Secondary hyperparathyroidism in patients with chronic kidney disease on dialysis -Hypercalcemia in patients with parathyroid carcinoma *ADVERSE:* -*hypocalcemia → QT prolongation and arrhythmia*, adynamic bone disease (a condition of profoundly decreased bone cell activity) -nausea *CONTRAINDICATIONS:* -hypocalcemia *PK:* *Route:* Oral

Calcitonin- Drug

*MECHANISM OF ACTION:* -*inhibits osteoclast function thus decreases bone resorption.* -Pharmacological doses of calcitonin, which inhibit bone resorption,*decrease tubular reabsorption to increase calcium and phosphate excretion.* *INDICATION:* -Postmenopausal osteoporosis in females >5 yrs postmenopause -Paget's disease -Hypercalcemia *ADVERSE:* -rhinitis (nasal spray formulation) -injection-site inflammatory reactions -hypocalcemia *CONTRAINDICATIONS:* -known hypersensitivity to salmon calcitonin (fish allergies) *PK:* *Route:* Nasal spray or subcutaneous/intramuscular injection

Glucagon (Drug)

*MECHANISM:* *-Reduces hypoglycemia by activating catabolic actions in the liver to increase blood glucose* (gluconeogensis) *-Activation of the glucagon receptor results in: -Increased glycogenolysis & gluconeogenesis -Decreased glycolysis and glycogenesis* -Glucagon also relaxes the smooth muscle of the GI tract. *INDICATION:* *-Patients with severe hypoglycemia secondary to excessive insulin treatment* -Glucagon administered through a parenteral route is also used as a *diagnostic aid for radiologic exam of the GI tract when decreased mobility is essential* *ADVERSE:* -Nausea and vomiting -Hypotension *CONTRAINDICATIONS:* -Pts with pheochromocytoma or insulinoma *-Hypoglycemia secondary to starvation, adrenal insufficiency or chronic hypoglycemia [levels of glucose stores in the liver may be depleted --> so there is nothing glucagon can do]* *PK:* *ROUTE:* -IV, IM, or subcutaneous injection [onset of action is 1-10minutes with a duration of effect ranging from 9-32 minutes] *Supplemental carbohydrates should be given at time of glucagon administration* --->exogenous glucagon causes an initial "hit" that increases blood glucose AND a secondary "hit" of insulin released from beta cells (glucagon is a huge stimulator of insulin release from beta cells)--> therefore carbs are needed to cover the secondary insulin surge

Sulfadiazone + Pyrimethamine (Daraprim)

*MECHANISM:* Targets folate pathway - DHPS & DHFR inhibitors; blocks production of THFA (tetrahdrofolic acid) *INDICATION:* Treat Toxoplasma gondii *Other clinical use: antimalatial and antibacterial *ADVERSE:* -allergies to sulfa - pyrimethamine toxicity (bone marrow suppression) --> avoid with folinic acid *Does not eliminate the encysted form *Depletes folates *Supplement with folinic acid (Leucovorin), which converts to THFA without DHFR *Don't want to do in a pregnant women *DO NOT USE BEFORE WEEK 18 OF GESTATION

Sodium Stibogluconate

*MECHANISM:* UNKNOWN: may interfere with unique trypanothione antioxidant system *RESISTANCE:* widespread *INDICATION:* Leishmaniasis (cutaneous or visceral) *ADVERSE:* well tolerated; pain at injection site *PK:* *Route: IV or IM injection

Pentamidine

*MECHANISM:* unknown *INDICATION:* - alternative tx for PCP (more adverse effects) - protozoans: Leishmaniasis, African trypanosomaisis: African "sleeping sickness" (T. brucei) --hemolymphatic stage *ADVERSE:* - *nephrotoxicity (25%)*: give with IV fluids (IV hydration) - *CV: fatal arrhythmias and heart failure* - *hypoglycemia* - hepatitis (less common) - inhaled form: cough, bronchospasm, headache common **MUST MONITOR PTS** -watch blood sugar, BUN, CBC, creatinine, EFG, blood pressure *DRUG INTERACTIONS:* - *Avoid other nephrotoxic drugs* *PK:* *Route: - IM injection or slow IV infusion -*inhalation (less toxic* - topical powder *Distribution: - bound to tissue; no CNS penetration (limited to fighting respiratory infections) *Excretion: extensive hepatic metabolism; renal excretion

tx for C. diff

*METRONIDAZOLE* *FIDAXOMICIN* (macrolide that targets RNA pol), *VANCOMYCIN*

Trazodone

*Most widely prescribed sleep aid in US* *Not FDA-approved for insomnia (use is "off-label")* *Few Randomized control trials* *Generally regarded as fairly safe drug but daytime sleepiness and motor/cognitive impairments have not been well studied* *Action:* -Serotonin reuptake inhibitor -Serotonin receptor antagonist -Alpha adrenergic receptor antagonist -Histamine receptor antagonist *Indication:* -depression -off-label: insomnia *Problems:* -Lack of randomized, controlled trials to assess efficacy for insomnia (particularly in patients without affective disorders and at lower doses) *EFFICACY UNKNOWN* -Tolerance to sedating effect -Daytime drowsiness -Discontinuation syndrome *Advantage:* -Lack of abuse potential -Shorter half-life than TCAs (less daytime sedation) -Less antimuscarinic activity than TCAs

Nicotinic Acid (Niacin)

*NOTE:* these drugs are often overlooked due to marketing strategies by Statins *CLASS:* Lipid Lowering Drugs *ACTION:* -Lipid lowering*-Reduces VLDL and LDL* -*No effect on synthesis of cholesterol or excretion of bile acids* *Blocks the synthesis of Triglycerides at DGAT2 and the secretion of the VLDL and ultimately LDL into the blood* [Not an inhibitor of cholesterol itself like the statins are] *The most effective agent available for raising HDL (15-40%)* -THE ONLY TRULY EFFECT AGENT AT RAISING HDL -Blocks HDL catabolism by blocking the receptor for bringing HDL into the hepatocyte *SUMMARY:* -Lowers TGs by 25-30% -Lowers LDL by 15 -40% (moderate; variable in different patients) -Raises HDL by 15-40% *INDICATION:* *-Reduces major coronary events* *-Possible reduction in total mortality from CVD* *ADVERSE:* -*Facial flushing* -*Dyspepsia (indigestion)* - limits compliance -pruritis (itching) -hyperglycemia -hyperuricemia -nausea, vomiting, diarrhea -*peptic ulcer* -myopathy -headache -*hepatotoxicity* -orthostatic HTN -impaired insulin sensitivity {Be careful if the person is diabetic; especially Type II diabetes} *CONTRAINDICATIONS:* -Liver disease (because of hepatotoxicity) -Severe gout -*peptic ulcer* *ADVANTAGES:* -Been around for a very long time; off patent -Cheap *PK:* -At 20 mg/day it acts as a vitamin B3 (Niacin) *-BUTat 1.5-6.0 grams/day; average dose 2 g/day (dyslipidemic)* *-Only the Nicotinic Acid form acts as lipid lowering, NOT niacinamide* -niacinamide is most of what is in enriched grains/vitamins *Absorption:* Near complete absorption - 30-60 min *T1/2:* short half-life ~ 60 min = frequent dosing (2-3x/day) *Rapidly absorbed and short half-life therefore it is typically given in slow release forms* -Until Statins were introduced, nicotinic acid was the only drug in the group to reduce incidence of recurrent MI and total mortality

"Riskier" combinations of lipid lowering agents

*Niacin + Fibrate (gemfibrozil)* -More effective than either drug alone, but may increase incidence of gall stones *Statin + fibric acid* -Certain fibrates inhibit glucuronidation of statins --> decreasestatin clearance, leading to increased plasma statin levels -Increased risk of myopathy *Statin + niacin* -Increased risk of myopathy

Loperamide

*Not Scheduled *OTC (Available without a prescription) Class: Opioids Indication: Treat diarrhea *Limited absorption and access to brain thus low abuse potential

Buspirone

*ONLY DRUG THAT IS USED SOLELY TO TREAT ANXIETY* *Action:* -Partial agonist at 5-HT1A receptors. -Also antagonist at D2 receptors *Does not bind GABA receptors* (like other meds) *Clinical Use:* -Treatment of generalized anxiety disorder *Problems:* -Delayed action thus not suitable for acute anxiety attacks. *Advantages:* -Lacks sedative, hypnotic, euphoric effects. -Lacks anticonvulsant and muscle relaxing effects. -Does not impair psychomotor performance. -Minimal abuse liability.

Tx of a pt with T2DM AIC > or = 9%

*Risk of glucose toxicity* Tx w/ insulin therapy +/- insulin sensitizer

Heroin

*Schedule I drug [Highly addictive; no clinical use] Mechanism: metabolized to morphine, very lipid soluble *Not more potent than morphine but faster: half-life = 3 min (morphine half-life = 2 hrs) *Produces sensations described as warmth, taste, high or intense pleasure *Followed by a period of sedation and tranquility *Lipid solubility and fast half-life are what contribute to it being so addictive

Buprenorphine

*Schedule III drug Mechanism: Partial agonist at mu opioid receptor; antagonist at kappa receptor; *Partial agonist at mu: Some activity --> still decreases cAMP (like in normal activation of the mu opioid receptor): Prevents withdrawal; but not activating the receptor to its full effect - not getting full euphoria like with a full agonist *Long duration of action due to slow dissociation Indication: Analgesic especially for difficult-to-treat pain (neuropathic, cancer); opioid dependence- as effective as methadone *Advantage: limited respiratory depression and constipation (because it is a partial agonist) Adverse: Resistant to naloxone reversal (due to slow dissociation from the receptor; not as much opportunity for nalaxone to slip in there as readily) *Concern about abuse potential, thus development of buprenorphine/naloxone (suboxone) combination: - With sublingual administration(buprenorphine =lipophilic), naloxone has negligible bioavailability -With IV injection, naloxone will precipitate opioid withdrawal in opioid dependent individuals *Makes sure the buprenorphine is being used as intended and discourage its use as an IV drug

Diphenoxylate

*Schedule V drug Class: Opioids Indication: Treat diarrhea; Not used for analgesia *Low solubility: limited use for parenteral injection *Combined with low-dose atropine to lessen risk of abuse -constipation effect of atropine = useful in treating diarrhea -adverse effects of atropine + low solubility (poor penetration of BBB)- discourages abuse of this drug

Commonalities of ALL Beta-lactams

*Selective Toxicity:* targeting of bacterial cell wall *Mechanisms of Resistance:* resistance to one usually confers resistance to the enitre class - alterations in PBP - beta-lactamase activity - decreased entry via mutated porin proteins - efflux pumps *Antagonism:* The following inactivate b-lactams: -Low (acidic) pH -Dextrose solutions -Aminoglycoside solutions: *Synergy or potentiation:* -Probenecid (gout) blocks renal excretion --> active b-lactam in blood longer *Adverse Effects:* remarkably well-tolerated -allergy (skin rash in 10%) (anaphylaxis 0.2%) *Contraindiation: anyone with previous allergic reaction to any beta-lactam* -Diarrhea, nausea, vomiting -renal tubule epithelium toxicity with cephalosporins -N/V/D common, especially with Augmentin -colitis --> can lead to superinfection with C. diff *Contraindication:* - anyone with previous allergic reaction to any beta-lactam - avoid giving with nephrotoxic drugs

"Safer" combinations of lipid lowering agents

*Statin + bile acid sequestrants for LDL-lowering* *Statin + cholesterol absorption inhibitor for LDL-lowering* [up to 60% reduction in LDL] *Niacin + resin * - *first choice against heterozygous familial hypercholesterolemia* - acid-neutralizing property of resin opposes GI upset of niacin

What drugs are contraindicated with MAO inhibitors (Phenelzine) to prevent serotonin syndrome

*Tricyclic Antidepressants* -Imipramine -Amitriptyline *SSRIs* -Fluoxetine *St John's Wort* *Meperidine*

Long-acting insulin analogs

*USED TO MIMIC BASAL INSULIN LEVELS* -Gives a long continuous level of plasma insulin *For basal insulin and overnight coverage* *Detemir* *Glargine*

Rapid-acting insulin analogs

*Used to mimic prandial insulin* *For meals or acute hyperglycemia* *Aspart* *Glulisine* *Lispro*

Short-acting insulin

*Used to mimic prandial insulin* *For meals or acute hyperglycemia* *Regular (R)*

Neomycin

*class:* Aminoglycosides *bacteriocidal*

Gentamicin

*class:* Aminoglycosides *bacteriocidal* *indication:* -G aerobes (Enterobacter, Proteus, Klebsiella, Pseudomonas aeruginosa)

Streptomycin

*class:* Aminoglycosides *bacteriocidal* *indication:* -Mycobacterium tuberculosis (part of drug cocktail)

Tobramycin

*class:* Aminoglycosides *bacteriocidal* *indication:* -G aerobes (Enterobacter, Proteus, Klebsiella, Pseudomonas aeruginosa)

Aminoglycosides (general) Gentamicin, Streptomycin, Neomycin, Tobramycin

*class:* Aminoglycosides *bacteriocidal* *mechanism:* "gunners" - bind to ribosomal protein; block translation initiation, cause miscoded proteins, block translocation [interfere with multiple points] -Entry into bacteria depends on porin that requires energy and O2 (do not use on anaerobic bacteria) *indication:* *Only effective against AEROBIC bacteria* [Porin pumps require ATP + O2Only] -G aerobes -*G+ aerobic when given with beta lactam* -Mycobacterium tuberculosis *adverse:* - *ototoxicity (dose-dependent):* vestibular - altered balance auditory - high range lost first - *renal toxicity (dose-dependent)* -Neuromuscular blockade (esp in MG) *contraindications:* - pregnancy: auditory damage to fetus (topical ok) - mild/mod infections --> used as empiric treatment for serious infections until pathogen is identified and safer, targeted antibiotic can be given *drug interactions:* - Beta lactam - compromises cell wall --> this is thought this helps the aminoglycoside get in because bacteria cell wall is damaged *don't mix in solution - would kill beta-lactam* *can co-administer to patient to get a synergistic effect* -ototoxic drugs (esp. with loop diuretics) - increased toxicity if given with aminoglycosides - *nephrotoxic drugs (esp cephalosporins)- cephalosporins may be directly toxic to renal tubular epithelium* - increased toxicity if given with aminoglycosides - Neuromuscular blockade agents (myasthenia gravis) - increased toxicity if given with aminoglycosides *PK:* *route:* NOT oral - IV - IM - topical forms *Distribution:* - low lipid solubility - specific pumps concentrate drug in renal tubule cells and hair cells of inner ear - entry into bacteria depends on porin which requires energy and O2 *elimination:* renal but is highly variable from patient to patient: - slower in neonates and elderly - CF/burn pts excrete faster *PK challenge* [The combination of a single route of excretion, high individual variability in excretion, and dose-dependent toxicity demands extreme care during administration]

Trimethoprim/Sulfamethaoxazole TMP-SMX

*class:* Anti-folates *mechanism:* bactericidal - synergistic effect by blocking 2 sequential steps in folate metabolism -*Synergistic antimicrobial effect: TMP and SMX bacteriostatic alone, but together can be bactericidal* - Minimizes development of drug resistance *selective toxicity:* *indication:* - recurrent UTIs - chronic bronchitis - sepsis, GI infections, B-lactam R ear infections *resistance:* minimized by combo therapy *indication:* *Recurrent UTIs, acute exacerbations of chronic bronchitis,* septicaemia,GI tract infections (Salmonella spp., Shigella), b-lactam resistant ear infections -Opportunistic infections in AIDS *adverse:* more pronounced in combo, esp. in elderly and AIDS -*Antifolates can produce megaloblastic anemia, leukopenia, granulocytopenia* --> *offset with suppl. folinic acid (LEUCOVORIN)* to restore folate -Nephrotoxicity - avoid in renal impaired *Drug-interactions:* - Other antifolates (methotrexate, pyrimethamine, trimetrexate) --> Potent additive antifolate activity in humans (don't want to deplete folates to the degree it is harmful) *PK:* *route:* oral but can be given IV *Distribution:* good including CSF and sputum *excretion:* renal

Trimethoprim

*class:* DHFR inhibitor *mechanism:* bacterioSTATIC - DHFR inhibition blocks conversion of DHF to THF (tetrahydrofolic acid) [therefore blocks the synthesis of purines and thymidine] *selective toxicity:* binds bacterial DHFR with a MUCH higher affinity than human DHFR *resistance:* increasing rapidly - reduced permeability - over expression of DHFR - mutated DHFR

ciprofloxacin (cipro)

*class:* Fluoroquinolones *mechanism:* *target topoisomerase and blocks replication* - *bacteriCIDAL* *selective toxicity:* -*Quinolones have a greater affinity for bacterial topoisomerases* *bacteria are actively growing (replicating and repairing DNA more than many quiescent human cells) and thus use their topoisomerases more active* *Indication:* -UTIs and GI tract infections caused by G- rods (Pseudomonas, enterotoxigenic E. coli "traveler's diarrhea") -Respiratory infections (currently as *alternative* treatments): Pneumonia, bronchitis caused by G- aerobes -Intracellular bacteria: Legionella pneumophila (*alt* to AZITHROMYCIN), Mycoplasma pneumoniae *indications for cipro only:* - Bacillus anthracis (G+) *as alt to PENICILLIN* *Used to be used for Neisseria gonorrhoeae- now use CEFTRIAXONE* *resistance:* - mutation of topo II or IV (mutants bind poorly to drug; mutants may grow more slowly) - multidrug efflux pumps: *AcrAB* multidrug efflux pump removes drug [overexpression of pump keeps drug levels low] - NO bacterial mediated chemical modifications of quinolones *adverse:* - GI: Anorexia, pain, nausea, vomiting most common (7- 20%) -*Heart: QTc-interval prolonged*--> arrhythmias, fainting - *CNS: peripheral neuropathy - risk of permanent nerve damage* Headache, dizziness, confusion, nervousness; Seizure risk increased by NSAIDs and theophylline (rare) -*Tendon damage, pain, or rupture possible* (age increases risk) -Exaggerated sunburn reaction *CONTRAINDICATED in children, pregnant/nursing women (FQs damage growing cartilage)* -exception: children with cystic fibrosis (benefits may outweigh risk) *drug- interactions:* 1. *antacids, milk and diet supplements because metals chelate quinolones and block adsorption* - take 2 hrs before or 2-6hrs after digestion of metals 2.Slows metabolism of *theophylline* (dimethylxanthine, ~caffeine), given for respiratory problems -Buildup of theophylline - nausea/vomit, CNS effects (tremors, agitation) 3. *Avoid in patients taking drugs prolonging QTc interval* because FQs do the same thing *PK:* -*concentrates in sputum and lung tissue* - good for lung infections -CNS penetration (about 10%)

levofloxacin (levaquin)

*class:* Fluoroquinolones *mechanism:* *target topoisomerase and blocks replication* - *bacteriCIDAL* *selective toxicity:* -*Quinolones have a greater affinity for bacterial topoisomerases* *bacteria are actively growing (replicating and repairing DNA more than many quiescent human cells) and thus use their topoisomerases more active* *Indication:* -UTIs and GI tract infections caused by G- rods (Pseudomonas, enterotoxigenic E. coli "traveler's diarrhea") -Respiratory infections (currently as *alternative* treatments): Pneumonia, bronchitis caused by G- aerobes, *Community-acquired pneumonia* -Intracellular bacteria: Legionella pneumophila (*alt* to AZITHROMYCIN), Mycoplasma pneumoniae *indications for levo only:* - S. pneumoniae (G+) with high-level penicillin resistance -Community-acquired pneumonia *indication:* - UTIs and GI tract infections caused by G- rods - pneumonia and bronchitis caused by G- aerobes - intracellular bacteria: legionella pneumophilia and mycoplasma pneumoniae *resistance:* - mutation of topo II or IV (mutants bind poorly to drug; mutants may grow more slowly) - multidrug efflux pumps: *AcrAB* multidrug efflux pump removes drug [overexpression of pump keeps drug levels low] - NO bacterial mediated chemical modifications of quinolones *adverse:* - GI: Anorexia, pain, nausea, vomiting most common (7- 20%) -*Heart: QTc-interval prolonged*--> arrhythmias, fainting - *CNS: peripheral neuropathy - risk of permanent nerve damage* Headache, dizziness, confusion, nervousness; Seizure risk increased by NSAIDs and theophylline (rare) -*Tendon damage, pain, or rupture possible* (age increases risk) -Exaggerated sunburn reaction *CONTRAINDICATED in children, pregnant/nursing women (FQs damage growing cartilage)* -exception: children with cystic fibrosis (benefits may outweigh risk) *drug- interactions:* 1. *antacids, milk and diet supplements because metals chelate quinolones and block adsorption* - take 2 hrs before or 2-6hrs after digestion of metals 2.Slows metabolism of *theophylline* (dimethylxanthine, ~caffeine), given for respiratory problems -Buildup of theophylline - nausea/vomit, CNS effects (tremors, agitation) 3. *Avoid in patients taking drugs prolonging QTc interval* because FQs do the same thing *PK:* *Distribution:* Excellent penetration of tissues and body fluids *Excretion:* renal

Fidaxomicin

*class:* Macrolide *bacteriostatic* *mechanism:* inhibits RNA polymerase **DIFFERENT than other macrolides that target translation** *indication:* *Clostridium difficile* *PK:* poorly absorbed, acts exclusively in the gut with little impact on normal flora

Clarithromycin

*class:* Macrolides *bacteriostatic* *indication:* - *Legionella pneumonia* (G-) - bronchitis - mycobacterium avium complex (AIDS) *drug interactions:* -Potent inhibitor of the cytochrome P450 system (CYP3A4) therefore interfere with metabolism of drugs by CYP3A4: - theophylline, anticoagulants --> increases the serum concentration of theophylline and anticoagulants - *rifabutin and rifampin decrease serum concentration of clarithromycin* *elimination:* Renal excretion eliminates 30% --> adjust dose in renal failure

Erythromycin

*class:* Macrolides *bacteriostatic* *indication:* - *Legionella pneumonia* (G-) - mycoplasma pneumonia -otitis media *adverse:* - *stimulates GI motility* --> GI intolerance may force switch of drug *sometimes used to clear bowel before surgery* - cholestatic jaundice (due to thickened bile/plugs) with erythromycin estolate -*do not administer with drugs that prolong QT interval* -Caution in patients taking antiarrhythmic drugs *contraindications:* - hepatic impairment *especially ERYTHROMYCIN ESTOLATE* [Estolate is often put onto erythromycin so the patient doesnt have to worry about food when they are taking the drug --> However there has been liver toxicity in pregnant women with this formulation] - in pts taking antiarrythmic drugs *drug interactions:* -Potent inhibitor of the cytochrome P450 system (CYP3A4) therefore interfere with metabolism of drugs by CYP3A4: -- theophylline, anticoagulants, digoxin (cardiac drug) --> increased concentration of DIGOXIN, THEOPHYLLINE and ANTICOAGs - antihistamines and FQs increase risk of arrhythmias *contraindications:* - in pts taking antiarrythmic drugs *PK:* *route:* oral of IV - food decreases absorption: 1 hr before or 2 hrs after meals *elimination:* LIVER (CYP3A4)

Azithromycin (zithromax)

*class:* Macrolides *bacteriostatic* *indication:* also is effective against G- - *H. influenzae pneumonia* (G-) - *Legionella pneumnia* (G-) - mycoplasma pneumonia - bronchitis - chlamydia and neisseria *adverse:* - can cause fatal irregular heart rhythm (prolongs QT) *drug interactions:* - antacids with Mg++ or Al+++: lowers serum peak concentration and impairs the effect of the drug - antihistamines and FQa increase risk of arrythmias *PK:* *route:* oral (double 1st dose, then once daily for 4 days) or IV - food decreases absorption: 1 hr before or 2 hrs after meals - *Concentrate in mØ and most tissues*

Macrolides (General): Azithromycin, Clarithromycin, Erythromycin, Fidaxomicin

*class:* Macrolides *bacteriostatic* *mechanism:* binds to 50S subunit and inhibits translocation - Accumulate in Gram-positive bacteria and in human mØ (Listeria) *selective toxicity:* ribosomes in bacteria and humans are different *indication:* G+ mostly and some G- *resistance:* occurs most often in S. pneumoniae, S. aureus, H. influenzae, and M. avium - "ribosomal protection" via Erm - efflux pump (Membrane pumps altered to favor removal of macrolide) - macrolide hydrolysis by bacterial esterases (modifies drug so it is not effective) - mutant 50S ribosomal protein (so drug no longer binds ribosome) *adverse:* -GI: Cramps, diarrhea, nausea, vomiting -Liver: Cholestatic jaundice (due to thickened bile/plugs) -Cardiotoxicity *contraindications:* - hepatic impairment *especially ERYTHROMYCIN ESTOLATE* (liver toxicity in pregnant women) *drug interactions:* see individual - *ALL are antagonized by chloramphenicol and clindamycin because of similar binding sites* *PK:* *route:* usually oral *Distribution:*: Concentrate in mØ and most tissues - esp. AZITHROMYCIN accumulate in G+ bacteria and Mphages - Excellent lung tissue penetration - CNS levels too low for therapy *Elimination:* Biliary excretion; slowed by liver damage

Polymyxin B & E

*class:* Polymyxin *mechanism:* disruption of membrane - cyclic polypeptid with long hydrophobic tail that acts like a detergent -interact and disrupt cell membranes *BacterialCIDAL* *selective toxicity:* NOT very selectively toxic --> potentially harmful to patient and is only used as a last resort *indication:* *drug resistant gram NEG bacteria* -*POLYMYXIN B*: eye, ear, topical use -*POLYMYXIN E*: ear (topical); also available in oral/IV form, but only as last resort (toxicity) *esp Acinetobacter or pseudomonas* CALLED THE "NUKE BOMB" *adverse:* not selectively toxic - *HIGH neuro and nephrotoxicity in oral and IV forms* - NOT SELECTIVELY TOXIC *PK* *route:* topical - oral and IV are available for polyE but is only used as a last resort due to toxicity *elimination:* renal, adjust dose in renal insufficiency

Sulfamethaoxazole

*class:* Sulfonamides *mechanism:* bacterioSTATIC - inhibition of folate acid synthesis through the *reversible inhibition of DHPS* (blocks the formation of dihydrofolic acid) - resembles PABA, an intermediate in folate acid synthesis *selective toxicity:* DHPS is not present in mammals (we obtain folate from our diet) *indication:* UTIs *adverse:* -*Hypersensitivity/allergic reactions - fever, rash, photosensitivity* - allergy in 1/3 (higher with G6PD deficiency (G6PD converts sulfa to sulfate, which does not form a hapten) - may precipitate in urine, drink lots of water *contraindications:* - avoid in PREGANT/NURSING and INFANTS because it can cause bilirubin displacement, jaundice - potentiates anticoagulants and hemolytic drugs (AVOID) *drug-interactions:* -potentiates toxic drugs, anticoagulants, hemolytic drugs *excretion:* renal *route:* oral (absorbable) *PK:* 6-12 hr half life

Doxycycline

*class:* Tetracyclines (old class of antibiotics) *bacteriostatic* *mechanism:* binds 30S subunit and blocks binding of aminoacyl tRNA -Pumped into bacteria (hint see resistance); high differential concentration *selective toxicity:* ribosomes are different *indication:* broad spectrum G+/- and other infections caused by: -Rickettsia (RMSF, typhus) *Doxycycline* - Vibrio cholerae *Doxycycline* - spirochetes (lyme dx and syphillis) *Doxycycline* - acne - anthrax- Bacillus anthracis (prophylaxis and treatment) - chlamydia - mycoplasma pneumoniae - some protozoal infections *resistance:* - mostly mediated by plasmid/transposon - efflux pump (most common) via tetA gene (antiporter pumps drug out) - ribosomal protection via tetM or tetQ (Bacterial protein binds ribosome and blocks binding of drug) - enzymatic inactivation of tetracyclines *adverse:* - *GI distress (in some cases GERD)* - *photosensitivity - esp. DOXYCYCLINE* - hepatotoxicity (dose-related reaction more likely in: more likely with pregnancy and renal impairment) - nephrotoxicity - superinfections: C.diff (colitis) and candida (mouth, bowl, vagina) - *SKELETAL: binds bones and teeth- AVOID IN CHILDREN* *contraindications:* - kids under 8 -pregnant/nursing mothers (Category D - can cause harm to fetus) - pts with liver impairment *drug interactions:* - Antacids (Al, Ca, Mg) - Sodium Bicarbonate - Fe salts (Normal meals and milk/dairy-Ca,Mg have little effect on drug) *PK:* *route:* oral - pumped into bacteria, generating a high differential concentration - highly lipid soluble *elimination:* LIVER; Unaffected by renal function ***convert to toxic forms over time so watch expiration date and dispose of unused medications ---> toxic forms can cause severe kidney damage, Fanconi syndrome***

Nitrofurantoin

*class:* UTI drugs *mechanism:* reductive metabolism by bacteria produces free radicals - bacteriCIDAL *selective toxicity:* we produce less free radicals during its metabolism and we have more effective antioxidant mechanisms *indication:* *uncomplicated LOWER UTI ONLY* - usually prophylaxis or alternative tx *resistance:* -Not useful against Enterobacter, Klebsiella, Proteus, Pseudomonas *adverse:* -Common: nausea, headache, gas -Rare: allergy, *pulmonary toxicity*, hepatotoxicity, neuropathy -Urine turns brown (harmless) *contraindications:* 1. pyelonephritis (upper UTI) or abscess because tissue levels are too low (FQs used intstead!) 2. not in babies < 1mo, OK in preg up to 38wks 3. Avoid in patients with significant renal impairment *drug interactions:* -antacids block absorption -probenecid/sulfinpyrazone block renal excretion of drug (defeats person- this is where the drug needs to go for a UTI) *excretion:* renal

Dapsone

*class:* antifolate, similar to sulfonamides *mechanism:* *antifolate similar to sulfonamides* - PABA analog --> inhibits DHPS *indication:* leprosy - daily therapy for 1 yr - use in combo with ***RIFAMPIN*** (cocktail therapy reduces development of resistance)

Vancomycin

*class:* lipoglycopeptide *mechanism:* inhibits bacterial cell wall synthesis - Binds to D-alanyl-D-alanine terminus of cell wall precursor (intercalates itself into the cell wall so the wall can't cross link) - bacteriCIDAL in dividing bacteria *indication:* G+ bacteria that are refractory to other antibiotics - *MRSA* - MRSE (multi-resistant Staphylococcus epidermidis) - Penicillin-resistant Strep. pneumoniae - Enterococci (but beware of VRE) *resistance:* -plasmid mediated - VanA: 7 genes that produce altered cell wall precursors (D-lactate instead --> so vanco can't bind) *adverse:* -*Rapid IV infusion may cause severe flushing - red man syndrome* (due to histamine release); slow infusion or give antihistamines -Allergies, skin rash/anaphylaxis (1%) *drug interactions:* *Additive toxicity with ototoxic or nephrotoxic drugs (e.g. aminoglycosides), or in renal impairment* *contraindications:* - G negatives because vanco cant cross OM -IM administration = very painful *PK:* *route:* IV, oral only for colitis - NO IM because it is painful *Distribution:*: good after IV (even CSF if meninges inflamed) - *poor oral absorption* (colitis only) *excretion:* renal

Chloramphenicol

*class:* protein synthesis inhibitor *bacteriostatic* *mechanism:* binds 50S subunit and blocks peptide bond formation *selective toxicity:* ribosomes are different *indication:* - brain abscesses: bacterioides fragilis and streptococci - meningitis: H. influenzae and Neisseria meningitidis - Rikettsia - salmonella typhi (typhoid fever) - bacterial conjunctivitis *resistance:* -plasmid encoded - CAT gene that acetylates drug so it cant bind ribosomes (chloramphenicol acetyl transferase) *adverse:* Strongly affects mitochondrial protein synthesis (quite toxic) - *Bone Marrow suppression*: ------>reversible; dose related (Serum concentrations >30 µg/ml) ------>Aplastic anemia (NOT dose related, Risk increased with repeated courses) - *Gray baby syndrome* ------>acute, dose-related ------>Newborns lack liver enzymes to metabolize drug --> Cardiovascular collapse due to overdose *Monitor drug levels; avoid accumulation* - *peripheral neuritis/optic neuritis* (Increased risk with long term therapy) *contraindications:* - pregnancy (unless its topical) - moderate infections that have safer alternatives *drug interactions:* - inhibits CYP450: blocks metabolism of many other drugs - Bone marrow depressants - potentiates BM depression - *antagonizes erythromycin and clindamycin (similar binding sites)* *PK:* -HIGH accumulation in CNS *Brain tissue levels may ultimately be up to 9-fold higher than serum levels; Good choice for CNS infections if other treatments fail* (not usually given as first line therapy) *elimination:* - liver metabolism (UDP glucuronyl transferase) - renal excretion: glomerular filtration

Clindamycin

*class:* protein synthesis inhibitor *bacteriostatic* *mechanism:* binds to 50S subunit and inhibits translocation -Passively enters bacteria, concentrate in mØ *selective toxicity:* ribosomes are different *indication:* - *ANAEROBIC G- bacilli: for septicemia and respiratory problems* - *AEROBIC G+ cocci:(if Penicillin resistant or patient allergy)* - some eukaryotes (fungi and protazoa) *adverse:* - diarrhea - *Antibiotic-associated colitis (stop drug; give metronidazole for the colitis)* *contraindications:* - C.diff (naturally resistant) = Do not use for colitis caused by Clostridium difficile - Avoid in patients with severe hepatic impairment *drug interactions:* - potentiates neuromuscular blockers - Blocks absorption of antidiarrheals; prolongs colitis - *antagonizes chloramphenicol and macrolides (similar binding sites on 50S)* *PK:* *route:* oral (unaffected by food) - passively enters bacteria and concentrates in macrophages - good distribution to many tissues *NOT IN CNS!* *elimination:* hepatic

Rifampin

*class:* rifamycins *mechanism:* inhibits DNA-dependent RNA polymerase and *blocks transcription* (can't make mRNA) *selective toxicity:* binds bacterial form with greater affinity *resistance:* - mutated drug target-> develops VERY fast; *avoid monotherapy* *adverse:* - hepatotoxicity in pts that already have liver problems -red/orange body fluids *indication:* inhibits many G+ and G- - TB (combo treatments) - leprosy (combo treatments) - prophylaxsis of meningococcal and H. influenzae meningitis *adverse:* well-tolerated -minor hepatotoxicity, usually in patients with prior liver problems *drug interactions:* - active metabolites formed in liver --> induces P450 enzymes in liver and increases metabolism of drugs processed by these enzymes *PK:* *route:* oral, have IV as alternative *distribution:* wide distribution- goes to CNS! (note: orange-red bodily fluids may result) --> tears and sweat (this is harmless) *excretion:* biliary and renal

Post-Coital ("Emergency") Contraception *PLAN-B = levonorgestrel* *PREVEN levonorgestrel + ethinyl estradiol*

*higher dose* but similiar to standard oral contraceptives *PLAN-B = levonorgestrel* *PREVEN levonorgestrel + ethinyl estradiol* *MECHANISM OF ACTION*: *Prevents ovulation, fertilization* - identical to oral contraception -In theory may also interfere with implantation (but no evidence to this) -Reduces risk of pregnancy by 50-90% - *NOT as effective as standard oral contraception* *INDICATIONS:* -Prevent pregnancy (prevents pregnancy only when taken before fertilization of the ovum has occurred) -Take within 72 hours of intercourse -Two doses 12 hours apart typical *ADVERSE:* - maybe worse than standard oral contraceptives because of the higher dose -Nausea (15-50%) -Vomiting (5-20%) -Abdominal pain, fatigue, headache, dizziness, breast tenderness also reported **Emergency contraception does not cause abortion.**

Isoniazid (INH)

*mechanism:* -Inhibits *mycolic acid (FA) synthesis*, a unique component of mycobacterial cell walls (efficient against all species of mycobacterium not just TB) -CIDAL for growing forms, STATIC for resting forms *selective toxicity:* - mycolic acid is a component of fungal cell wall (good selective toxicity) *resistance:* yes multiple loci can give rise to resistance *indication:* *Used alone for prophylaxis; in combo to treat TB* - tx for 24 mo *adverse:* - hepatotoxicity - peripheral neuritis: offset with pyridoxine (vit B6) - rash - hemolysis with G6PD - convulsions in pts with sz *PK:* *route:* readily absorbed orally or parenterally *distribution:* Enters cells, tissues & fluids (including CSF) *metabolism: liver acetylases, influenced by genetic polymorphism* *Rapid acetylators, t1/2 1 hr* *Slow acetylators, t1/2 2 hrs (show more pronounced adverse effects)* *excretion:* renal glomerular filtration

Metronidazole

*mechanism:* reductive metabolism in *ANAEROBES* produces free radicals that damages DNA and proteins and lipid (the anaerobic organisms process the bacteria to these damaging free radicals) *selective toxicity:* human cells don't process metronidazole in the same way as anaerobes (we don't generate a lot of free radicals and we have really good superoxide mechanisms in our cells (Ex: catalase) *indication:* *ANAEROBES* (bacterial, parasites, and fungi) - Clostridium difficile (antibiotic-associated colitis) - Bacteroides (B. fragilis, opportunistic infection of peritoneal cavity) -Helicobacter - as part of "triple therapy" including other antibiotics *RESISTANCE:* resistant strains of T. vaginalis and Giardia increasing, new med available *ADVERSE:* usually mild - headache, nausea, dry mouth, metal taste, GI distress -disulfiram effects - *avoid alcohol when taking metronidazole* -*Very rare = CNS effects; Caution with patients with active disease of the CNS* *Generally safe for children* *drug interactions:* - flushing, HA, GI with alcohol *PK:* *route:* - oral - IV - topical gel(T. vaginalis) *Metabolism:* liver *distribution:*good distribution even to CNS! *elimination:* renal; metabolites released in urine *(sometimes harmless red-brown)*

Dihydrotestosterone

-*Testosterone is transformed to dihydrotestosterone (DHT) in certain target tissues by 5 a-reductase* *Note:* DHT creates different complexes and regulates different sets of genes from testosterone *DHT* *External Genitalia* -Differentiation during gestation -Maturation during puberty -Adulthood prostatic disease *Hair Follicles:* -increased growth during puberty *Androgenic Effects:* increased body and facial hair acne scalp hair recession prostate enlargement

MPTP

-An illicit street chemist was synthesizing and selling a meperidine analog (MPPP) known as "China White" to heroin users. -If the reaction is conducted for too long or at too high of a temp, MPTP is formed. *MPTP* -Converted by MAO-B to toxic metabolite MPP+ [MAO-B found mostly in the brain] -MPP+ is taken up selectively by dopaminergic neurons and inhibits mitochondrial oxidation reactions producing oxidative stress -Causes irreversible selective destruction of nigrostriatal dopaminergic neurons -Produces PD-like state ("frozen addict" syndrome)- *Parkinson's Disease Iatrogenic Pathogenesis* -Prevent with selegiline/rasagilene - in theory

Atypical Antipsychotics

-Blocks dopamine receptors and also produce significant *blockade on serotonin (5-HT2) receptors* *Rarely associated with extrapyramidal side effects [less risk of tardive dyskinesia]* -Differing degrees of anticholinergic side effects - sedation, blurry vision, constipation, sedation *More effective at treating the negative symptoms of schizophrenia than typical antipsychotics* *Atypical antipsychotics = Clozapine*

Platinum analogs Common Mechanism of Action

-Exert cytotoxic effects in the same manner as alkylating agents. [alkylating-like agent] -Kill tumor cells in all stages of the cell cycle and *bind DNA through the formation of intrastrand and interstrand cross-links, leading to inhibition of DNA synthesis and function.* [cell cycle non-specific] -The primary binding site is the *N7 position of guanine*

Canagliflozin

-Fairly new drug *CLASS:* Sodium-Glucose Cotransporter 2 Inhibitors *MECHANISM:* -*Inhibit sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules* --->Reduce reabsorption of filtered glucose from the proximal tubular lumen --> *Increased urinary excretion of glucose, reducing plasma glucose concentrations* (causes polyuria) *NOTE: SGLT-2 normally reabsorbs 90% of filtered glucose in the S1 segment of the proximal renal tubule (SGLT-1 - the other 10%) *INDICATION:* -Adjunct to diet and exercise to improve glycemic control in T2DM. *ADVERSE:* -Yeast infection -UTI -Enhanced serum potassium *-Ketoacidosis* (serious, but rare) *WATCH FOR THIS* -Increased incidence of fractures *CONTRAINDICATIONS:* -Renal impairment *PK:* *ROUTE:* Oral 1x daily

Tx of a pt with T2DM AIC 7% to 9%

-Metformin + SGLT-2 inhibitor -Metformin + Incretins (obese) -Metformin + Secretagogue (non-obese)

Muscarine

-Mimics the effect of acetylcholine at cholinergic receptors on target tissues innervated by the ANS (mostly PNS, plus SNS innervation of sweat glands) -Muscarinic receptors are selectively activated by muscarine

Isoproterenol

-Synthetic Compound *Stimulates beta1 and beta2 receptors NOT alpha*

Acarbose

-Used infrequently (GI disturbances); know for boards *CLASS:* Alpha-glucosidase inhibitors (Inhibitors of carbohydrate absorption) *MECHANISM:* Controls hyperglycemia by *inhibiting alpha-glucosidase in the small intestine* --->This inhibition delays carbohydrate digestion and absorption to give rise to a *smaller spike in postprandial glucose with a smaller risk for hypoglycemia, lactic acidosis and/or significant weight gain* (don't get as large of a spike in glucose after carbohydrate administration) *INDICATION:* -Adjunct to diet and exercise to improve glycemic control in T2DM. *ADVERSE:* *-Gastrointestinal disturbances (flatulence,nausea, and diarrhea)* -low serum iron levels *CONTRAINDICATIONS:* -Diabetic ketoacidosis -Diseases of the colon (inflammatory bowel disease, colonic ulceration, partial intestinal obstruction or predisposal to intestinal obstruction) *-Chronic intestinal diseases associated with digestion or absorption disorders or conditions that may deteriorate with increased gas formation in the intestine* DON'T GIVE TO PATIENTS WITH PRE-EXISTING GI ISSUES -Breastfeeding *PK:* *ROUTE:*Oral; taken daily with first bite of mean

Classical Chemotherapy (5 groups to know)

1) Antimetabolites (S phase) 2) Alkylating and alkylating-like agents (cell cycle non-specific) 3) Cytotoxic antibiotics (cell cycle non-specific) 4) Microtubule inhibitors (M phase) 5) Topoisomerase inhibitors

Type of target therapy

1. Chemical inhibitors -signal transduction inhibitors -gene expression modulator -apoptosis inducer -angiogenesis inhibitor 2. Hormone therapies 3. Immunotherapies 4. Toxin delivery molecules 5. Gene therapy

What is the current recommendation for gonorrhea?

3rd generation cephalosporins *Cephtriaxone* -may soon join TB as a disease once cured that may be incurable -Gonorrhea has now been classified as a super bug according to CDC (Because of history to drug resistance -developed resistance to sulfa drugs then penicillin now fluoroquinolones) *New combo therapies: injectable GENTAMICIN + oral AZITHROMYCIN*

atypical antidepressants

A mixed group of agents that have actions at several different sites- mechanism not well understood *They are not more efficacious than TCAs or SSRIs, but their side effects are different* *heterocyclic antidepressant - bupropion* *heterocyclic antidepressant - mirtazapine* *Heterocyclic antidepressant / 5-HT antagonist- trazodone*

Typical Antipsychotics

Action is due primarily to *blockade of D2 receptors* Can have high or low potency *Presence of extrapyramidal side effects depends in potency* - high potency = frequent extrapyramidal side effects - low potency = extrapyramidal are relatively rare *Typical antipsychotics (low potency): Chlorpromazine* *Typical antipsychotics (high potency): Haloperidol*

E-Cigarettes

Advantages -Pure nicotine: avoid many carcinogens found in tobacco -Vaporize the nicotine: avoid second-hand smoke -Help break the smoking habit: still have physical sensation of smoking Disadvantages -Nicotine is addictive -Nicotine is toxic -Drinking the nicotine liquid could be fatal to a young child -No evidence that e-cigs are effective in smoking cessation -No FDA regulation -Not pure nicotine: what else is in each e-cig? -Most e-cigarettes are produced in China -How much nicotine is actually in each (vs how much is claimed)? -What levels of nicotine are harmful? -How safe is inhalation of pure nicotine? -Minors can purchase them (they come in many fruity flavors) -No advertising regulations -Marketing campaign may attract minors and result in increased nicotine use/abuse

bactericidal protein synthesis inhibitors

Aminoglycosides: gentamycin, streptomycin, neomycin and tobramycin (highly polar cations; All have 3 amino sugars)

Possible alternative treatement for Leshmania

Amphoterocin B Leshmania contain ergosterol in cell membrane

Beta lactamase inhibitors

Beta-lactamase inhibitors : -b-lactams with low antimicrobial activity, but potent inhibitors of b-lactamase *When used in combination with a more active b-lactam, the spectrum of the active drug is broadened* cavulanic acid tazobactam sublactam ***increases effectiveness by significantly lowering the MIC, increases spectrum, and decreases resistance ***

What is the first line therapy for T2DM?

Biguanides -Insulin sensitizers -Metformin

Combination Therapy Example

CHOP -Cyclophosphamide -Hydroxydaunorubicin -Oncovin (trade name for vincristine) -Prednisone (not required)

First line treatment for Malaria

Chloroquine (if no resistance) *If chloroquine-resistant: -Quinine and doxycycline *Substitute QUININE + CLINDAMYCIN in pregnant women

Epinephrine

Class: Adrenergic agonist Mechanism: agonist at alpha and beta receptors Indication: Anaphylaxis or cardiac arrest adjunct with local anesthetics (to produce vasoconstriction and decrease absorption) Adverse: Increased blood pressure and heart rate; pharmacokinetics (can't take orally) *Stimulates Alpha1&2 and Beta1&2 receptors*

Dopamine

Class: Adrenergic/Dopaminergic agonist Mechanism: agonist at adrenergic and dopaminergic receptors-give i.v.; dilation of blood vessels in kidney via D1 receptors -Also has direct alpha and beta receptor agonist properties and indirect sympathomimetic activity Indication: shock; may be useful in selected patients with CHF Adverse: expected adrenergic effects -Must be given IV infusion (monoamine and cateocholamine-broken down in liver)

Methyldopa

Class: Alpha2 agonist Mechanism: False neurotransmitter: methyl-DA serves as precursor forming methyl-NE which is an agonist at alpha2 receptors and acts presynaptically to decrease release Reduces output of vasoconstrictor adrenergic signals to SNS Indication: hypertension (especially during pregnancy) Adverse: rare but serious hepatotoxicity and hemolytic anemia *Used in pregnancy because of its effectiveness & safety for mother and fetus *Methyldopa has NO EFFECT on HR -Normally because of the baroreceptor reflex a drop in BP would cause an increase in HR due to the release of NE but methyldopa blocks the release of NE

Brimonidine

Class: Alpha2 agonist Mechanism: alpha2 receptor agonist Indication: glaucoma or ocular hypertension -Lowers intraocular pressure Adverse: sedation (especially in children); CNS depression

Clonidine

Class: Alpha2 agonist Mechanism: alpha2 receptor agonist - acts presynaptically (in CNS- brainstem) to decrease SNS activity to heart and blood vessels Indication: hypertension, neuropathic pain Adverse: withdrawal after prolonged use (hypertension, tachycardia, angina, or MI), hypotension, sedation, dry mouth

Meperidine

Class: Analgesics *Controlled Substance: Schedule II [Highly addictive; but has medical use] Mechanism: Mu agonist, some effects at delta and kappa; some inhibition of NE and serotonin transporters Indication: Analgesic (although use is declining);but often used during labor because, unlike morphine, meperidine does not reduce force of uterine contraction; also used during anesthesia because reduces post-anesthesia shivering *Metabolized to normeperidine which has significant antimuscarinic effects (thus dilates pupils rather than constricts) and is associated with seizures ==> different effects than normally seen with opoids Adverse: respiratory depression, constipation, potential for abuse, -Effects from metabolite: negative inotropic action on heart, antimuscarinic effects, tachycardia, potential to produce seizures, -Serotonin syndrome

Pentazocine

Class: Analgesics *Schedule IV drug Mechanism: agonist at kappa opioid receptor; antagonist at mu Indication: analgesia: especially moderate to severe pain; preoperative medication and supplement to analgesia Adverse: increased heart rate and blood pressure at high doses; dysphoria due to activity at kappa receptor; Chronic ingestion may produce dependence. *Advantage: Limited respiratory depression and constipation (antagonist at mu receptors) *Pentazocine/naloxone combination (Talacen) reduces misuse as injectable. -Naloxone = antagonist at mu, delta, kappa ; Blocks the effects of pentazocine if try to inject ---> Therefore decreases abuse potential -When taken orally, naloxone is inactivated by hepatic metabolism -Can get the effects of the oral administration of the drug and prevent the misuse of it as a IV drug

Codeine

Class: Analgesics **Controlled Substance: Schedule II [Highly addictive; but has medical use] *Cough Preparations: Schedule V (low dose of codeine) Mechanism: Prodrug of morphine (metabolized to morphine), agonist at mu opioid receptor, slight action at delta and kappa (similar to morphine) *LESS analgesia than morphine *MORE lipophilic than morphine Indication: Analgesia (mild-moderate pain, especially when combined with aspirin or acetaminophen), antitussive (poorly understood), antidiarrheal Adverse: Constipation (more than other opioids), Respiratory depression (rarely) -Poor, intermediate, extensive, and ultrarapid metabolizers -Caution with ultra metabolizers, renal failure (codeine is cleared renally), CYP inhibitors, pregnant/nursing women *See slide 52 for codeine cases *FDA issued an alert directing physicians who prescribe codeine-containing drugs to nursing women of the potential risks and signs of neonatal morphine overdose: Increased sleepiness, Difficulty breastfeeding or breathing, Decreased tone (slide 57)

Methadone

Class: Analgesics **Controlled Substance: Schedule II [Highly addictive; but has medical use] Mechanism: Mu agonist with long half life (24hr) *Racemic mixture which blocks NMDA receptors and monoaminergic reuptake transporters binds extravascularly and is slowly released back into plasma leading to this long half-life Indication: Analgesic especially for difficult-to-treat pain (neuropathic, cancer); treatment for opioid/heroin dependence Adverse: Respiratory depression, prolonged QT-based cardiac arrhythmias (rare) *May be involved in as many as one-third of all prescription opioid-related deaths -overestimate tolerance, ramp up too quickly -polysubstance abuse (combining with alcohol or benzodiapenes can cause CNS depression)

Morphine

Class: Analgesics *Controlled Substance: Schedule II [Highly addictive; but has medical use] Mecahnism: Mu agonist, with some effects at delta and kappa receptors *Hydrophilic thus slow onset of action Indication: Analgesia (4-6 hr pain relief), suppression of cough Adverse: nausea, vomiting, histamine release (may contribute to hypotension and pruritus), respiratory depression, constipation, potential for abuse *Use caution in patients with chronic kidney disease and neonates PK: First Pass Metabolism; Many routes of administration and formulations

Fentanyl

Class: Analgesics *Controlled Substance: Schedule II [Highly addictive; but has medical use] Mechanism: Mu agonist, some effects at delta and kappa receptors Indication: : analgesia: popular for postoperative or labor analgesia, chronic pain, anesthetic adjuvant Adverse: respiratory depression, constipation, potential for abuse (similar to morphine) *Advantage: very lipid soluble, easily passes through skin and mucous: fast onset of action, short duration. -Can be formulated as transdermal patch -Because lipid soluble - can get redistribution into fat and released later *Advantage: : Unlike morphine, no release of histamine; less vasodilation and orthostatic hypotension

Remifentanil

Class: Analgesics *Controlled Substance: Schedule II [Highly addictive; but has medical use] Mechanism: Mu agonist, some effects at delta and kappa receptors Indication: Moderate to severe analgesia, anesthesic adjuvant Adverse: respiratory depression, constipation, potential for abuse (similar to morphine) *Advantage: rapid onset (1-1.5 min after iv administration); short half-life (5 min) due to ester linkage and breakdown by plasma esterases

Hydromorphone (Dilaudid)

Class: Analgesics *Controlled Substance: Schedule II [Highly addictive; but has medical use] Mechanism: Mu agonist, some effects at delta and kappa receptors Indication: moderate-to-severe pain Adverse: respiratory depression, constipation, potential for abuse (similar to morphine) *Advantage: less histamine release and no opioid-active metabolites (preferred in patients with renal impairment or hemodynamic instability)

Tramadol

Class: Analgesics *Not scheduled Mechanism: orally active with many active metabolites: "weak" mu agonist, NE/5HT reuptake inhibitor, alpha adrenergic agonist Indication: mild-moderate pain, may modulate the emotional aspects of pain *Advantage: Low risk of respiratory depression, constipation, and abuse (because not very active at MORs) Adverse: -Association with seizures -Risk of serotonin syndrome when given with MAOI, SSRIs, TCA -Associated with increased risk of suicide

Ziconotide

Class: Analgesics Mechanism: Blocks N-type calcium channels, preventing neurotransmitter release [presynaptic terminal --> decreases NT release and vesicular mobilization] Indication: chronic severe pain refractory to other therapies Adverse: - Only given intrathecally -Psychosis, cognitive impairment, hallucinations, changes in mood or consciousness, nausea *Boxed warning: Severe psychiatric symptoms and neurological impairment have been reported.*

Oxycodone

Class: Analgesics; Codeine-like Compounds **Controlled Substance: Schedule II [Highly addictive; but has medical use] Mechanism: Mu agonist *Available in combination with acetaminophen (Percocet) and with ibuprofen *Available in extended release formulation which results in more drug/pill -Problem emerged with people grinding up tablets and injecting --> led to an increase in robberies and overdoses Indication: Mild to moderate pain Adverse: constipation, respiratory depression, potential for abuse (Increased risk of abuse with slow release form -oxycontin) -Developed non-crushable form of oxycontin

Hydrocodone

Class: Analgesics; Codeine-like Compounds *C-III: hydrocodone/acetaminophen Mechanism: Mu agonist; metabolized to hydromorphone via CYP2D6 *Used in combination with NSAIDs, antihistamines or acetaminophens {Until Feb 2014 hydrocodone was unavailable in its pure form in the US and was ALWAYS formulated with another drug} *In Feb 2014 FDA approved extended-release hydrocodone --> this removes acetaminophen from the hydrocodone preparation thus decreasing hepatotoxicity risk Indication: mild to moderate pain; also used as antitussive Adverse: Respiratory distress, constipation Adverse: constipation, respiratory depression, potential for abuse -For hydrocodone/acetaminophen there are concerns about hepatic toxicity due to acetaminophen

Dobutamine

Class: Beta1 agonist -but also acts at beta2 and alpha1 receptors -More inotropic than chronotropic effect-->resulting in increased contractility and CO Mechanism: agonist at beta1 receptors; must give i.v. Indication: cardiac failure especially acute emergencies; lab stress test Adverse: expected cardiac effects

Terbutaline

Class: Beta2 agonist Mechanism: agonist at beta2 receptors Indication: uterine relaxation to prevent premature labor, bronchodilation Adverse: tachycardia due to nonselective effects at cardiac beta1 receptors in mother and fetus; monitor maternal HR; tremor

Phenylephrine

Class: Decongestant Mechanism: Alpha1 adrenergic agonist Indication: nasal decongestion via vasoconstriction in nasal mucosa; hypotension, vascular failure in shock(IV); vasoconstrictor in regional anesthesia; mydriatic in ophthalmic procedures; symptomatic relief of eye redness; hemorrhoids Adverse: potential for systemic absorption leading to increased blood pressure and resulting bradycardia (baroreceptor reflex)

Ephedrine Pseudoephedrine (Sudafed) Medical

Class: Decongestant Mechanism: Indirect sympathomimetic (in periphery and CNS), direct alpha and beta effects (less at alpha) Indication: nasal decongestion(vasoconstriction relieves swelling in nasal mucosa) Adverse: with addition of MAO inhibitors, increased risk of hypertensive crisis - this displaces NE from vesicles (indirect sypathomimetic) and if you don't have MAO it can cause hypertensive crisis *Note: more sustained action than epinephrine because of resistance to both MAO and COMT (orally active)

Tyramine (in foods)

Class: Indirect sympathomimetic Adverse: can lead to a hypertensive crisis (the "wine and cheese effect") when foods high in tyramine are eaten by a person on a monoamine oxidase inhibitor due to an increase in NE release from vesicles, a decrease in its degradation by MAO, an increase in its release into the synapse, and an increase in receptor activation

Amphetamine (Adderall)

Class: Indirect sympathomimetic (also other actions) Mechanism: Indirect sympathomimetic leading to an increase in release of NE along with DA ("reward pathway" and addiction) Indication: attention deficit disorder and narcolepsy; also available for clinical use to suppress appetite but tolerance develops rapidly, potential for abuse, and adverse rxns can be life-threatening Adverse: abuse/addiction, hypertensive crisis, seizure, increased BP, cardiac arrhythmias, angina, stroke, increased risk of sudden cardiac death, psychosis, convulsions *Controlled Substance; Schedule II *One of the most potent ISA of CNS -10-30mg oral dose -safer, wakefulness, alertness, decreased sense of fatigue, elevation of mood, elation, euphoria, increased initiative, self-confidence, ability to concentrate BUT increases error, improvement in physical performance -Higher dose or prolonged use: depression and fatigue, palpitation, dizziness, vasomotor disturbance, agitation, confusion

Methamphetamine

Methylphenidate (Ritalin)

Class: Indirect sympathomimetic (similar to amphetamine) Mechanism: Indirect sympathomimetic leading to an increase in release of NE along with DA ("reward pathway" and addiction) Indication: attention deficit disorder and narcolepsy Adverse: hypertensive crisis, seizure, abuse potential

Cocaine

Class: Inhibition of norepinephrine transporter (also dopamine and serotonin transporter and also a local anesthetic) Mechanism: block reuptake of norepinephrine from synaptic cleft resulting in greater adrenergic receptor activation (also blocks voltage-gated Na+ channels) *Enhance NE signaling- concentration of NE stays in the synaptic cleft for longer [Does not affect NE already stored] Indication: Schedule 2 drug; drug of abuse; some special uses as a local anesthetic in surgery involving nasal mucosa or lacrimal ducts (highly vascularized areas - cocaine also binds alpha1 adrenergic receptor--> vasconstriction -->decreases bleeding and diffusion) Adverse: increase in blood pressure and heart rate leading to an increased risk for cardiac arrhythmias, myocardial infarction, and strokes (due to peripheral inhibition of NE); addictive potential due to increased DA

Metyrosine

Class: Inhibitor of catecholamine synthesis Mechanism: competitive inhibitor of tyrosine hydroxylase (rate limiting enzyme for synthesis of all catecholamines) *Depletes catecholamines everywhere Indication: Pheochromocytoma (tumor of adrenal gland resulting in catecholamine synthesis: mostly NE) Adverse: sedation, depression (crysalluria, GI upset)

Phenelzine

Class: MAO inhibitor Mechanism: inhibits MOA and breakdown of monoamines Indication: depression Adverse: MAO-I can cause acute life-threatening wine and cheese syndrome

Tranylcypromine

Class: MAO inhibitor Mechanism: inhibits MOA and breakdown of monoamines Indication: depression Adverse: MAO-I can cause acute life-threatening wine and cheese syndrome

Reserpine

Class: Monoamine-depleting agent Mechanism: specifically irreversibly inhibits vesicular monoamine transporter (VMAT1 peripheral and VMAT2 CNS) responsible for transporting monoamines (or their precursors) into the vesicle *Depletes stored NE Indication: Hypertension (peripheral and central mechanisms but rarely used because of adverse effects Adverse: Sedation,Severe depression(*suicide in susceptible individuals) as well as expected peripheral effects from decreasing NE (orthostatic hypotension; increased GI activity)

Pilocarpine

Class: Muscarinic agonist Mechanism: agonist at muscarinic receptors Indication: glaucoma, relief of dry mouth owing to hypofunction of salivary glands (Sjogren's syndrome, cancer radiotherapy) Adverse: PSNS effects such as bradycardia; even if used topically can be systemically absorbed to cause widespread PSNS effects and even CNS effects *SLUD Salivation Lacrimation Urination Defecation

Methacholine

Class: Muscarinic agonist Mechanism: agonist at muscarinic receptors Indication: provocative test for hyperreactive airways, rarely used due to cardiovascular and respiratory concerns (testing if the patient has asthma) Adverse: as expected; can cause bronchoconstriction; can cause heart problems- AV block; asthma, peptic ulcer (increases secretions in stomach), coronary insufficiency NEVER give IV or IM - acute respiratory distress/cardiac arrest/CV collapse

Bethanechol

Class: Muscarinic agonist Mechanism: agonist at muscarinic receptors Indication: urinary retention, GI stimulation Adverse: as expected Contraindications: Asthma, peptic ulcer, coronary insufficiency

Atropine

Class: Muscarinic antagonist Mechanism: antagonist at muscarinic receptors Indication: treatment of organophosphate poisoning, AChE poisoning, preoperation inhibition of salvation/secretions, pupillary dilation Adverse: antimuscarinic effects such as dry mouth, blurred vision, urinary retention, constipation, sedation, confusion

Scopolamine

Class: Muscarinic antagonist Mechanism: antagonist at muscarinic receptors, lipophilic so gets into brain (much more lipid soluble than atropine) Indication: motion sickness (transdermal administration) Adverse: potential antimuscarinic effects: dry mouth, blurred vision, sedation -confusion and psychosis at high doses

Ipratropium

Class: Muscarinic antagonist Mechanism: antagonist at muscarinic receptors: it's inhaled and charged so stays in lungs and isn't well absorbed systemically Indication: chronic obstructive pulmonary disease and occasionally for asthma Adverse: few (because its poorly absorbed from lungs);toxic doses may cause hypotension (ganglionic blockage) and muscle weakness (neuromuscular blockage)

Nevirapine (NVP)

Class: NNRTI Mechanism: noncompetitive inhibition of reverse transcriptase: not substrate analogues *Binds an allosteric site that impairs the activity of HIV RT Indication: HIV, combination therapy -lowers viral load, raises CD4s Selective Toxicity: target viral RT Mechanisms of Resistance: single mutation in RT confers resistance, can arise in a single dose, resistance to one = resistance to all; never give as monotherapy Adverse Effects: -Allergic rxn: potentially life-threatening rash <2% (Stevens-Johnson syndrome) -Hepatotoxicity esp. with prolonged treatment (elimination is hepatic via CYP) -GI effects- diarrhea nausea, pain are common Drug Interactions: increases metabolism of protease inhibitors[adjust dose of protease inhibitor]; rifampicin (TB drug) lowers NVP levels- DO NOT co-administer PK: -Absorption: oral F >90%; lower for other NNRTIs -Distribution: highly liphophilic drug- widely distriuted to tissues -Elimination: hepatic (induces cytochrome P450- a lot of other drugs act on this CYP- potential for drug i/as ;half-life of 25-30 hrs)

Zidovudine (AZT)

Class: NRTI Mechanism: compete with endogenous nucleosides for viral reverse transcriptase thus blocking their conversion from ssRNA to ss cDNA (function as *chain terminators) and blocking viral replication -looks like a nucleotide; inhibits RT Indication: HIV infection, combination therapy -suppression of HIV infection; elevate CD4 counts (helps to reduce opportunistic infection) -during pregnancy reduced HIV transmission to fetus Selective Toxicity: targets viral RT with greater affinity than human DNA polymerases Mechanisms of Resistance: mutations in reverse transcriptase, avoid monotherapy - HIV RT is an error-prone enzyme and viruses have short generation times Adverse Effects: Blood (granulocytopenia-up to 45%, anemia), CNS (headache, seizures, encephalopathy), GI (nausea,diarrhea), Whole body (muscle pain, weakness) Metabolic (lactic acidosis from mitochondrial damage, hepatotoxicity) Drug Interactions: activation prevented by ribavirin, many others PK: -Absorption: oral F 60-65%; IV infusion possible; azido group makes AZT lipophilic- diffuses across cell membranes and BBB -Distribution: CSF concentration about 60% of serum levels -Elimination: glomerular filtration, renal tubular secretion favor rapid elimination

Oseltamivir (Tamiflu)

Class: Neuraminidase inhibitor Mechanism: sialic acid analogues; inhibition of viral neuraminidase thus preventing viral release from host cell (Neuraminidase cleaves sialic acid to release virus from host cell) Indication: influenza A and B: must treat within 48 hrs of onset *reduces time of illness *active against amantadine/rimantadine-resistance influenza A Selective Toxicity: viral neuroaminidase Mechanisms of Resistance: mutations in neuroaminidase Adverse Effects: transient (1-2 days) mild moderate GI distress, minimized with food *Reports of potential delirium and suicidal ideation (rare but serious; goes away if patients stops medication) PK: -Absorption: Rapid oral absorption -Elimination: Primarily unchanged via kidney (decrease dose for children and patients with renal impairment)

Succinylcholine (AKA: suxamthonium or Sux)

Class: Neuromuscular blocker Mechanism: depolarizing blockade at nicotinic receptors -Remains at receptors and is not metabolized as quickly as ACh Indication: paralysis during surgery Advantage: Fast onset (1 min); Short duration (5-10 min) Adverse: muscle soreness, potential for hyperkalemia, malignant hyperthermia

Atomoxetine

Class: Norepinephrine transport inhibitors;selective inhibitor --> enhances NE levels Mechanism: block reuptake of norepinephrine from synaptic cleft resulting in greater adrenergic receptor activation Indication: Attention deficit disorder ADHD *NOT a controlled substance *NON-stimulant (isn't associated with agitation or sleeplessness) *No potential for addiction Adverse: Surprisingly little CV effect because in CNS it has a clonidine-like effect (acting on alpha2 receptors to prevent the sympathetic outflow) while potentiating NE effects centrally

Acyclovir

Class: Nucleoside analogues Mechanism: DNA polymerase inhibitor, chain termination *Acyclic guanosine nucleotide analogue -competitive inhibitors of nucleic acid polymerases -some serve as "suicide supbstrates" - chain terminators- no 3'OH present on drug molecule; therefore when it gets incorporated into DNA it ends DNA synthesis Indication: HSV and others (VZV, EBV) Selective Toxicity: activated (phosphorylated)only by the viral protein thymidine kinase *Acyclovir = a prodrug; needs to be acted on by a pathogen to be activated -Therefore acyclovir has little impact on uninfected cells because only virally infected cells contain thymidine kinase (TK) Mechanisms of Resistance: mutation in viral thymidine kinase or viral DNA polymerase Adverse Effects: generally well tolerated Nephrotoxicity with rapid, high IV dosing or patients with renal insufficiency Drug resistance: infrequent; mutation in viral TK or viral DNA pol Drug Interactions: nephrotoxic drugs-increased risk of renal damage, zidovudine- may cause severe lethargy PK: -Absorption: oral F (10-30%);IV; topical -Distribution: widely distributed in body fluids- including CSF -Elimination: glomerular filtration; renal tubular secretions t1/2=3 hrs

Ganciclovir

Class: Nucleoside analogues Mechanism: DNA polymerase inhibitor, chain terminator Indication: CMV (pneumonia or retinitis, typically in immunocompromised patients) Selective Toxicity: activated only by the viral protein thymidine kinase *Ganciclovir = a prodrug; needs to be acted on by a pathogen to be activated -Therefore ganciclovir has little impact on uninfected cells because only virally infected cells contain thymidine kinase (TK) Mechanisms of Resistance: mutation in viral thymidine kinase or viral DNA polymerase Adverse Effects: bone marrow suppression, nephrotoxicity *More toxic than acyclovir, but more potent against CMV Drug Interactions: nephrotoxic drugs- increased risk for renal damage PK: -Absorption: intravitreal (given right into eye), IV, oral F = low 6-9% -Distribution: same as acyclovir: widely distributed in body fluids- including CSF -Elimination: same as acyclovir: glomerular filtration; renal tubular secretions t1/2=3 hrs

Naltrexone

Class: Opioid Receptor Antagonists *Not Scheduled Mechanism: Mu, delta, kappa antagonist with long duration of action (10 hours) Indication: Acute opioid overdose, particularly respiratory depression; to decrease craving for alcohol in chronic alcoholics (may be due to effects on endogenous endorphin levels) *well-absorbed orally; long duration of action *

Naloxone

Class: Opioid Receptor Antagonists *Not Scheduled Mechanism: Mu, delta, kappa antagonist with short duration of action (1-2 hrs) Indication: Acute opioid overdose, particularly respiratory depression; formulated with buprenorphine and pentazocine to prevent abuse Adverse: -Watch for relapse with naloxone due to short duration of action -Much higher doses needed for buprenorphine reversal due to its slow dissociation -Can precipitate acute withdrawal syndrome *Given IV due to large first pass effect (not effective orally)* *Naloxone auto-injector (Evzio) recommended to be used by family or caregivers to treat person known or suspected to have had an opioid overdose

Sildenafil (Viagra)

Class: Phosphodiesterase inhibitor Mechanism: blocks a phosphodiesterase in the penis leading to increased cGMP, smooth muscle relaxation, vasodilation, and erection Indication: Erectile dysfunction Adverse effects: Potential for severe hypotension with nitrates

Botulinum Toxin (BOTOX)

Class: Toxin Mechanism: Destroys synaptic proteins involved in exocytosis of vesicles containing acetylcholine -Enters cholinergic nerve terminals and enters presynaptic vesicles and destroys various synaptic proteins that are involved in the exocytotic release of ACh--> decreases all release of ACh Indication: dystonias, cerebral palsy, spasm of ocular muscles, anal fissure, hyperhydrosis, reduction of wrinkles Adverse: potential systemic absorption and subsequent effects; not reversible

Imipramine

Class: Tricyclic Antidepressant Mechanism: block reuptake of norepinephrine and serotonin by blocking the transporters resulting in greater activation of adrenergic and serotonergic receptors Non-selective (NE,5-HT) uptake inhibitors Indication: Depression, eneuresis (bed wetting) in children Adverse: Tachycardia and arrhythmias, increased risk of sudden cardiac death, dry mouth and constipation if anti-muscarnic (non-selective effects)

Buproprion

Class: antidepressant Mechanism: not entirely clear but does (weakly) inhibit norepinephrine and dopamine transporters -->increases level of NE and DA in synaptic cleft Indication: depression; smoking cessation aid Adverse: delay in effect by a few weeks;lowered seizure threshold; potential for hypertensive crisis with MAOIs

Hexamethonium

Class: ganglionic blocker Mechanism: inhibition of ganglionic nicotinic acetylcholine receptor; paralysis of the entire autonomic nervous system Effects: generally increase in heart rate (unless anesthetized and then can see decrease - goes to pacemaker); decrease in blood pressure (hypotension), decreased perspiration; mydriasis(pupillary dilation), blurred vision(cycloplegia); decreased GI tone and motility; urinary retention; dry mouth Indication: mostly used to test med student's knowledge of blocking autonomic tone and baroreceptor reflex -used to be used clinically for treatment of hypertension; but now there are much better drugs so it is no longer used -dissecting aortic aneurysm and autonomic hyperreflexia, and to control hemorrhage in surgery Adverse: potentially a major headache for medical students

Mecamylamine

Darifenacin

Class: muscarinic antagonist Mechanism: M3 receptor-selective muscarinic antagonist Indication: overactive bladder -Proposed advantages over non-selective muscarinic antagonist used to treat OAB: lower incidence of constipation; less tendency to cause confustion Adverse: less antimuscarinic adverse but can still occur;most common side effect: dry mouth; constipation

Tolterodine

Class: muscarinic antagonist Mechanism: antagonist at muscarinic receptor; no apparent selectivity among receptors but does show some therapeutic selectivity Indication: overactive bladder Adverse: less antimuscarinic adverse but can still occur

Nicotine

Class: nicotinic agonist Mechanism: agonist at nicotinic receptors Indication: mostly used for non-therapeutic reasons in cigarettes Adverse: addiction, increased heart rate, increased blood pressure *Low doses of nicotine: stimulate reticular system (alerting) and dopamine release(addictive) *Higher doses of nicotine: seizures, loss of receptor specificity leading to muscarinic effects: bronchorrheae, excessive secretions, GI disturbance (including nausea and vomiting), neuromuscular blockade

Varenicline (Chantix)

Class: nicotinic partial agonist Mechanism: partial agonist at neuronal nicotinic receptor so provides submaximal activation (thus avoiding full-blown withdrawal) and blocks the full activation by nicotine -produces low to moderate release of dopamine at reward centers in brain, mimicking nicotine's effect and redcing withdrawal symptoms Withdrawal occurs when there is a decrease in receptor activation -blocks the binding of nicotine and therefore the positive reinforcement obtained through smoking Indication: smoking cessation aid Adverse: potential for mood changes and suicide ideation; nausea (30%), headache, abnormal dreams, constipation, vomiting

Tubocurarine

Class: non-depolarizing nicotinic blockade Mechanism: competitive antagonist at the nicotinic receptor at the neuromuscular junction *NON-depolarizing blockade Indication: induce paralysis during major surgical procedures Adverse: minor; falls in arterial pressure (non-selective effect)

Foscarnet

Class: non-nucleoside inhibitor Mechanism: inorganic pyrophosphate analogue (looks like a phosphate group); inhibition of viral DNA and RNA polymerases and HIV reverse transcriptase *Does not have to be activated by TK ; good to use if resistant to acyclic nucleosides Indication: CMV retinitis (especially if ganciclovir fails); HSV or VZV (if acyclovir fails) Selective Toxicity: targets viral polymerases Mechanisms of Resistance: mutation in targets Adverse Effects: nephrotoxicity, hypocalcemia---> CNS effects (headache, anxiety) Drug Interactions: nephrotoxic drugs *pentamidine increases hypocalcemia risk PK: -Administration: IV only -Elimination: renal

Ribavirin

Class: nucleoside inhibitor Mechanism: guanosine analogue inhibits IMPDH and thus synthesis of guanine nucleotides (blocks viral mRNA metabolism); may also inhibit viral RNA polymerase -IMPDH =inosine monophophate dehydrogenase; a purine metabolic enzyme *inhibition of IMPDH decreases GTP levels --> can't make viral RNA or DNA Indication: chronic hepatitis C- oral form used with interferon, RSV (respiratory syncytial viruses) in children-inhaled form Adverse Effects: hemolytic anemia (dose-related, reversible); teratogen- pregnancy category X (6 months required for "washout" after long-term treatment) Drug Interactions: prevents activation (phosphorylation) of zidovudine PK: -Absorption:oral, inhaled; widely distributed including CSF/brain; *concentrates in RBCs; up to 40 day half-life(*very long) -Elimination: hepatic metabolism; renal excretion

Indinavir (IDV)

Class: protease inhibitor Mechanism: inhibition of HIV protease -HIV protease is essential for the production of mature, infectious virus--> mediates post-translational processing of viral gene products Indication: HIV, combination therapy -lowers viral load; raises CD4s Selective Toxicity: targeting viral protease Mechanisms of Resistance: mutations in viral proteases; develops rapidly; use in combination therapies Adverse Effects: -Lipid metabolism: hyperlipidemia, fat redistribution (creating "buffalo hump"-truncal obesity) -Metabolic effects: hyperglycemia, -Renal effects: nephrolithiasis (kidney stones in 4%) Drug Interactions: other drugs metabolized by CYP3A4 may accumulate to dangerous levels; other drugs inducing CYP3A4 may increase metabolism of protease inhibitors PK: Absorption: oral F of 60-65%; impaired by high fat meal [dietary restrictions are given to patients given this drug] -Elimination: PIs metabolized primarily via CYP3A4, can inhibit CYP3A4; <20% excreted unchanged in the urine

Tx for cryptococcal meningitis

Flucytosine + amphotericin B

What do you prescribe to T2DM pts when oral hypoglycemic drug tx fails?

Insulin and/or Insulin analogs

*cephalosporins are generally NOT active against which*species? (x7)

MRSA enterococcus listeria legionella clostridium campylobacter acinetobacter

Common features of antimetabolites

Many drug names end in *"-bine", "-dine" or "-tine"* *Cell cycle S phase specific* *Common ADVERSE EFFECT for this class:* - Myelosuppression - Diarrhea - Mucusitis

Ephedrine Pseudoephedrine ("ephedra") NON-medical

Mechanism: beta 2 receptor agonist in skeletal muscle; increase force of contraction and rate of contraction in muscle Indication: dietary supplements for weight loss and strength training [Increases satiety-->decreased food intake] Adverse: More than 100 deaths since 1994; Increased BP and stroke; Cardiac arrhythmia and MI; CNS stimulation and seizures; CNS effects are thought to result from amphetamine-like action in the brain; Can't be used long term- tolerance occurs rapidly Similar adverse effect of amphetamines

LAST resport treatment for T brucei chronic stage

Melarsoprol (Mel B)

Tx of a pt with T2DM AIC < or = 7%

Metformin UNLESS PATIENT HAS *KIDNEY DYSFUNCTION*

Medical abortion

Mifepristone (RU-486) + misoprostol (Mifeprex) -20% of all abortions in the US are medical abortions

Suvorexant

NEW drug- April 2014 *Controlled Substance:* C-IV *Action:* *Orexin receptor antagonist* -->Orexin receptors in lateral hypothalamus and play a role in generating and maintaining wakefulness *Clinical Use:* -Insomnia (onset and maintenance) BUT don't have a huge effect *Problems:* -Potential for next day drowsiness -complex sleep behaviors *Potential Advantage:* -Not CNS depressant -does not seem to produce rebound insomnia

Drugs for UTIs (4x)

Nitrofurantoin Sulfonamides Trimethoprim Trimethoprim/sulfamethoxazole

Acetycholine

Order of observed effects with increasing doses of IV ACh: 1. At parasympathetic postganglionic terminals (M) 2. At selective sympathetic postganglionic terminals (M) - sweat glands 3. At ALL autonomic preganglionic terminals (ALL AUTONOMIC GANGLIA, N) 4. At the neuromuscular junction in skeletal muscle (N) 5. In the CNS (N and M)

Zosyn

Piperacillin/Tazobactam (beta lactamase INHIBITOR) *Route*: IV

Treatment to eradicate hypnozoites dormant in liver

Primaquine

Antifungal drug that is also used for UTIs and inhibits folate synthesis

TMP-SMX treats Pneumocystis jiroveci pneumonia

Norepinephrine

The principle sympathetic post-ganglionic NT everywhere EXCEPT: 1. Adrenal medulla - Epinephrine 2. Sweat glands - Acetylcholine 3. Renal vasodilator fibers- Dopamine -Produced endogenously like E *Stimulates Alpha and Beta1 receptors NOT Beta2*

Augmentin

amoxicillin + cavulanic acid (beta lactamase INHIBITOR) One of the most common combination therapies *Get: greater activity of the drug and minimizes resistance* *Route*: oral

beta lactams + aminoglycosides

b-lactams inactivated by aminoglycosides in solution ...BUT potentiate their effect in vivo beta lactam compromises cell wall and helps aminoglycoside get in ex:penicillin enhances uptake of streptomycin *don't mix in solution - would kill beta-lactam* *can co-administer to patient to get a synergistic effect*

STD tx for TB

isoniazid, rifampin, ethambutol, OR streptomycin + pryrazinamide

bacteriostatic protein synthesis inhibitors

tetracyclines chloramphenicol macrolides clindamycin (Structurally dissimilar classes; yet same general mechanism of action)

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