N115: Week 2:: CNS Pharmacology Objectives and Study Questions

Buspirone (Buspar): partial agonist 5HT1a also D2 activity) selective anxiolytic; not a benzodiazepine

Unique molecule that hits one seratonin receptor that is very responsive but take awhile to work. It has: - no sedation or euphoria (can drive!) - no abuse potential - no interaction with other CNS depressants - expensive, slow onset of anxiolytic activity (takes at least a week) - may have weak antidepressant activity --Note distinct from bupropion (Wellbutrin), which is 3rd gen antidepressant

8. What set of adverse effects does carbamazepine share with phenytoin? Name the three anticonvulsant drugs (classes) that are hepatic enzyme inducers.

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*Antimuscarinic (anticholinergic)drugs for PD MOA: block relative excess cholinergic function in basal ganglia.*

*- may be used in mild cases and during early stages,more effective for tremor and rigidity; less on bradykinesia --anticholinergics effective for younger patients with tremor-dominant PD and rigidity* 1. trihexyphenidyl (Artane) and benztropine (Cogentin), biperiden (Akineton) 2. diphenhydramine (Benadryl) an antihistamine

Alzheimer Disease (AD)

*Most common cause of dementia Pathophysiology: --atrophy of cortex; loss of cortical and subcortical neurons, especially cholinergic cells --senile plaques (made of beta-amyloid) and neurofibrillary tangles( made of toa) --tangles coordinate with memory loss --role of -amyloid --inflammatory response --oxidative injury & free radical formation Characteristics of AD- progressive memory loss Diagnosis of AD-lesion, definitive from autopsy

Explain how PD works for neurons

*TIP NOTE: Normally, signaling in the basal ganglia represents a balance between cholinergic and dopaminergic neurotransmission. So part of the parkinsonian symptoms that arise in PD may be related to both the loss of DA and the subsequent relative increase in cholinergic signaling.

Seizure: Brief episode of excessive synchronized electrical discharge Epilepsy: chronic pattern of seizures Partial Seizures: frequently follow brain injury simple or focal -consciousness not impaired in the beginning but may spread

- 60-70% patients seizure free with therapy - 2 or more seizures in a year will usually be treated - Single seizure typically not treated in absence of clearly identified pathology (30-70% recurrance) - Heterogenous in terms of cause: genetic, infective, traumatic, neoplastic, degen. - complex partial seizures -alteration in consciousness often arises in temporal lobe; may stare, swallow, fumble - both may progress

PD Treatment: surgery:: Deep brain stimulation (DBS) and Pallidotomy

- Deep brain stimulation (DBS) --targets include subthalamic nucleus, globus pallidus, thalamus --improves motor function and reduces motor fluctuations --reduces L-dopa dosing and dyskinesias --reversible- can turn off stimulator - Pallidotomy --unilateral destructive lesions of the globus pallidus --also effective in reducing L-dopa dosing --irreversible, with more potential complications --much less common option with success of DBS *Tip Note:Surgery is typically entertained for patients with poor response to medications, or prolonged exposure to PD meds at high doses leading to dyskinesias. What surgeries do is go into the basal ganglia itself and try to destroy some cells, or "jam" them with DBS. In general, surgical procedures can significant reduce PD symptoms, but not completely eradicate them. But most importantly. Such procedures can decrease the doses that are needed to treat patients, and that, in and of itself, is an important goal, particularly in regards to quality of life issues.

6. Discuss prevention approaches that may slow decline in AD patients.

- Dietary supplements --vitamin E, gingko biloba not consistently effective - Prevention --Exercise and Mediterranean Diet --epidemiology supports NSAIDs, statins, curcumin, hormone replacement therapy, fish oil** --existing clinical trials have not validated epidemiology

1. Describe 3 ways that the CNS adapts to prolonged drug exposure (Lehne). How will the opioid receptors change in a patient's brain when a receptor agonist such as morphine is given chronically? What happens when an antagonist (ex. antipsychotic) is given long term?

- Drugs have to cross the blood-brain barrier Capillaries in brain have tight junctions that only allow lipid soluble molecules to cross or molecules that are carried by transporter proteins - Therapeutic effects appear to arise from modulation of neurotransmitter function Communication between neurons - Brain adapts to chronic medication use Neurotransmitter function alterations can occur soon after introduced to specific drug, but clinical effects arise from how the brain adapts to chronic changes in neurotransmitter function - - Neurons adapt receptor expression to long term treatment. Agonists induce down-regulation, antagonists induce up regulation -If an antagonist is given long term it can increase mortality

Sedative-hypnotic drugs includes barbiturates, alcohols, chloral hydrate, new novel agents

- Increasing dose of most sedatives results in hypnotic effects - Benzodiazepines are most important sedative-hypnotics : --MOA: enhance inhibitory activity of GABA by binding to benzodiazepine site on receptor --original use: antianxiety --Also used as: -Anticonvulsants -sedation/anesthesia -hypnotic -muscle relaxation

5. What is the name and mechanism of action of memantine (Namenda)? AD Treatment: Memantine (Namenda):: MOA: Blocks N-methyl-D-aspartate (NMDA) receptor ion channels

- Inhibits calcium influx into neurons caused by excessive glutamate signaling --reduces "noise" in normal learning and memory processes --prevents neurotoxicity associated with excessive calcium influx - Symptomatic therapy for moderate to severe AD --synergistic effects when combined with AChE-I - Better tolerated than the AChE-Is --most common side effects include lightheadedness, confusion, and headache --dosing must be adjusted in patients with renal dysfunction *Tip Note: Schematic how how memantine blocks transmission from certain subtypes of glutamate receptors.

Propofol: MOA: promotes GABA release (Diprivan) IV anesthetic for induction and maintenance of general anesthesia. Popular for day surgery, critical care sedation for ventilated patients

- Onset similar to IV barbiturates (thiopental) but recovery and ambulation is faster. Antiemetic so less PONV Distribution half-life 2-8 min; elim T1/2 ~ 0.5-1hr. --Hypotension during induction; neg inotrope --*high risk of bacterial infection due to lipid medium *must be given IV because of - Abuse: not controlled but abused by OR staff -(controlled status in progress? -Not for 'high' but to produce short restful sleep (wrong) -escape, euphoria, calm, contentment; sleep is restful; "alluring" drug for abuse - After waking, patients are talkative and euphoric - animal studies show a big effect on reward centers light up

Partial seizures- focal epileptic discharges

- simple partial seizures: no alteration of consciousness - complex partial seizures: impaired consciousness, automatisms - can progress to generalized seizures --but for partial onset, EEG at start very different and drugs very different

Generalized seizures- involve both hemispheres

- tonic-clonic (grand mal): prolonged contractions of extensor muscles followed clonic jerking - absence (petit mal): brief, abrupt loss of consciousness; characterized by staring - myoclonic- sudden shock-like muscle contractions - atonic- sudden loss of muscle tone (helmets) *TIP NOTE: I think a key point that I want to emphasize that your textbook doesn't- the key difference is between partial-onset seizures and generalized-onset seizures. Even though they can end up looking the same, particularly the tonic-clonic seizures, the abnormal brain activity at the start is very different. And the drugs that work best for partial seizures are not the same as the ones that work best for primary generalized seizures. Atonic seizures- those are the kids that wear helmets all the time, because they can fall so unexpectedly.

Depression alternatives

--ECT(electroconvulsive therapy) remains rapid and effective treatment for severe acute depression 50-60% of those who do not respond to pharmacologic treatment will respond to ECT --Vagus Nerve Stimulation-developed for drug-resistant epilepsy, but effective after 12 months (no benefit after 10 weeks) for treatment-resistant (but $25K) --St. John's Wort: herb may be equal to TCAs in mild to moderate depression but many drug interactions (induces CYP and accelerates elimination by increasing p-glycoprotein synthesis; serotonin syndrome) --Transcranial magnetic stimulation (daily 40minx6wks) --Light therapy: for SAD (seasonal affective disorder) and nonseasonal major depression --Botox effective in about 10 studies since 2013

AD Treatment: Acetylcholinesterase inhibitors (AChE-Is)

--Increase cholinergic transmission by reducing ACh metabolism --Symptomatic therapy for mild to moderate AD -decrease rate of cognitive decline, but do not stop or reverse AD - possible utility in mild cognitive impairment and severe AD --Three drugs currently commercially available -donepezil (Aricept), galantamine, rivastigmine -patient responses can be idiosyncratic

Benzodiazepines Adverse Effects: by themselves are relatively safe drugs. (-lam or -pam drugs= benzodiazepines)

--relatively few; excessive or additive sedation with other CNS depressants - tolerance and cross tolerance with EtOH - abuse potential - long half lives so requires months of gradual dose reduction - additive effects with other sedatives -interactions: cimetidine may double the half-life of diazepam, barbiturates induce metabolic enzymes

Atypical Antipsychotic New Drugs

--resperidone (Risperdal); approved for autism spectrum disorder tantrums, aggression. also acute mania in BD. --quetiapine (Seroquel), aripiprazole (Abilify) -Used for psychosis, agression in AD; black box warning for all cause mortality

SNRI: Serotonin/ Norepinephrine reuptake inhibitors

--venlafaxine (Effexor) may be useful in refractory patients --duloxetine (Cymbalta) approved for GAD diabetic peripheral neuropathic pain, and other chronic pain including osteoarthritis

3. Describe the mechanism of action for levodopa and carbidopa. Describe the mechanism of action of the other dopaminergic drugs used in PD (overview slide).

-Levodopa: precursor of dopamine that gets converted to dopamine in the brain; MOA: increase dopamine in brain -Ex. Sinemet, Paropa, Atamet - Carbidopa: increases L-dopa delivery to brain to 10%; MOA: inhibits peripheral decarboxylase - Entacapone: increases plasma t (1/2) of L-dopa= increase availability; MOA: inhibit COMT (catechol-O-methyltransferase= enzymes that degrade catecholamines catecholestrogens, and various drugs and substances having a catechol structure) *Tip Note: There are a couple strategies for increasing l-dopa delivery to the brain, but decreasing peripheral conversion to DA and decreasing metabolism of L-dopa by the COMT enzymes, this also allowing for increased L-dopa delivery to the brain.

2. Drug therapy in Parkinson's disease may be directed at what two neurotransmitters? Which of these is most useful in mild or early disease?

-Main Neurotransmitters: dopamine and acetylcholine in striatum -Mild/Early Parkinson's Disease (PD): the dopamine neurotransmitter receptor because we are modulating the dopamine pathway Nigrostriatal. --Nigrostriatal Pathway: motor control, death of neurons in this pathway can result in PD.

Non-benzodiazepine hypnotic: Ramelteon: safe compared to other hypnotics

-Mechanism of action: Melatonin receptor agonist -Melatonin: hormone that regulates circadian rhythm in mammals. Low doses reset the clock, higher have direct hypnotic effects Ramelteon is Effective for sleep onset but not maintenance; available sustained and immediate release (SR and IR) ex. helps with jet leg Well tolerated: minimal somnolence, fatigue, dizziness compared to placebo. First pass drug-1.8% bioavailability! No abuse potential shown; not a controlled substance 8 studies show significant benefit for Melatonin (available as supplement) - Supplements not FDA- regulated; may have impurities or inaccurate dose.

PD Treatment: dopamine agonists (D2)

-Use as monotherapy in younger patients --lower risk of dyskinesias --may have neuroprotective effects -Also useful as adjunctive therapy with L-dopa -Ergot derivatives --bromocriptine, pergolide --older, less specific, more adverse effects -Non-ergot derivatives --pramipexole (Mirapex) compulsive behaviors!, ropinirole (Requip), apomorphine (Apokyn) --newer, more specific, better side effect profile --apomorphine administered SQ for acute symptom relief *TIP NOTE: We tend to use these in younger patients because it seems that most patients get the peak of their benefit from L-dopa over the first 3-5 years of treatment. Since the younger onset PD patients are likely to like longer, we often want to "save" this L-dopa effect to when they are older.

mood stabilizers: anticonvulsants and atypical antipsychotic, antidepressants

1) anticonvulsants: - valproic acid (Depakote)-may be first line with better side effect profile (2001 was used in 70% of bipolar patients). --preferred for acute mania --May work in refractory patients; dose can be increased more rapidly. --May be combined with lithium if monotherapy with either fails 2) atypical antipsychotics (olanzapine, resperidone) -severe mania or symptoms of psychosis 3) Antidepressants: may be necessary during depressive phase --always with mood stabilizer to avoid precipitation of mania --bupropion (Wellbutrin), venlafaxine (Effexor), and SSRIs preferred --tricyclics and newer agents may precipitate mania so bupropion often used ***Lehne: fish oil has been shown to have mood stabilizing properties

4. Describe early and late adverse effects of levodopa. What are some strategies for dealing with loss of effectiveness problems after 3-5 years of therapy? What drug may provide some preventative effects if used early?

ADVERSE EFFECTS: - Nausea/vomiting: seen early in treatment in as many as 80% of patients, resolves with continued therapy, common anti-emetics relatively contraindicated - Loss of effectiveness: wearing-off effect: end of dose deterioration, on-off effect: rapid fluctuation between no effect and increased mobility but with disabling dyskinesias - Dyskinesias: involuntary movements, treat with reduction in L-dopa dosing - Psychosis: visual hallucinations, paranoia, treat with clozapine, quetiapine - Postural hypotension: treat with fludrocortisone and/or midodrine Treatment Strategies: --increase total dosing or dose frequency --use sustained release formulations --supplement with other PD medications --drug holiday Preventative Drug: Common antiemetics like **Compazine or Phenergan** have dopamine blocking effects, which can counter act the whole point of trying to get more dopamine into the brain. *Tip Note: In general, patients with much prefer being "on" than "off," and the vast majority of them would prefer to be "on" with lots of dyskinesias and abnormal movements than to be "off" and frozen.

7. What are the 2 major mechanisms of action for anticonvulsants? Name the 3 major older generation drugs for partial and tonic-clonic seizures and their MOA. What cluster of symptoms is classified as cerebellar-vestibular symptoms? What other adverse effects may be associated with phenytoin? Which of these major drugs may be hepatotoxic?

AED mechanisms: 1. Ion channel blockade - Prolonged inactivation of sodium channels: - phenytoin, - carbamazepine, - lamotrigine - valproic acid - Blockade of voltage-gated calcium channels - valproic acid - ethosuximide 2. GABA potentiation: Enhancement of GABA-mediated inhibition - direct action on GABA receptor - benzodiazepiines - barbiturates - topiramate - indirect GABA effect decreased reuptake or metabolism, increased release: - gabapentin - pregabalin - tiagabine - vigabatrin 3 Older Generation Drugs 1.Phenytoin (Dilantin): --MOA: suppresses action potential through inactivation of sodium channels --USED FOR: partial and generalized tonic clonic seizures; general use (except absence), non sedative --Adverse effects: cerebellar-vestibular symptoms: nystagmus, ataxia, diplopia, vertigo, cardiac toxicity (arrhythmias, hypotension especially when given iv), gingival hyperplasia, hirsutism, small increase in dose may cause a large change in blood levels (due to saturation of metabolism) EX. of Blood level changes: at low blood levels 5-7 days to ready steady state after dosage change; at high blood levels may take 4-6 weeks before blood levels are stable 2. Carbamazepine (Tegretol) --MOA: inactivates sodium channels (same as dilantin) --USE: drug of choice for partial seizures and may be first for generalized tonic-clonic seizures, and trigeminal neuralgia (chronic pain), bipolar depression --Adverse Effects: --not sedative in usual dosage range --vertigo, ataxia, diplopia, and blurred vision (cerebellar-vestibular). --Small risk of serious bone marrow suppression --Water retention --Rash --Induction of hepatic enzymes: --reduced plasma levels of other --AEDs --in young patients may need to increase oral contraceptive dose. 3. Valproic Acid (Depakene, Depakote) --MOA: blocks sodium and calcium channels --Uses: can be used for all seizure types, Less effective than carbamazepine for partial-onset seizures, Also used for bipolar disorder --Complications: pancreatitis, rash, weight gain, hair loss, tremor and bone marrow suppression --Drug-drug interactions: hepatic enzyme inhibitor Can increase phenytoin and phenobarbital levels MOST HEPATOXIC DRUG IS: Valporic Acid (Depakene)** ---hepatotoxicity (can be fatal) --Careful monitoring of liver function when starting (most deaths within 4 mo) --Worse in combination with other AEDs and in young children S/S of Cerebellar-Vstibular: --vertigo, ataxia, diplopia, and blurred vision *happens with Carbamazepine (Tegretol)

9. What is the mechanism of action of antipsychotic drugs? What is the name of a new drug that often helps the patient population refractory to other drugs? Describe the extrapyramidal motor symptoms that are seen with conventional antipsychotics drugs. What is the name for the motor syndrome that may be permanent? Describe advantages of newer antipsychotic drugs.

Antipsychotic drugs MOA: drugs produce neuroleptic syndrome: psychomotor slowing, emotional quieting, dysphoria (feeling of misery). Therapeutic effect takes 10 days to 2 weeks. --Conventional: block DA receptors CLASS: Phenothiazines 1. chlorpromazine (Thorazine), thioridazine (Mellaril)low potency; low extrapyramidal effects 2. thiothixene (Navane) depot form; fluphenazine (Prolixin) depot form 3. prochlorperazine (Compazine) and promethazine (Phenergan)-non-psychiatric antiemetics --Atypical: moderate blockade of DA receptors with potent blockade of 5HT receptors Adverse effects: fewer extrapyramidal effects, but weight gain, sedation, antimuscarinic effects New drug for Refractory pop: Extrapyramidal Motor symptoms: 1. pseudoparkinsonism-may develop after 1 month; indistiguishable from PD; 2. dystonia-acute muscle spasms face and neck. benztropine (Cogentin) or diphenhydramine occurs hours or days --anticholinergics 3. akathisia-motor restlessness; dec. dose, --benzo, B-blocker, anticholinergics 4. tardive dyskinesia-facial dyskinesia; follows months to years. May be permanent; prevention Motor Syndrome that may be permanent= tardive dyskinesia-facial dyskinesia; Advantages of newer antipsychotic drugs: effective for positive and negative S/S; are preferred to conventional drugs --clozapine (Clozaril) original one; useful in refractory patients. blocks DA4 but also 5HT2, alpha1 and H1.

8. Name three drugs that may be used to treat ADHD in children. List the mechansim of action and major adverse effects of amphetamines? Explain the apparent paradox of why stimulants are helpful in ADHD? What is the MOA for the newly approved drug for ADHD atomoxetine (Strattera)? What is the reason for the recent black box warning?

CLASS: Amphetamines: increase norepinephrine, catecholines, dopamine Treat ADHD(Attention deficit hyperactivity disorder) 1. amphetamine: racemic mixture (Adderall) 2. methylphenidate (Ritalin) 3. dexmethylphenidate (Focalin) Amphetamines MOA: blocks re-uptake and cause release of catecholamines; increase alertness, reduce fatigue, improve task performance, reduce negative behavior Adverse Effects: -insomnia (decrease pm dose) -anorexia -growth suppression (give during/after meals) -cardiac stimulant -↑ HR, BP, force of contraction, arrythmias -primarily concern for adults/black box - Tolerance might have to give higher dose because our body metabolizes it quickly -drug holidays for children: doesn't really help with the drug tolerance - physical dependence/ addiction potential (all stimulants are Schedule II) -psychosis in overdose Stimulants are helpful in ADHD pts because: probably stimulates diffuse thalamic system and improves ability to sustain attention. --Decreased blood flow and energy utilization in prefrontal cortex and basal ganglia --amph seem to increase activity in these area of ADHD brain Atomoxetine (Strattera) MOA: NE re-uptake inhibitor; effects take at least a week Recent BBW: GI, suicidal thinking in children; weight loss and growth suppression

7. To what class of drugs do coffee and chocolate belong? What is the mechanism of action of these drugs? Name a bronchodilator that belongs here and major adverse effects.

CNS Stimulants= coffee, chocolate MOA: probably antagonist at adenosine receptors. nonspecific stimulants. *Central effect increased alertness; peripheral: vasoconstriction of cerebral blood vessels, cardiac stimulation, diuresis* Bronchodilator: theophylline, theobromine Adverse Effects --withdrawal-headaches --excess stim (cardiac and CNS) (gittery and tachy) --GI irritation

10. List the MOA for the following drugs of abuse: cocaine, amphetamine, MDMA, GHB, Ketamine, LSD, cannabinoids. What are the advantages of ketamine for pediatric procedural anesthesia?

Cocaine MOA: block reuptake of DA, NE, 5HT; also local anesthetic action, vasoconstriction Amphetmine MOA: block catecholamine uptake and causes release t1/2: 10h MDMA-methylenedioxy-derivatives of methamphetamine. (ecstasy) MOA: binds to 5HT transporter and causes profound release of 5HT GHB-gamma hydroxy butyrate MOA: not completely clear but thought to inhibit central DA release; may mediate some effects through GABA receptor Ketamine (Special K) MOA: NMDA antagonist: dissociative anesthetic (catatonia, amnesia and analgesia without actual loss of consciousness) unpleasant dreams and hallucination LSD MOA: Acts at multiple sites in brain and spinal cord, probably through 5HT2 receptors Cannabinoids MOA: Active ingredient is THC. Acts through THC receptor which is widespread in brain and causes release of DA in reward circuit (like cocaine and opioids). Advantages of Ketamine for Pediatric procedural anesthesia: useful for pediatric procedures outside OR (like ED) note: 2011 guidelines say adults and babies too --no anesthesiologist required --may be useful for depression, pain

EDUCATION on ADHD medication therapy Controversy to help parents feel confident in administering these drugs to their chiildren

Controversy: Large NIMH trial (1998) Ritalin works well enough to erase diagnosis for 82-85% of children. (Suggested higher doses for many) Underestimation of ADHD? Other studies show only half of children with ADHD are treated Increased support for appropriate medication; long record of safety and efficacy

5. What is the mechanism of action of donepezil (Aricept) treatment for Alzheimer's disease (AD)? What are the main adverse effects? What is the name and mechanism of action of memantine (Namenda)?

Donepezil (Aricept) MOA: increase cholinergic transmission by reducing ACh (neuotransmitters to other signals sending info) metabolism --decrease rate of cognitive decline (modestly effective) cannot reverse AD. --Common side effects include nausea/vomiting, diarrhea, bradycardia, lightheadedness, insomnia, vivid dreams --side effects may be reduced by using q day or patch formulations *TIP NOTE: This is a mechanistic view of how it works. Now it focuses on neostigmine a different AChE-I that is not used for AD, but a similar concept- i.e. that the drug can block off the metabolizing enzyme, thus allowing for more signaling through various ACh receptors.

Benzodiazepine-like drugs: 'Z 'drugs: more selective bc only bind to BZ1, for rapid absorption= short half-life,

Ex. Zaleplon (Sonata)- useful in elderly and for falling asleep but not maintaining sleep; also can be taken @ 3am Ex. Zolpidem (Ambien) binds BZ1 selectively with minimal muscle relaxing and effects: Approval restricted to short term (few weeks) but many have taken long term with no apparent tolerance or increase in adverse effects; Drowsiness, complex sleep behaviors (driving, cooking, sex) Ex.Exzopiclone (Lunesta): not restricted to short-term use (based on a 6 mo study); Limited data and comparison studies --Adverse effects: unpleasant taste, HA, complex sleep behaviors; rebound insomnia if D/C

5. What factors are considered in selection of an antidepressant agent? Most available agents are equally effective for depression but differ from each other in what way? Name three other clinical uses for antidepressants.

Factors to Consider prior antidepressant selection: Difference between types of agents: 3 clinical uses for antidepressants: 1. Panic disorder 2. enuresis 3. fibromyalgia

Anxiety disorders: Uncontrolled worrying lasting 6 mo or longer; S/S= Vigilance, tension, apprehension, poor concentration, difficulty falling or staying asleep Distinct from situational anxiety (normal response to stressful situation)

First line: benzodiazepines -Buspirone -Four antidepressants (venlafaxine, paroxetine, escitalopram, duloxetine) -Buspirone and antidepressants preferred for long term

4. What is the mechanism of action for Monamine Oxidase (MAO) inhibitors? What food/drug interactions can occur with these drugs?

Inhibitors MOA: inhibit enzyme that degrades catecholamines and serotonin in nerve terminals Adverse Effects: --CNS stimulation (anxiety insomnia etc) may induce mania --orthostatic hypotention Food/Drug Interactions: ***cause hypertensive crisis --foods high in tyramine (cheese, aged meat like salami, pepperoni, Chianti wine, yeast extract marmite) --patients must be able to follow strict diet --sympathomimetic amines (levodopa) or other antidepressants may cause hypertensive crisis

1. What is the usual time lag for antidepressant therapeutic effects? What is the mechanism of action for tricyclic antidepressants? Name the prototype, and the most common adverse effects. Can tolerance develop for adverse effects? Why must suicide risk be considered when patients are treated with antidepressant drugs?

Lag Time Effects: Tricyclic antidepressants MOA: block reuptake of norepinephrine and serotonin at H1, Ach, 5HT2a, alpha NE receptors, plus NE and 5Ht uptake (6 targets!) Prototype: Amitriptyline (Elavil) Adverse Effects: --sedation, CV effects (tachycardia, orthostatic hypotension), antimuscarinic effects, weight gain. Increased risk of seizures and mania, highly bound to plasma proteins and lipophilic so long t1/2 --At high concentrations Na channel effects-->fatal arrhythmias Tolerance_____ develop for adverse effects suicide risk must be considered with pts treated with antidepressants because it is a psychotic drug and can alter the

Dogs and chocolate (Lehne p.422): Caffeine and theobromine in chocolate metabolized slowly by dogs (t1/2 17 h compared to 2 h for humans) --Can be fatal (seizures, coma, dysrhythmias, resp failure) but this is rare

Lethal dose for 10# dog: --9oz milk chocolate (3 candy bars) --3 oz bittersweet chocolate --Only 1 oz of unsweetened baker's chocolate --Keep brownies away

6. Describe the time lag for effectiveness with Lithium therapy. Why must blood levels be monitored carefully? Discuss compliance issues, adverse effects and alternative therapy.

Lithium: MOA not known. Use had decreased; suicide risk has been shown to be 2.7 times less likely with Lithium. time lag: 1-3 weeks 1. time lag for effectiveness- antipsychotic or sedative benzodiazepine (lorazepam or clonazepam) may be used Dec 2006 Atypical antipsychotics are usually first line for acute mania 2. narrow therapeutic window 3. Compliance- monitoring blood levels is critical. Short half-life so need 2-4x daily dosing; one or more episodes/year are candidates for maintenance therapy --Lithium is also an effective adjunct in unipolar depression when monotherapy ineffective Adverse Effects: Lithium toxicity:**affected by Na level, dehydration may cause lithium retention and toxicity (diuretics, diarrhea) --Mild (<1.5mEq/L; therapeutic is 0.6-1.2 mEq/L) : N/V, diarrhea, anorexia (transient) Polyuria in 50-70%thirst; need to hydrate slurred speech, hand tremor may occur at therapeutic levels --Moderate Toxicity (1.5-2 mEq/L): persistent GI upset, confusion, ECG changes, sedation, incoordination --Severe (above 2 mEq/L): ataxia, giddiness, seizures, stupor, coma, death

PD Treatment: other drugs: MAO-B inhibitors and Amantadine (Symmetrel)

MAO-B inhibitors -EX. selegiline (Eldepryl), rasagiline (Azilect) - inhibit dopamine metabolism, prolong L-dopa effects - may have neuroprotective effects, so should be administered early in disease course -Amantadine (Symmetrel) --MOA:stimulates dopamine release, blocks dopamine re- uptake, blocks cholinergic and glutaminergic receptors - most useful for dyskinesias - effects typically short-lived - significant adverse effects: --insomnia, agitation, irritability, --hallucinations, restlessness

8. What is the MOA of phenobarbital? What is the drug of choice for absence seizures?

MOA: Potentiates GABA signaling through direct receptor binding Primidone is metabolized into phenobarbital Effective for generalized tonic-clonic and partial seizures, but now used primarily in children (absence seizures/petit mal seizures)**

9. Which new generation antiepileptic has a GABA mechanism and is also useful as a spasmolytic and pain adjunct? Which of the newer generation drugs have potential as monotherapy? What advantages/disadvantages are associated with the use of newer antiepileptic agents?

Newer AEDs: Topiramate (Topamax) --MOA: Blocks sodium and calcium channels. Also potentiates GABA and blocks glutamate receptors --Broad spectrum effectiveness --partial and generalized seizures, in children and adults --can be used as monotherapy --also used for migraine prophylaxis --Advantages - Effective for broader spectrum of seizure types - Typically fewer and less severe adverse effects and drug-drug interactions - Periodic blood and hepatic monitoring usually unnecessary - Potentially safer in pregnancy --Disadvantages - Less clinical experience with their usage - Much more expensive - Efficacy equivalent, but not clearly superior to older AEDs - Serum levels take longer to check, do not assist with dosing *TIP NOTE: Serum levels in these drugs more useful to judge compliance- whether your patient is actually taking the drug.

Antimuscarinic adverse effects* --dry as a bone (inhibition of secretions) --red as a beet (flushing related to absence of sweating) --hot as a hare (temperature ↑ from absence of sweating) --blind as a bat (cycloplegia and mydriasis) --mad as a hatter (mental confusion, delirium) --also fast as a bullet (tachycardia)

Result from blockade of the muscarinic subtype of acetycholine receptor and are sometimes (less specifically) called 'anticholinergic effects. prominents with antidepressants, antipsychotics, and antihistamines

2. What is the mechanism of action for the SSRI antidepressants? Name the prototype and major adverse effects. What advantages does this class offer over tricyclic antidepressants? What atypical antidepressant is stimulating, increases libido, and is also approved for smoking cessation?

SSRI Antidepressants MOA: block the reuptake of the serotonin, very selective Prototype: fluoxetine (Prozac) Adverse Effects: non-sedating but may produce restlessness, insomnia, Serotonin syndrome from too much serotonin (agitation, confusion, sweating, tremors, fever more likely when combined with related drugs especially MAOIs, can be fatal), N/V, weight gain after initial loss Advantages of this class> Tricyclic antidepressants: Safer in OD than tricyclics; but often see withdrawal syndrome SSRI's decrease libido, sexual function (70%) Bupropion (Wellbutrin, Zyban) some stimulant effects like amphetamine; antidepressant MOA not clear (naltrexone/bupropion= Contrave for weight loss 2-4X more than diet/exercise) --will stimulate, increase libido, and approved for smoking cessation

10. Describe therapy for status epilepticus. Describe strategies for pregnant patients who need to take these drugs.

Status Epilepticus (SE) - Definition: Continuous tonic-clonic seizures lasting >5-10 minutes - Medical emergency --20% of patients die --SE > 20 minutes can cause permanent neurologic injury - Treatment guidelines --early SE (< 20 minutes): lorazepam or diazepam --established SE (20-40 minutes): --phenytoin/fosphenytoin or phenobarbital or valproic acid --refractory SE (>40 minutes): --midazolam or propofol or pentobarbital *TIP NOTE: SE is the kind of situation where being able to administer AEDs either IV or rectally is really necessary, because the patient won't be able to take medications orally. IM is not a great option because the time to absorption can be so variable, and time is of the essence when patients are seizing uncontrollably. Pregnant Patients: --AED use preferred over uncontrolled seizures, which can: -induce labor and cause miscarriage - result in fetal hypoxia, subsequent delayed development, or increased epilepsy risk in the child --AED use associated with have higher rates of birth defects - oral-facial clefts, midline heart defects, neural tube defects - optimal AED for pregnancy remains unclear *TIP NOTE:In general, the concept for AEDs and pregnancy is that if it ain't broke, don't fix it. If you are going to change a patient off valproic acid, for instance, you should do it in the planning stages for a pregnancy, rather than the pregnancy itself. What you really don't want to do in the middle of a pregnancy is to switch the patient over to a new AED that doesn't control their seizures.

3. Discuss treatment options for patients who are refractory to initial antidepressant therapy. Which mixed action agents may be especially useful for these patients?

Treatments for pt with Refractory episodes to initial antidepressant therapy: Mixed action Agents:

Conventional (FGAs/originals) vs. atypical (SGAs/newer) antipsychotics

more recent large studies show FGA and SGA equally effective in most cases, except for clozapine, which is more effective than others SGAs cost 10x more SGA metabolic effects problematic SGAs approved for bipolar disorder decision will depend on patient (diabetes? refractory?); if all else equal, may be FGA.

Psychosis: loss of touch with reality. Schizophrenia is most common psychosis (1% incidence in US)

positive symptoms: exaggerations of normal function ---hallucinations, delusions, agitation, paranoia negative symptoms: loss of normal function ---lack of motivation, poverty of speech, blunted affect: face is generally dead without expression- usually with drawl from social interaction, poor self-care, social withdrawal cognitive symptoms ---disordered thinking, reduced ability to focus attention, learning and memory difficulties