Pharmacology and receptors

describe characteristics of a2 adrenoceptors

- Gi/o protein-coupled receptors with 7 transmem domains of amine-binding subfamily; - three receptor subtypes but this is currently of little clinial relevance; - interaction of an a2 agonist with receptor results in: 1. inhibition of adenylyl cyclase 2. activation of receptor operated K channels 3. acceleration of Na/H+ exchange 4. inhibition of voltage-gated Ca channels - present on presynaptic membrane of noradrenergic neurons; - activation inhibits release of norepi (negative feedback); - postsyn a2 adrenoceptors exist in vascular smooth muscle, liver, pancreas, platelets, kidney, adipose, eye --> exert distinct physiologic function; - medullary dorsal motor complex in brain has high density of these receptors

What are metabolic effects of catecholamines?

- Hyperglycemia, hyperlactatemia, hypokalemia. a agonism --> inc BG by decreasing insulin secretion and glycogenolysis - B agonism --> increased glucagon and ACTH secretion and lipolysis - B2 agonism --> inc cellular K+ uptake

How are opioids metabolized and eliminated?

- Metabolic elimination by hepatic conjugation and metabolite excretion in urine; - opioid overdoses can change kinetics of elimination from first to zero order by saturating processes responsible for elim and prolonging duration of action

What is ephedrine and how does it act?

- Sympathomimetic amine, works by increasing release of norepi from sympathetic nerve endings. - may also have some direct B agonist effects - Prolonged use can deplete norepi stores, leading to tachyphylaxis.

What is dopexamine?

- Synthetic dopamine analogue with activity at dopamine and beta-2 receptors. - May be useful for afterload reduction.

What is the MOA of beta lactams?

- interfere with bacterial cell wall synthesis; binding to an inhibiting the trans-peptidases and peptidoglycan-active enzymes (penicillin-binding proteins) that catalyze the cross-linking of the glycopeptides which for the bacterial cell wall - bacteriacidal but do require that cells be actively growing to be efficacious - difference in susceptibility of G+ and G- depends on number and type of drug receptors, the amount of peptidoglycan present (G+ organisms have a much thicker cell wall) and amount of lipid in the cell wall - lipid insolubule, do not enter living cells well - large Vd but cross membranes poorly - excreted actively by the kidneys

What are contrainidcations to epidural injection?

- local infection, - coagulopathy, - neurologic dysfunction, - obesity, - hypovolemia/hypotension

In general, what is the MOA of opioids?

- raise pain threshold or decrease perception of pain by acting at receptors in dorsal horn of spinal cord and mesolimbic system Mesolimbic system: - brain stem nucleus raphe magnus and locus coeruleus - midbrain periaquaductal gray matter - thalamic and hypothalamic nuclei Dorsal horn: - induce postsyn inhibtion of nociceptive projection neurons (T cells) - may act presynaptically to inhibit release of substance P from primary afferent nerves Mesencephalon and medulla: - activate descending endogenous antinociceptive system that modulates nociception in dorsal horn via release of serotonin and +/- NE Limbic system: - alter emotional component of pain response --> makint it more bearable - receptor binding of endogenous or exogenous ligands activates G proteins as second messengers, modulates adenylate cyclase acvitiy and thereby alters transmembrane transport of effectors; - do not alter responsiveness of afferent nerve endings to noxious stimuli or impair conduction along peripheral nerves

Describe effects of a2 agonists in the CNS

- stimulation of presyn a2 receptors in CNS decreases release of norepi; produce sedation by inhibition of noradrenergic neurons in the locus ceruleus (upper brainstem); sedation characterized by increase in stages I and II sleep and decrease in REM; - Produce analgesia via stimulation of receptors in dorsal horn of the spinal cord and in brainstem where modulation of nociception is initiated - decrease development of tolerance to opioids; synergistic with other pain meds; decrease anesthetic requirements by up to 80% in dogs and cats - mediated by decreased norepi release from locus ceruleus - neuroprotective effects - due to decrease in norepi or glutamate or to activation of imidazoline receptors; or inhibition of acute expression of immediate early genes involved in cerebral damage and inhibition of massive norpie release after brain injury; have anticonvulsant effects - hypothermia - due to inhibition at hypothalamus of central noradrenergic mechs responsible for control of body temp; may also prevent thermoregulatory response to infection

In what two ways does AVP regulate water homeostasis?

1) regulating fast shuttling of aquaporin-2 to cell surface 2) stimulates synthesis of mRNA-encoding aquaporin-2

What is the dose of atipamezole? What are effects of IV administration?

5-10x administered dose of dexmed; dysphoria; possible hypotension

Prehypertension in people

>120-139/80-89

Silverstein definition of hypertension

>150/95, MAP 115 on 3 separate visits, no signs >150/95, MAP 115 on one occasion with end organ signs >180/120, MAP 140 medical emergency

What two hormones act on the oxytocin receptor?

AVP, oxytocin

Describe the most important physiologic effects of opioids

Analgesia, sedation, muscle relaxation, behavior modification. 1) CNS depressant - effects on cerebral cortex; - disorientation or excitement - results from effects on hypothalamus, indirect activation of dopaminergic receptors 2) respiratory depression - RR and TV by directly depressing pontine and medullary respiratory centers; produce delayed response (altered threshold) and decreased response (altered sensitivity) to arterial CO2 leading to retention of CO2 - tachypnea - may be due to excitation and/or alteration of the thermoregulatory center - bronchoconstriction - wooden chest; patients chest muscles become spastic? 3) CV system - minimal or no effects in BP or myocardial contractility; can produce vagally mediated bradycardia - histamine release - methadone, morphine, meperidine 4) GI - initial stimulation (vomiting, diarrhea) followed by ileus 5) release of ADH - urine retention; possibly also bladder atony 6) changes in body temperature - decreased temp because thermoregulatory center in hypothalamus is reset to lower setting; increases in body temp occasionally, more common in cats

How does anemia induce hypertension?

Anemia causes chronic vasodilation, then with resolution overcompensation occurs increasing peripheral vascular resistance

Compare and contrast aspirin and other NSAIDs as antiplatelet agents.

Asprin is irreversible, other NSAIDs cause reversible blockade so weaker efficacy; drugs with higher specificity for COX2 (i.e. the coxibs) are thought to have minimal effects on platelet reactivity;

What is isoproterenol and what is it used for?

B receptor agonist. Causes inc HR and vasodilation. Increased HR and CO and decreased BP. Can be used to augment forward flow with careful monitoring of BP.

On what receptors does dopamine act? What is the net effect?

B1 ++, B2 +, a1&a2 ++ D1 - postsynaptic receptors responsible for vasodilation D2 - presynaptic receptors inhibit norepi release from sympathetic nerve endings (which promotes less vasocontriction) Dopaminergic vasodilatory predominates at low doses Beta at medium doses Alpha at high doses

B1, B2, a1 and a2 agonists have what effects?

B1 - HR, contractility, ectopic pacemaker activity B2 - vasodilation, bronchodilation Postsynaptic a1, presynaptic a2 - vasoconstriction, some ectopic pacemaker activity

Cholinomimetic drugs: MOA, indications, adverse effects

Bethanechol, ranitidine, nizatidine MOA: raniti and nizatin inhibit acetylcholinesterase; beth is cholinomemetic that binds muscarinic receptors Indications: bethanecol promotility throughout GIT, others better for colonic Adverse effects:

describe the differences between midazolam and diazepam

Diazepam · Diazepam is not water soluble · Formulated in a 40% propylene glycol and 10% alcohol vehicle · **Propylene glycol is an irritant to blood vessels leading to phlebitis and thrombosis and risks propylene glycol toxicity (metabolic acidosis, hyperosmolality, neurological sequelae, organ dysfunction) · Adsorbs to plastic (don't store in plastic) · Protect from light Midazolam · Water soluble so well absorbed IM · Poorly bioavailable when given per rectum · Shorter acting --> can be titrated

What is the endogenous precursor to norepinephrine?

Dopamine

How does hyperadrenocorticism induce hypertension?

GCC induce hepatic production of angiotensinogen

What type of receptor is the V3 receptor and how does it exert its effect?

Gq protein-coupled activation of phospholipase C and phosphoinositide pathways. Increased levels of inositol phosphate and diacylglycerol activate voltate-gated calcium channels --> increased intracellular Ca and ACTH release

What type of receptor is the V1 receptor and how does it exert its effect?

Gq protein-coupled activation of phospholipase C and phosphoinositide pathways. Increased levels of inositol phosphate and diacylglycerol activate voltate-gated calcium channels --> increased intracellular Ca and vasoconstriction

What type of receptor is the V2 receptor and how does it exert its effect?

Gs protein-coupled signaling pathway --> increased intracell cAMP --> fusion of aquaporin-2 bearing vesicles with apical plasma membrane of collecting duct principal cells --> increased free water absorp.

What receptors other than a2-adrenoceptors do a2 agonists activate?

Imidazoline receptors: I1 - BP regulation, may act synergystically with a2s I2 - exert control on central noradrenergic and hypothalamic-pituitary-adrenal axis activity; regulation of small intestinal motility

How does DM induce hypertension?

In type 1, diabetic nephropathy In type 2: 1. hyperinsulinemia causes sodium, water retention, increased sympathetic activity 2. hypertrophy of vascular smooth muscle secondary to mitogenic effects of insulin 3. hyperinsulinemia leads to increased intracellular Ca and vascular smooth muscle contraction

What are the three most potent stimuli for arginine vasopressin release? List at least three additional stimuli. List at least three things that inhibit release.

Increased osmolality, hypotension, decreased effective circulating volume. Stimuli: Pain, nausea, hypoxia, hypercarbia, pharyngeal stimuli, glycopenia, drugs (acetylcholin, high-dose opioids, dopamine, ang II, prostaglandins, glutamine, histamine), mechanical ventilation. Inhibitors: glucocorticoids, low-dose opioids, atrial natriuretic factor, GABA

Cisapride: MOA, indications, adverse effects

MOA: - 5-HT4 receptor AGONIST - doesn't cross BBB or have any adni-dop efffects - no antiemetic effect and no extrapyramidal signs like metoclop - increasing motility of colon, eesoph, stomach, small intestine - adverse: in humans, heart arrhythmias and deaths - metabolized by liver by cyto P450 system - drugs that inhibit metab may make more dangerous (clarithro, erythro, flucon, itracon) Indications: GERD, poor gastric emptying, constipation Adverse effects: cardiac arrhythmias in people

Clopidogrel: MOA, indications, adverse effects

MOA: - Thienopyridine drug that interferes with platelet aggregation - IRREVERSIBLE binding to the P2Y12 receptor; - prodrug that requires hepatic biotransformation into active components via hepatic P-450 enzymes; - agonism at the P2Y12 receptor associated with integrin activation and platelet granule secretion - ADP-induced TXA2 production --> clopidogrel works to inhibit these things; - decreases the amplification of platelet aggregation response that normally occurs when P2Y12 is activated; - decreases ADP and collagen-induced platelet aggregation - decrease in platelet serotonin release (an indicator of dense granule secretion); - decreases release of procoagulant molecules from platelet granules and so may slow in vivo thrombus growth by delaying additional platelet activation Indications: thromboprophylaxis Adverse effects: - vomiting - diarrhea - anorexia - non regen anemia in some cat on long-term - in humans major bleeding risk, aspirin can increase

Phenobarbital: MOA, indications, adverse effects

MOA: - barbiturate that facilitates GABA-ergic activity by prolonging opening of chloride channels associated with GABA(A) receptor; - believed to inhibit glutamate receptors and voltage gated Ca channels; - high oral bioavail, 45% protein bound; - metabolized mainly in liver, 25% excreted unchanged by kidneys; - clinical response in 60-80% of epileptic dogs; - loading dose intended to achieve 20-40 mcg/ml; - half life varies among dogs and over time in same dog due to autoinduction of hepatic enzymes responsible for its metabolism; - in dogs half life 37-89 hours; steady state reached after 5 half lives so check levels in 2-3 weeks; Indications: - seizures Adverse effects: - sedation, - ataxia, - proprioceptive deficits, - PU/PD, - polyphagia; - less commonly excitation, - BM suppresion, - hepatotox, - superficial necrolytic dermatitis; - elevations in ALP before elevations in ALT; - thyroid hormone levels may be decreased

Naloxone: MOA, indications, adverse effects

MOA: - bind with great affinity to mu, kappa, delta opioid receptors, competitively displacing agonists with lesser affinity and reversing; - naloxone also tested in model of hypovolemic shock and reduced splanchnic capacitance leading to improvement in venous return, MAP and CO Indications: reversal of opioids Adverse effects: short duration of action compared to many opioids; pain, excitement, stress with reversal; may be difficult to reverse buprenorphine

Gabapentin: MOA, indications, adverse effects

MOA: - binding of a2delta subunit of neuronal voltage-gated Ca channels, leading to inhibition of release of excitatory neurotransmitters into synapse; - 34% metabolized by liver Indications: - sedation, - analgesia, - seizures Adverse effects: - sedation, - ataxia, - elevated LEs

Levetiracetam: MOA, indications, adverse effects

MOA: - binding to synaptic vesicle protein SV2A, resulting in decreased release of neurotransmitter into synapse; - minimal hepatic metabolism; - 90% excreted in urine Indications: - seizures Adverse effects: - sedation, - salivation, - ataxia and stiff gait at very high doses

Metoclopramide: MOA, indications, adverse effects

MOA: - central dopaminergic ANTAGONIST - peripheral 5-HT3 ANTAGONIST - 5-HT4 AGONIST - stimulates and coordinates esoph, gastric, pyloric, duodenal motor activity - inc lower esoph sphincter tone, stimulates gastric contractions, relaxes pylorus and duodenum - readily crosses BBB, dopaminergic antagonism at CRTZ produces antiemetic effect - dop atnagonomism in striatum --> extrapyramidal signs (muscle spasms, motor restlessness, aggression) - these tx with antichol effects of diphenhydramine; sensitive to light; excreted by kidneys Indications: prokinetic, nausea Adverse effects: caution in patients with dec GFR may cause extrapyramidal signs (behavior changes, hallucinations, hyperactivity, frenzied behavior)

Rivaroxaban: MOA, indications, adverse effects, monitoring

MOA: - direct inhibitor of FXa; does not require AT for inhibitor activity; Indications: prevention of stroke in humans with Afib, thromboprophylaxis Adverse effects: hemorrhage Monitoring: anti-Xa activity

Abciximab: MOA, indications, adverse effects

MOA: - fibrinogen receptor antagonist, - focused on the final common pathway of platelet activation: the expression of active GPIIb/IIIa fibrinogen receptor; - all activated platelets are inhibited from contributing to clot formation; - chimeric Fab-fragment molecule that noncompetitively inhibits GPIIb/IIIa; - restoration of platelet fx in ~48 hours Indications: humans for percutanous coronary intervention in treatment of ACS and MI in high risk patients Adverse effects: - bleeding - thrombocytopenia - nausea - vomiting

Bromide: MOA, indications, adverse effects

MOA: - halide anticonvulsant; - hyperpolarization of neuron via movement of bromide ions intracell through chloride channels; - not metabolized but excreted unchanged in urine; - half life 25 days but can be affected by changes in GFR; - bc bromide reabsorbed in renal tubules through chloride channels, change in chloride of diet can affect clearance from body Indications: - seizures Adverse effects: - Fatal pneumonititis in cats; - neuro deficits (sedation, agitation, caudal paresis, ataxia, decreased pelvic limb flexor withdrawals), - polyphagia, - PU/PD, - vomiting, - pancreatitis; - bromism - toxic concentrations of bromide (altered mentation, ataxia, UMN or LMN paresis); pancreatitis and increase in PLI

Unfractionated heparin: MOA, indications, adverse effects, monitoring

MOA: - heterogenous mixture with molecules from 5k-30k Da; - 1/3 UFH molecules contain sequence necessary to bind AT; - fractions of higher-weight hep form large ternary complex that inactivates FIIa and FXa with ratio of 1:1; - lower weight molecules not long enough to bind FIIa but still have affinity for FXa with 4:1 FXa:FIIa activity; - once bound to AT, UFH inhibits FIXa, FXa, FXIa, FXIIa and FIIa, with most profound effects on FIIa and FXa; - indirect anticoagulant since it works by enhancing preexisting properties of AT; - also has direct anticoag effect by causing **release of TFPI** from endothelial surface; activity lower in conditions where AT decreased - potentiates AT - AT --> inhibits II and X - some inact of IX, XI, VII, XII - TFPI release in endothelium - 20-50% UFH pentasaccharide activate AT - clearance: fast macts, endothelial cell binding --> depol; slow clearance kidneys - non-linear clearance effect - short duration action (60 min) - poor bioavail SQ - reversal = protamine sulfate Indications: thromboprophylaxis Adverse effects: - hemorrhage, - thrombocytopenia - hypersensitivity (derived from bovine/porcine tissues) - causes inc of lipoprotein lipase --> inc plasma FFAs - hyperkalemia, suppressed aldosterone synthesis (uncommon) Monitoring: dose-adjusted monitoring of PTT, with goal of 1.5-2x normal or baseline; however, relationship of PTT to anti-Xa so more accurate to measure anti-Xa

Warfarin: MOA, indications, adverse effects, monitoring

MOA: - inhibits activity of vitamin K epoxide reductase in the liver; - FII, VII, IX, X produced in liver as inactive zymogens that must be modified by carboxylation in the presence of Vit K so that they can bind Ca and participate in coagulation; - during this process, Vit K is converted to Vit K epoxide; Vit K epoxide reductase is required to reduce Vit K back to the active form necessary for coagulation factor formation; - Warfarin inhibits vit K epoxide reductase, so Vit K cannot be recycled, which causes rapid depletion of VitK and the dependent coag factors; - FVII has shortest half life (6.2 hrs) so PT will be prolonged first; - Proteins C and S also vit K dependent so have very transient procoagulant phase prior to anticoag phase Indications: MI, venous thromboembolism, Afib, prosthetic heart valves in people Adverse effects: hemorrhage, sometimes fatal; can occur in GI/urinary/intracranial/pulmonary parenchyma Monitoring: weekly PT or INR; INR = [PT patient / PT reference]^ISI, where ISI = international sensitivity index, or relative strength of thromboplastin reagent INR corrects for intralab and interlab variability and for use of thromboplastin reagents of varying strength

Butorphanol: MOA, indications, adverse effects

MOA: - mixed agonist-antagonist (K agonist, mu antag); - ceiling effect that limits analgesic effectiveness; - less potential than agonists to cause reflexive increases in ICP so safer sedative for patients with head trauma, increased ICP for other reasons or increased IOP; - can be used for partial reversal of effects of mu agonists Indications: sedative, cough suppression, weak analgesic, partial reversal of pure mus Adverse effects: ceiling effect, limited analgesia, partial opioid reversal

Buprenorphine: MOA, indications, adverse effects

MOA: - partial agonist (mu), with limited agonist activity at mu receptors; - moderate analgesic with greater duration of action than others; - doesn't stimulate vomiting, - may be useful with increased ICP or IOP Indications: sedation, analgesia Adverse effects: sedation, not as much pain control

Methadone: MOA, indications, adverse effects

MOA: - pure m-agonist, - noncompetitively binds NMDA, - more lipid soluble than morphine but causes less sedation and vomiting Indications: sedation, analgesia Adverse effects: vomiting, diarrhea, bradycardia; histamine release causing bronchoconstriction and hypotension - contraindicated in patients with mast cell tumors

Zonisamide: MOA, indications, adverse effects

MOA: - sulfonamide; - inhibition of voltage gated Na channels - inhibition of T-type Ca channels - modulation of dopaminergic activity - enhancement of GABA activity in CNS - inhibition of carbonic anhydrase activity - excreted mostly in urine as metabolites, - likely undergoes extensive hepatic metabolism; - coadmin of phenobarb may shorten half life Indications: - seizures Adverse effects: - ataxia, - sedation, - vomiting, - anorexia, - KCS, - decreases in total T4, - idiosyncratic hepatopathy in dogs

Benzodiazepines: MOA, indications, adverse effects

MOA: · Benzodiazepines bind to receptors that facilitate the inhibitory actions of GABA. · Potential other actions o Serotonin antagonist o diminished release or turnover of ACh in the CNS · Act at the limbic, thalamic, and hypothalamic level of the CNS · Effects: anxiolytic, sedative, hypnotic, skeletal mm relaxation, anticonvulsant · In humans --> recognized to have amnestic effects · No analgesia · Metabolized in the liver to active metabolites, then after conjugation urinary excretion Indications: Sedative (rarely sufficient alone, reduction of doses for other sedatives/induction agents); anticonvulant therapy; appetite stimulation (effect involves binding to benzodiazepine receptors and appears to increase the attraction to tastes) Adverse effects: Diazepam · Diazepam is not water soluble · Formulated in a 40% propylene glycol and 10% alcohol vehicle · **Propylene glycol is an irritant to blood vessels leading to phlebitis and thrombosis and risks propylene glycol toxicity (metabolic acidosis, hyperosmolality, neurological sequelae, organ dysfunction) · Adsorbs to plastic (don't store in plastic) · Protect from light Long-term benzos · Dysphoric or excitatory signs · Delayed awakening · Seizures and acute benzodiazepine withdrawal reported in people · Sedative effects highly variable in dogs and cats · Fulminant liver failure (PO diazepam cats) - likely idiosyncratic

Ondansetron, dolasetrol: MOA, indications, adverse effects

MOA: 5-HT3 receptor antagonists which are found peripherally (where they're responsible for vagal afferent input) and centrally (CRTZ, MVC); metabolized by liver; inhibits emesis at low and high doses while enhancing emesis at intermediate doses; eliminated in urine and bile Indications: Nausea, vomiting Adverse effects: constipation, diarrhea, somnolence, prolongation of QT interval?

ACEi: MOA, indications, adverse effects

MOA: Competitively inhibits conversion of agnI to angII; results in decreased angI and II, inc bradykinin; agnII normally stimulates kidneys to retain Na so ACEi reduce plasma volume; prevent aldosterone release leading to dec Na and H2O; decrease in preload and afterload; reduce intraglom pressure; inhibit growth factors that lead to hypertrophy and sclerosis Indications: hypertension, heart failure, proteinuria (through maintaining hep sulfate layer of glom BM) Adverse effects: weakness, lethargy, azotemia, hyperkalemia, production of dry cough induced by bradykinin

Cimetidine: MOA, indications, adverse effects

MOA: H2 receptor antagonist; block histamine receptor on gastric parietal cell; competitive inhibitor of gastric acid secretion (do not decrease gastric acid secretion as well as noncomp PPIs); maximal effect occurs immediately on initiation of tx; least potent H2RA; with oral admin, absorp delayed by food; undergoes substantial first-pass effect; metabolized extensively by liver; markedly inhibits hepatic P-450 enzymes and has been used therapeutically to lessen acetamin tox; Indications: reduction of gastric acid Adverse effects: decreases metabolism of theophylline, lido, metro so can cause toxicity; decreases hepatic BF by 20%; apathy, nausea, vomiting, CNS aberrations and cytopenias in people; anecdotal reports of hemolytic anemia in cats; thrombocytopenia in people; causes only transient increases in serum gastrin concentrations

Famotidine: MOA, indications, adverse effects

MOA: H2 receptor antagonist; block histamine receptor on gastric parietal cell; competitive inhibitor of gastric acid secretion (do not decrease gastric acid secretion as well as noncomp PPIs); maximal effect occurs immediately on initiation of tx; most potent H2RA; longest duration of action; undergoes substantial first-pass effect; least orally bioavailable; excreted almost unchanged in urine; Indications: reduction of gastric acid Adverse effects: apathy, nausea, vomiting, CNS aberrations and cytopenias in people; anecdotal reports of hemolytic anemia in cats; thrombocytopenia in people; causes only transient increases in serum gastrin concentrations

Spironolactone, eplerenone: MOA, indications, adverse effects

MOA: K-sparing diuretic; competitively antag aldosterone binding to receptor on late distal tubule and CD to increase Na, Ca, H2O excretion, decrease K loss; positive effect on myocardial remodeling and fibrosis Indications: hyperaldosteronism, CHF Adverse effects:

Furosemide: MOA, indications, adverse effects

MOA: Loop diuretic; binds to and inhibits Na-K-2Cl cotransporter on apical membrane of epithelial cells in thick ascending loop of Henle; decreased Na, Cl results in marked natriuresis and diuresis and decreases medullary gradient; increased distal delivery of Na leads to Na-K exchange with promotes kaliuresis; blockade of active NaK2Cl cotrans decreases energy expenditure and oxygen consumption of tubular epithelial cells; improves renal O2 supply by dec renal vasc resista and increas renal blood flow; blockade of chloride flux in macula densa inhibits important regulatory tubuloglomerular feedback and kidney may not be able to adjust GFR in response to loss of tubular solutes Indications: CHF, AKI, hypercalcemia Adverse effects:

Maropitant: MOA, indications, adverse effects

MOA: NK-1 receptor antagonist that blocks action of substance P in CNS and peripheral NK1 receptors in GI tract; extensive first pass metab in liver, higher bioavail when given parenterally; reduces visceral pain and reduce MAC of sevo during anesthesia if given IV; may have some anti-tumor activity Indications: vomiting, nausea, visceral pain Adverse effects: bone marrow hypoplasia in puppies < 11wks

Sodium nitroprusside: MOA, indications, adverse effects

MOA: Results in nitric oxide release --> stimulates production of cGMP in vascular smooth muscle --> activates kinase that leased to inhibition of Ca influx into smooth muscle and decreased Ca-calmodulin stimulation of myosin light chain kinase --> decreases phosphorylation of myosin light chainss --> decreases smooth muscle contraction --> vasodilation; minimal change in renal blood flow, only slight increase in HR Indications: hypertensive crisis, reduced preload and afterload in CHF Adverse effects: shock, hypotension, cyanide toxicity --> Secondary to Na nitroprusside administration: Na nitroprusside oxidizes sulfhydryl groups present on erythrocytes and cell membranes and reacts with Hb to produce MetHb; this results in production of NO and 5 cyanide groups; ree cyanide converted to thicyanate by thiocyanate oxidase within erythrocytes or transsulfuration reaction with thiosulfate by rhodanese enzyme in liver; thiocy freely filtered by glomerulus; both cyanide and thio toxic and of concern in patients with renal insuff (dec thio clearance), hepatic insufficiency (dec transsulfuration by rhodanese enzyme), patients receiving diuretics; neonates and geriatrics may have reduced rhodanese enzyme; felines more sensitive to erythrocyte oxidative damage so total dose reduction; clincal signs include development of nitroprusside resistance, depression, stupor, seizures, metabolic acidosis, inhibition of mitochondrial cytochrome c oxidase (increased lactate and venous oxygen tension due to this)

Vaptans: MOA, indications, adverse effects

MOA: antagonize V2 receptor in kidney and promote solute-free water clearance; Indications: treatment of free water retention in hypervolemic hyponatremia (CHF, liver failure) or normovolemic hyponatremia (SIADH) Adverse effects:

Promazine derivatives: MOA, indications, adverse effects

MOA: antidopaminergic and antihistamine effects that block the CRTZ and at higher doses the MVC; also have anticholinergic, antispasmodic and a-blocking effects; antiarrhythmic qualities; metabolized by liver Indications: vomiting, sedation, antiarrhythmic? Adverse effects: vasodilation and hypotension; increased CVP, changes in HR (bradycardia or tachycardia); caution in patients with liver disease (esp PSS)

Hydralazine: MOA, indications, adverse effects

MOA: arteriolar dilator acting directly on smooth muscles; may work by preventing oxidation of nitric oxide and thereby lowering BP Indications: Hypertension, hypertensive crisis Adverse effects: reflex sympathetic activation (i.e. reflex tachycardia), lupus-likd reaction, anorexia, nausea, vomiting, diarrhea, muscle cramps, tremor

ARBs: MOA, indications, adverse effects

MOA: displace AngII from AT1R, antagonizing known effects (vasoconstriction, sympathetic activation, aldosterone release, renal sodium resorption) Indications: hypertension Adverse effects: well tolerated

Acetezolamide: MOA, indications, adverse effects

MOA: inhibits type II (cytoplasmaic) and type IV (membrane) CAs from proximal tubular epithelium; net decrease in prox reabsorp of NaHCO3; proximal site of action leads to compensatory increase in distal sodium reabs; blockade of ocular and brain CA decreased production of aqueous humor and CSF; blockaed of rbc CA hampers CO2 removal from tissues Indications: rarely used as diuretics except in some combo protocols; mainly used to treated elevated IOP Adverse effects:

PPIs: MOA, indications, adverse effects

MOA: irreversibly inhibit hydrogen-potassium ATPase on luminal side of the parietal cell, stopping secretion of H+ ions into gastric mucosa; omeprazole susceptible to destruction by gastric acid so admin as enteric coated granules absorbed into duodenum; abspor diminished by food; omep undergoes first pass hepatic metabolism; rest is selectively sequestered in acidic environment of parietal cells and transformed to active drug, thus best to give 1 hour before feeding to max acidity of parietal cell and increase amt of omep sequestered there; 2-5 days before max effects seen but effects continue a few days after d/c tx Indications: gastric acid reduction Adverse effects: rare. Diarrhea; omep and esopep ihibit hepatic P-450 enzymes so may cause decreased antiplt activity with clopidogrel admin and decreases clearance of other drugs; hypoMg, elevated LEs in people, hypersensitivity in people

Tramadol: MOA, indications, adverse effects

MOA: mild analgesic with slight m-opioid binding activity; interference with both serotonin storage and norepi reuptake; principal metabolite has greater mu binding than parent compound Indications: Adverse effects: sedation, constipation, vomiting, mydriasis in cats

Erythromycin (anti-emetic): MOA, indications, adverse effects

MOA: motilin receptor agonist; increases LES tone and small and large bowel peristalsis Indications: promotility Adverse effects: tolerance with sustained use

Sucralfate: MOA, indications, adverse effects

MOA: octasulfate of sucrose combined with AlOH; binds tightly to epith cells in acidic environment of stomach, esp to base of erosions and ulcerations, where may remains for 6 hours; serves as physical barrier to ulcer protecting it from pepsin and bile acids; stimulates local production of prostaglandins and binding to epidermal growth factor (favors mucosal repair) Indications: GI ulceration Adverse effects: constipation

Mannitol: MOA, indications, adverse effects

MOA: osmotic diuretic; nonreabsorbed sugarl alcohol; causes hyperosm resuling in water shift from ICF to ECF; freely filtered by glomerulus, does not undergo tubular reabsorption; increased tubular flow rate and osmotic diureisis; increased urine flow reduces tubular reabsorption of urea; in AKI may cause: decreased renal vasc resist, decreased hypoxic cellular swelling, decreased renal vascular congestion, decreased tendency of erythrocytes to aggregate, protection of mitochondrial function, decreased free radical damage, renoprotection? Indications: increased ICP, AKI Adverse effects: very high doses may cause acute tubular injury so use cautiously to avoid accumulation, volume overload, hyperosm

Fenoldapam: MOA, indications, adverse effects

MOA: peripheral dopamine-1 agonist; maintains or increases renal perfusion while lowering BP Indications: severe hypertension, hypertensive crisis, possible uses in AKI Adverse effects: reflex tachycardia, increased IOP, headache and flushing in humans

Misoprostol: MOA, indications, adverse effects

MOA: prostaglandin E1 analog with both antacid and mucosal protective effects (stimulates secretion of mucus and HCO3 and increases gastric mucosal blood flow); act directly on parietal cells to inhibit both nocturnal acid secretion and secretions in response to food, pentagastrin and histamine; rapidly absorbed, undergoes first past metabolism in liver to active form Indications: tx of refractory ulcers or bad NSAID tox Adverse effects: diarrhea, uterine contraction, abortion

Morphine: MOA, indications, adverse effects

MOA: pure m-agonist Indications: sedation, analgesia Adverse effects: vomiting, diarrhea, bradycardia; histamine release causing bronchoconstriction and hypotension - contraindicated in patients with mast cell tumors

Fentanyl: MOA, indications, adverse effects

MOA: pure m-agonist; 100x more potent than morphine Indications: pain, sedation Adverse effects: dysphoria, short duration of action

Hydromorphone: MOA, indications, adverse effects

MOA: pure m-agonist; 10x more potent than morphine Indications: pain, sedation Adverse effects: panting, hyperthermic reactions in cats

Aldosterone blockers: MOA, indications, adverse effects

MOA: spironolactone blocks aldosterone in distal tubule and CD, decreased Na H2O reabsorption and K excretion; aldosterone considered proinflammatory, profibrotic and causes endothelial dysfx secondary to vasoconst and vascular remodeling so may block some of these effects Indications: K-sparing diuresis, hypertension Adverse effects: hyperkalemia

Hydrochlorothyadize: MOA, indications, adverse effects

MOA: thazide duretic; inhibit NaCl cotransporter on apical membrane of distal tubule; anticalciuretic; pradoxically reduce urine production in severely polyuric animals with DI by inducing mild hypovol and increasing prox tubular sodium conservation Indications: combo protocols with other diuretics; reduction of calciuresis in patients with calcium-cont uroliths Adverse effects:

Why is DDAVP preferred over AVP for central DI?

More antidiuretic activity, less vasopressor activity

Which opioids are associated with histamine release?

Morphine, methadone, meperidine

Examples of Beta-lactams

Penicillins Cephalosporins Carbapenems Monobactams

What are mechanisms of hypertension in kidney disease?

Pressure natriuresis and RAAS, increased levels of endogenous vasoconstrictors (endothelin, thromboxane), decreased vasodilators ( prostacyclin, nitric oxid)

Through what mechanism can vasopressin cause vasodilation?

Stimulation of P2 class of purinoreceptors (ATP receptors) leading to vasodilation mediated by NO and prostacyclin

What are the primary vasopressin receptors, tissues affected and principal effects?

V1 - vascular smooth muscle. Vasoconstriction at high doses, vasodilation in the cerebral, renal, pulmonary and mesenteric vessels at low doses. V2 - Basolateral membrane of distal tubule, principal cells of renal collecting duct, endothelial cells, platelets, vascular endothelium. Increased water permeability, increased von willebrand factor release, stimulation of platelet aggregation, vasodilation V3 - Pituitary. ACTH release Oxytocin - uterus, mammary gland, GI tract, endothelium. Contraction, vasodilation.

What type of AVP receptor affects coagulation and how?

V2 stimulates release of platelets from bone marrow, enhances release of vWF and factor VIII from endothelial cells

Ca channel blockers: MOA, indications, adverse effects

dihydropyridines (amlodipine, nicardipine, etc) reduce BP MOA: block influx of Ca in vascular smooth muscle cells necessary to cause smooth muscle contraction thereby dec SVR; inhibit slow transmembrane Ca influx into cell via voltage-gated L-type Ca channels Indications: hypertension, hypertensive crisis Adverse effects: tachycardia, nausea, constipation, weakness, afferent art vasodilation in excess of efferent causing decrease in perfusion and possible kidney damage

What causes the decreasing responsiveness of CHF patients to loop diuretics?

hypertrophy of distal nephron results increased compensatory solute reabsorption; commonly requires loop diuretic be paired with more distal for sequential nephron blockade

Aspirin: MOA, indications, adverse effects

i.e. acetysalcylic acid MOA: - irreversible blockade of platelet COX1 --> long-lasting platelet inhibition (permanent for life of platelets ~6 days in dogs), --> reason for success of "ultra low dose" protocols; - TXA2 is potent vasoconstrictor and platelet agonist produced by activated platelets via Cox enzyme in cytosol; - Arachidonic acid from platelet membrane is used to produce TXA2 --> inhibition of COX1 decreases TXA2 production --> antiplatelet effects (decreased rate of aggregation) of aspirin; - cats in general have reactive platelets and may not benefit from ASA tx due to sensitivity of platelets to other agonists that minimize contribution of TXA2 to secondary aggregation Indications: thromboprophylaxis Adverse effects: - effects less well study/established in cats - GI irritation --> nausea, vomiting, anorexia, diarrhea - occult to severe GI blood loss - hypersensitivity reported in dogs

Nucleoside analogs: MOA, indications, adverse effects

i.e. cangrelor, ticagrelor MOA: - inhibit effects of ADP on aggregation; - reversible inhibition of P2Y12 receptor; - do not require hepatic metabolism for effect; - noncompetitively inhibit ADP binding to P2Y12; - after cessation, platelet function returns to normal within 1-12 hours Indications: thromboprophylaxis Adverse effects: - hypersensitivity - hemorrhage - anaphylaxis

Low molecular weight heparin: MOA, indications, adverse effects, monitoring

i.e. dalteparin, enoxaparin MOA: - 1/3 size UFH (4-5,000 Da) - contain molecueles weighting ~5k Da; - 30% of molecules can bind both AT and FIIa; - due to size, exert primary effect on FXa; - no long tail --> no binding to II (or very little) - longer elimination half life (3-6h) than UFH so dosed q12-24h - 100% SQ bioavail - more predictable effects - clearance kidneys - protamine reverses 60% anti-Xa activity (favors larger chains) Indications: thrombophrophylaxis Adverse effects: caution in patients with dec GFR because LMWH excreted mainly in kidneys; Monitoring: anti-Xa 4-6 hours after administration

Alpha Adrenergic receptor antagonists: MOA, indications, adverse effects

i.e. prazosin MOA: selectively antagonizing a receptors; prazosin comp antag of postsynaptic a1 receptors Indications: primary or adjunctive tx of htn in dogs; pheo, micturition disorders bc relax urethra Adverse effects: profound hypotension

Beta Adrenergic receptor antagonists: MOA, indications, adverse effects

ie propranolol (B1, B2), atenolol (B1) MOA: blockade of renin release, reduction of HR, contractility, dec PVR, reduction in central adrenergic drive Indications: when primary tx fails, HCM, supraventricular and ventricular tachycardias Adverse effects: brochospasm, hyperkalemia, bradycardia, insulin resistance, depression

What effect does venular vasoconstriction have?

increases venous return by decreasing venous capacitance up to a point, then with excessive tone, increased resistance so decreased venous return

Causes of secondary hypertension

kidney disease, DM, Cushings, hypert4, hepatic disease, pheo, hyperaldosteronism, polycythemia, chronic anemia, EPO, steroids

What are Beta lactamases?

most gram neg rods and staph produce enzyme which inactivates B lactam abx by cleaving B lactam ring; found on plasmids, which allows for transmission of resistance within and among bacterial species

What is neuroleptanalgesia?

opioid with anxiolytic drug

what is a complication of diazepam in cats?

oral administration can result in idiosyncratic acute hepatic necrosis

Primary hypertension

result of imbalance between CO and SVR

What are penicillin-binding proteins?

transpeptidases, peptidoglycan-active enzymes that catalyze the cross-linking of the glycopeptides which form the bacterial cell wall

What is mecA?

type of mutation acquired by staph that codes for PBP-2a. Alters cell wall permeability, prevents binding of B lactam abx and causes resistance in staph spp to B lactams (MRS)

How would additional venoconstriction with a catecholamine affect venous return and CO in euvolemic vs hypovolemic patient?

- Adequate effective circulating volume but vasodilation --> increased CO due to venoconstriction of capacitance vessels - Hypovolemia with pre-existing vasoconstriction --> further venoconstriction of resistance vessels leads to decreased venous return and CO

Describe effects of a2 agonists on the cardiovascular system

- Biphasic CV response: initially BP and SVR increase leading to reflex bradycardia and decrease in CO; second phase is decrease in arterial pressure; HR and CO remain lower than normal; bradycardia may be accomp by other arrhythmias; CV effects dose-dependent - Vasoconstrictive effect caused by stimulation of a2 adrenoceptors on vasc smooth muscl of a and v; - Bradycardia - baroreceptor response; may also be related to central sympatholytic action of a2 agonists that leaves vagal tone unopposed, to an increase in parasymp efferent activity or to presyn mediated reduction in norepi release in cardiac sympath nerves - CO may be improved with combining these drugs with anticholinergic but no good studies - Induce blood flow redistribution; BF to heart, brain, kidneys might be partially or totally preserved at expense of poor BF to skin muscle intestine - maintains balance between myocardial O2 demand and supply despite CV effects - May be arrhythmogenic - reduction in HR may reveal foci that are normally inhibited by impulses coming from SA node; however, administration is protective against vtach or fib after ischemia reperfusion - Ca channel blockers may inhibit vasoconstriction while preserving central effects

Describe effects other than CNS and CV of a2 agonists

- Decreased RR but maint of minute ventilation - inhibit sympathetic outflow, modulate stress response to anesth and sx; decrease plasma levels of circulating catecholamines - inhibition of insulin release - stimulation of a2 receptors on B-islets causes reduced insulin release and hyperglycemia - increased release of growth hormone --> hyperglycemia - inhibit release of ADH and its effect on renal tubules --> promote diuresis and natriuresis - inhibit release of renin, increase secretion of ANP - decrease in salivation, LES pressure, esoph, gastric, intestinal motility, gastric secretion - vomiting in 8-20% of dogs, 90% of cats - stimulation of a2 adrenoceptors in CRTZ