Exam 5 Drugs 4 PDF

ANTIPSYCHOTICS Drug ANTIPSYCHOTICS TYPICAL ANTIPSYHOTICS (low potency) TYPICAL ANTIPSYCHOTICS (high potency) • MOA o Drug Specifics All of these drugs block dopamine receptors, particularly the D2 receptor § Clinical efficacy against positive symptoms correlates with D2 antagonism § Many side-...

ANTIPSYCHOTICS Drug ANTIPSYCHOTICS TYPICAL ANTIPSYHOTICS (low potency) TYPICAL ANTIPSYCHOTICS (high potency) • MOA o Drug Specifics All of these drugs block dopamine receptors, particularly the D2 receptor § Clinical efficacy against positive symptoms correlates with D2 antagonism § Many side-effects correlate with D2 antagonism • Side Effects o Dysphoria o Endocrine § Increased secretion of prolactin (hyperprolactinemia) • Negative feedback is blocked with blocked dopamine à increased prolactin* • D2 receptor block in pituitary • Release of prolactin is under negative regulation by dopamine secreted from cells in the tuberoinfundibular system of the hypothalamus § Females • Galactorrhea • Excessive or spontaneous production of milk o Given oral dopamine antagonist to increase breast milk production § Males • Gynecomastia o Sexuality o Loss of sex drive o Impotence in males o Weight gain* o Akathisia* § Slowing of movement* o Hypotension (alpha1-blocking effect) o Poikilothermia § Failure to regulate body temperature § Body and environment become the same temperature chlorpromazine • Phenothiazine class (Thorazine) • Original prototype prochlorperazine • Phenothiazine class (Compazine) • Antiemetic promethazine • Phenothiazine class (Phenergan)* • Antiemetic thioridazine (Mellaril) fluphenazine • Phenothiazine class (Prolixin, others) • A depot form • Used IM for long duration action in non-cooperative patients haloperidol • Butyrophenone class (Haldol) • Also used as antiemetic • Standard against which older and newer drugs are judged o Relatively “clean” D2 antagonist* § Some 5HT2 antagonism § Some alpha1 antagonism o Half-life of approximately 20 hours o Highly effective against positive symptoms § Some effect against negative symptoms Greater potential for extrapyramidal motor side-effects* than many typical (and all atypical) antipsychotics Stereotypical butyrophenones* Large side effect profile* IV or IM* Haloperidol ester o Haldol Decanoate o Injectable depot preparation form Butyrophenone class Antiemetic (prevents PONV) QT prolongation led to “black box” warning Not used as antipsychotic because it is too sedating Butyrophenone class Brand new antiemetic (better at treatment or rescue) No QT prolongation Used at very high doses orally as an antipsychotic o 10 mg IV vs 400-800 mg PO o • • • • droperidol (Inapsine)* amisulpride (Barhemsys)* ATYPICAL ANTIPSYCHOTICS • • • • • • • • pimozide (Orap) thiothixene (Navane) trifluoperazine (Stelazine) aripiprazole • Partial dopamine agonist* (Abilify) o Effective treating schizophrenia—weak D2 partial agonist, blocks full agonist dopamine o Effective treating depression—partial DA agonist provides therapeutic efficacy • Partial 5HT1a agonist (~buspirone)* • Partial 5HT2a antagonist* • Efficacious in treating o Positive symptoms o Negative symptoms o Depression § Used in patients with both depression and psychosis/schizophrenia • Remarkably low incidence of side-effects, including less weight gain* than olanzapine • No incidence of metabolic syndrome or hyperprolactinemia clozapine • Original atypical antipsychotic (Clozaril) o Appears to be more efficacious than other antipsychotics, but most dangerous o Essentially devoid of extrapyramidal motor side-effects o Causes blood dyscrasias (agranulocytosis) in about 2% of patients § Monitor blood, weekly at first o Because of this side effect other agents are used first o Other side effects are strong sedation, weight gain, Type II DM, anticholinergic effects (dry mouth, urinary retention), and hypotensive effects o Because of adverse effects, reserved for refractory patients* § Even though its more efficacious, it’s not used first line* o Most useful for treatment-resistant schizophrenia or suicidal ideation* olanzapine (Zyprexa) • quetiapine (Seroquel) • • • risperidone (Risperdal) MOOD STABILIZERS ziprasidone (Geodon) Lithium carbonate (Li+) (Eskalith) • • • • • • • • • Rapidly becoming the standard against which other atypical antipsychotics are judged o Side effect profile more acceptable o Weight gain significant SE* o Somnolence significant SE (sedating) o Metabolic syndrome § All atypical antipsychotics (except aripiprazole) use results in metabolic syndrome à Type II DM • Development of type 2 DM can be prevented* Binds D2 and 5HT2 with modest affinity Antipsychotic activity against positive and negative symptoms Some alpha1 binding o Orthostatic hypotension* Minimal extrapyramidal effects Limited weight gain and hyperglycemia can occur Pharmacodynamics o High affinity for 5HT2 and D2 receptors o Little affinity for muscarinic receptors o Compared to other atypical antipsychotics, risperidone has greater potential § EPS § Hyperprolactinemia § Weight gain Typically administered as Li2CO3 Lithium Carbonate Multiple and Variable Effects o Effects on electrolytes (substitutes for Na+) o Effects on neurotransmitter systems § DA § 5HT § ACh o Many of these effects are seen acutely, yet lithium must be taken for 2-3 weeks before clinical effects are seen § If patients can tolerate SE, lithium is a very effective drug* Effects on Phosphoinositide Signaling o Depletion of PIP 2 à reduced IP3/ DAG PI3 signaling o PIP depletion à decreased responsiveness to receptors that use phosphoinositide second messenger signaling § Muscarinic receptors o A depletion of PIP2 sufficient enough to produce decreased responsiveness may not occur until lithium has been administered for 2-3 weeks § Consistent with the latency to clinical improvement Adverse Effects o Tremor* o Hypothyroidism o Renal dysfunction (polydipsia & polyuria) o Cardiac conduction problems o Gastric distress • valproic acid (Depakene) divalproex (Depakote) • • • • • carbamazepine (Tegretol) lamotrigine (Lamictal) • • • • • • • • • • • • MOOD STABILIZERS: ATYPICAL ANTIPSCYHOTICS + COMBOS o Mild cognitive impairment o Edema o Weight gain Narrow Therapeutic Window o Acute ~1-1.4 meq/L o Maintenance ~0.6 - 1.4 meq/L o Toxic levels ~ 2.0 meq/L o Plasma drug levels must be monitored o NOTE: 20-40% of bipolar patients do not respond to lithium Valproic Acid + Sodium Valproate = Divalproex Sodium o Combo of the two - less GI distress § Both anticonvulsants at lower doses* Wider therapeutic window and faster onset than lithium (4-5 days) May act through increasing GABA levels GI (N&V) & hepatic problems Congenital neural tube defects o Don’t use with pregnant women* Alopecia (hair loss) Most probably act through blockade of voltage dependent sodium channels Aplastic anemia and agranulocytosis Pharmacokinetic tolerance through autoinduction of metabolism o Tolerance is quickly developed (ramped up metabolism) o Similar to P450 sensitization Hyponatremia (~3%), diplopia, ataxia, GI upset, sedation, weight gain Not effective in acute mania, used for maintenance therapy o Often used as an add-on / adjunct drug for chronic management* Blocks sodium and/or calcium channels Can be used as a potentiating agent for antidepressants Helps prevent switches to mania in bipolar patients treated with antidepressants Side effects o Dizziness o Headache diplopia o GI upset o Somnolence o Skin rash § Can be deadly à Steven Johnson Syndrome* Valproic acid doubles concentration of lamotrigine Carbamazepine halves concentration of lamotrigine olanzapine (Zyprexa) aripiprazole (Abilify) quetiapine (Seroquel) risperidone (Risperdal) olanzapine + fluoxetine (Zyprexa + Prozac = Symbyax) ANTIHYPERTENSIVES Drug DIURETICS THIAZIDE DIURETICS LOOP DIURETICS K+ SPARING DIURETICS CA+2 CHANNEL BLOCKERS (CCB) • • • • • • Drug Specifics First line therapy for many patients Deplete body of Na+ stores Initially reduce BP by reducing blood volume and CO After 6-8 weeks à CO returns to normal with PVR declines Often used in combination with other agents (see a 10-15mmHg drop when used alone) MOA o Enhanced Na+ loss leads to: § H2O loss § ¯ blood volume § ¯ CO effect is usually slight § ¯ BP (change is more than can be accounted for from preceding effects) o Chronic effects: § Na loss causes § ¯ responsiveness of arterioles to NE § ¯ arteriolar resistance • Advantages o Frequently effective by themselves o Combat Na+ retention (many antihypertensive drugs promote Na+ retention) o Potentiate effects of other antihypertensive drugs o African-Americans and elderly respond well o Minimal hypotension o Loop diuretics are effective in renal failure Hydrochloro• Selection thiazide o Usually thiazides first ie. HCTZ, chlorthalidone, or indapamide § Least potential for harm § Satisfactory for mild and moderate hypertension • Side effects o Hypokalemia o Hyperuricemia o Hypertriglyceridemia o Hypercholesterolemia o Glucose Intolerance chlorthalidone indapamide metolazone furosemide • Selection bumetanide o Loop diuretic for severe hypertension o IV for hypertensive crisis torsemide • Side effects ethacrynic o Hypokalemia acid o Hyperuricemia spironolactone • Selection eplerenone o K+-sparing in combination with thiazides or loop diuretics amiloride • Side effects triamterene • ¯ Ca++ influx, resulting in smooth muscle relaxation • At the heart, decrease cardiac contractility and CO • Uses CA+2 CHANNEL BLOCKERS (CCB) (dihydropyridin es) CA+2 CHANNEL BLOCKERS (CCB) (nondihydropyridine s) ALPHA BLOCKERS o Hypertension o Angina (Prinzmetal variant for “ipines”) o Verapamil and diltiazem for arrhythmias • Advantages o Efficacious o Low incidence of side-effects • Disadvantages o Headache; flushing o Potential problem of verapamil and diltiazem if used with beta-blockers nifedipine • Relatively selective for smooth muscle* calcium channels (L-type) • Hemodynamics o SVR ¯¯¯ o HR ­ o AV node conduction 0 o Myocardial contractility 0 or ¯ • Side effects o Headache ++ o Postural dizziness +++ o Flushing +++ o Peripheral edema. +++ o Constipation + verapamil • Relatively selective for cardiac muscle* Ca channels (L-type) • Additional uses= arrhythmias • Hemodynamics o SVR ¯¯ o HR ¯ o AV node conduction ¯¯ o Myocardial contractility ¯¯ • Side effects o Headache + o Postural dizziness + o Flushing + o Peripheral edema. + o Constipation +++ diltiazem • Relatively selective for cardiac muscle* Ca channels (L-type) • Additional uses= arrhythmias • Hemodynamics o SVR ¯ o HR ¯¯ o AV node conduction ¯ o Myocardial contractility 0 or ¯ • Side effects o Headache + o Postural dizziness + o Flushing + o Peripheral edema. + o Constipation + prazosin • MOA o Block post-synaptic alpha1 receptors o ¯ SNS effect on vasculature o ¯ preload; ¯ afterload à ¯ BP • Uses o o o o o o BETA BLOCKERS BETA BLOCKERS Not first-line drugs (side-effects) Use in combination with other classes Useful in BPH Being replaced by tamsulosin (alpha1A selective) Advantages § Don’t adversely affect serum lipids § BPH Disadvantages § Increased risk for HF (ALLHAT trial) § First-dose hypotension (severe) § Salt and water retention (must use diuretic) § Fatigue and light headedness terazosin doxazosin • Pharmacodynamics o Cardiac function § ¯ contractility § ¯ HR § ¯ CO § Immediate and ongoing effect o Peripheral Resistance § Block of B2 can lead to increase in BP (usually does not) § Block of renin release ¯es total peripheral resistance (usual effect) • Renin regulates angiotensin II and aldosterone • Side Effects o AV block o Severe Bradycardia o Bronchospasm and respiratory distress o Exacerbation of CHF and pulmonary edema o Delayed recovery from hypoglycemia o Beta- blockers without ISA § ­ triglycerides and ¯ HDL o Beta-blockers with ISA § Stimulate the beta-adrenergic receptors and oppose the action of epinephrine released propranolol • Non-selective beta-blocker • Advantages: cheap, efficacious, extensive history • Disadvantages o Contraindicated in asthma, acute decompensated HF, and AV conduction problems* o Inhibits glycogenolysis, impairs recovery from hypoglycemia, also blocks tachycardia/tremors typically seen with hypoglycemia, which are warning signs for diabetics nadolol • Non-selective beta blocker timolol • Non-selective beta blocker pindolol • Non-selective beta blocker • Intrinsic sympathomimetic activity o Partial B2 agonist • “The vasodilating beta blocker”, more notable ¯ in peripheral resistance penbutolol • Non-selective beta blocker ALPHA/BETA BLOCKERS DIRECT RENIN INHIBITOR ACE INHIBITORS atenolol • • bisoprolol esmolol metoprolol • • • • acebutolol carvedilol carteolol labetalol nebivolol labetalol carvedilol aliskiren • • • • • -pril captopril benazepril enalapril fosinopril lisinopril moexipril quinapril perindopril ramipril trandolapril • Beta1-selective 2nd generation Preferred in individuals who also have o Asthma o Diabetes o Peripheral vascular disease Beta1-selective 2nd generation Beta1-selective 2nd generation Beta1-selective 2nd generation Preferred in individuals who also have o Asthma o Diabetes o Peripheral vascular disease Beta1-selective 2nd generation Non-selective 3rd generation Non-selective 3rd generation Non-selective 3rd generation Beta1-selective with direct vasodilating (NO) 3rd generation MOA o o Blocks the action of renin upon conversion of angiotensinogen to angiotensin 1 Similar in adverse reaction to ACE inhibitors o o o o o Block conversion of angiotensin I to angiotensin II ¯ angiotensin II-mediated release of aldosterone ¯ breakdown of bradykinin ¯ overly active SNS Overall result is ¯ preload, ¯ afterload à ¯ BP • MOA • Uses HTN Renal insufficiency High plasma renin § No clear correlation between plasma renin and antiHTN response o DM (proteinuria) o HF • Advantages o Predictable, typically mild, dose-related side-effects o Blunts hypokalemia caused by diuretics o Little orthostatic hypotension or SNS activation o No effect on triglycerides, cholesterol • Disadvantages o Initial dose BP problem § Especially if hypovolemic o Cough (3-15%) o Skin rashes (SJS) /neutropenia o Acute renal failure in renal artery stenosis o Angioedema o African-Americans and elderly may not respond well (combine with diuretic) o o o o o ANGIOTENSIN II RECEPTOR BLOCKERS (ARB) VASODILATORS ARTERIAL DILATORS Contraindicated in pregnancy Hyperkalemia possible (especially if combined with other drugs that increase K+) • Specifics o Enalapril § Pro-drug converted to active compound (enalaprilat) in liver by hydrolysis § No SH groups (less allergy) o All other “prils” § Pro-drugs (all except Lisinopril) converted to an active agent in liver § Long duration of action -sartan • MOA o Block AT1 subtype of the AT2 receptors losartan § Conversion from AT1 à AT2 has happened, but now we candesartan are blocking the AT2 receptor eprosartan • Effects and side-effects irbesartan o Similar to ACE inhibitors olmesartan § Remember that side-effects are pretty benign telmisartan o No cough valsartan • Avoid during pregnancy • ACE inhibitors generally prescribed first* • Reduce BP by decreasing systemic vascular resistance • Hypotension (orthostatic) is a difficult side-effect for most patients • Arteriolar Vasodilators o Dilate arterioles o ¯ PR o à compensatory responses (initiated by baroreceptors) § ­ Sympathetic Nervous System § ­ Renin/Angiotensin System hydralazine • Consequences of SNS and RAS activation o ­ HR o ­ renin release o Na+ and H2O retention o ­ SNS with arterial “block” but venous constriction § ¯ed afterload § ­ed preload o ¯ antihypertensive effectiveness o ­ myocardial O2 consumption (angina) o ­ myocardial work (CHF) o hypotension side-effects such as palpitation, pounding headache, edema, orthostatic hypotension • Must be combined with a beta blocker and a diuretic • Use only with caution in angina or HF • MOA o Mechanism is unknown • Uses o Severe hypertension o Pregnancy • Adverse Effects o Tachyphylaxis (see often in anesthesia uses) o o ARTERIOVENODILATORS minoxidil nitroprusside • • • • ANTI- NE nitroglycerin reserpine • • • • CENTRAL ACTING methyldopa clonidine • • • Headache, palpitation, GI Systemic lupus (high doses, slow acetylators, reversible) MOA o NO cGMP mechanism o Dilates arteries and veins (mainly veins) o NO formation ® ­ cGMP ® relaxation o Dilates arterioles and veins o ¯ myocardial oxygen demand Uses o Hypertensive emergencies o CHF (with hydralazine) o Surgery (controlled hypotension) Adverse Effects o Excessive hypotension o Cyanide/thiocyanate toxicity Cover from light* MOA o Adrenergic neuronal depleting agent o Blocks vesicular uptake and storage of NE (and others) o Result is depletion of catecholamines throughout the body Long lasting effect Inexpensive Generally unacceptable side effects o CNS § Depression* § Nightmares (seldom used) o Don’t use if patient has history of depression o Nasal stuffiness o Unopposed parasympathetic activity Miosis, bradycardia, aggravation of ulcers, diarrhea o Fluid retention MOA o Reduce sympathetic outflow from brainstem sites § Reduce peripheral vascular resistance o Stimulate alpha2 receptors Methyldopa o Pro-drug o Not first-line § CNS: dry mouth, sedation, fatigue, depression, nightmares § Sexual dysfunction § Hemolytic anemia, hepatitis (rare) Clonidine o Part of effect may be via imidazoline receptors in brainstem o ¯ es heart rate and CO more than methyldopa o Not first-line o Give with diuretic (Na retention) o Useful in opioid withdrawal o Adverse effects § CNS: drowsiness (sedation*), dry mouth, depression o Rebound hypertension* HEART FAILURE & ANTIARRHYTHMICS NONINOTROPIC DRUGS Class Drug Specifics ACE inhibitors • • • • • • • • Angiotensin II antagonists (ARBs) • • ¯ production of angiotensin II o Vasodilation o ¯ Na and H20 retention o ¯ed response to sympathetics o ¯ tissue remodeling o Net effect= ¯ preload, afterload, mortality ­ circulating bradykinin o Vasodilator § Promotes NO formation § ­es synthesis of prostacyclin o Prevents vascular and cardiac cell growth o Stimulates tPA release o “kinin” autocoids produce tissue irritation and pain § Likely accounts for major side effects of ACEI Effect on Morbidity o Relieve dyspnea o Prolong exercise tolerance o ¯ need for emergency care Effect on Mortality o ¯ risk of death due to slowing of cardiac remodeling and disease progression Uses in HF o All patients with LV systolic dysfunction § + diuretic with fluid retention o LV systolic dysfunction with no symptoms (slows remodeling) o Disclose SE (improvement may take weeks to months) o Generally, NOT used in acute failure Adverse Effects o Dry, persistent cough (bradykinin related) à often intolerable o Severe hypotension in hypovolemic patients o Acute renal failure (particularly in renal artery stenosis) o Hyperkalemia § ¯ aldosterone à ¯ Na and K exchange o Angioneurotic edema § Rapid swelling in upper respiratory tract § 0.1-0.2% incidence § Typically, within first week of therapy, often first dose § Bradykinin related Contraindicated in pregnancy Choice of ACEI o Captopril, enalapril, and lisinopril shown to be beneficial o Start at low dose and increase as tolerated o Captopril is a lesser choice due to multiple administrations per day (compliance issue) May see these referred to as Angiotensin II Blockers o Blockers of the compound angiotensin II Two receptor subtypes for angiotensin II o Angiotensin 1 § Responsible for the effects of angiotensin II that must be • • • VasodilatorsArteriodilators (¯ afterload) • VasodilatorsVenodilators (¯ preload) • • • diminished in HF § “Sartan” drugs block this receptor o Angiotensin 2 § Role of these receptors is less clear § Some evidence that their activation opposes effects of AT1 For patients who fail on ACE-Is Approved only for hypertension o But also found as a benefit for HF patients who are intolerant of ACE-I (with candesartan, losartan and valsartan) Adverse Effects o Incidence similar to placebo o Do not elevate bradykinin o No cough Hydralazine o MOA § Mechanism is unknown § ¯ es SVR (decreases afterload) à ­ ed SV o Has minimal effects on venous capacitance o Most effective when combined with venodilators o When combined with isosobide dinitrate, the combination has been shown to ¯ mortality in HF (but not as effective as ACEIs) o Adverse Effects § Tachycardia, angina § Drug-induced lupus syndrome • Dose-related • Incidence of 5-10% • Reversible on discontinuing the drug Useful in patients with high filling pressure o ­ compliance, not a ¯ in volume § Combine with a diuretic Organic nitrates o Isosorbide dinitrate o Nitroglycerin o Pharmacodynamics § ¯ preload § ­ exercise capacity § ¯ symptoms of congestion (vasodilating) o Mechanism/Toxicity § Review angina material § Tolerance is a significant issue such that pts must be drug free 6-8 hours per day o Uses § Combined with hydralazine, ¯ mortality § Used by themselves, they ¯ congestion § Nitroglycerin is used IV in acute HF to ¯ ventricular filling pressures Sodium nitroprusside o Mechanism § Rapidly hydrolyzed to NO and CN o Pharmacodynamics § ¯ es both preload and afterload o Indications § Short term therapy in acute HF Adverse Effects § Hypotension § CN is rapidly metabolized to thiocyanate –thiocyanate and/or cyanide toxicity limit duration of drug use All patients with symptoms who have fluid retention o Loop diuretics for acute HF o Most HF patients require loop diuretics chronically to maintain euvolemia o Resistance occurs to loop agents* § If so, add metolazone (thiazide-like diuretic) Should seldom be used alone, even if symptoms are well-controlled o Monotherapy with a diuretic may cause adverse neurohormonal activation due to volume depletion o Mortality is improved by other drugs Adverse Effects o Review from previous material o Diuretic-induced hypokalemia* is particularly important for patients taking cardiac glycosides Contraindications o Acute, decompensated* stages of HF, § Sympathetics are highly active in acute HF § Beta-blocker poses a significant danger of reducing CO to intolerable levels When HF is under control (ACE-I and diuretics), a beta-blocker is useful in slowing the remodeling of the heart MOA is not entirely clear (two most likely candidates) o 1. High sympathetic tone in HF causes beta-receptor down regulation § Beta-blockers may counteract this effect by inducing receptor spread o 2. Beta-blockade may directly prevent remodeling caused by catecholamines Carvedilol o b (and a) Adrenergic Antagonist o Approved for class II and III heart failure o Use results in decreased hospitalizations and all-cause mortality* o Improves symptoms and slows progression o Nonselective b-blocker + a1 blocking effect o Dramatically ¯ mortality in Class II and III pts (class IV is less clear) o Adverse effects § Symptomatic hypotension common initially § Fluid retention: may have to ­ diuretics § Bronchospasm danger in asthmatics § Heart failure may worsen initially* Other approved agents include metoprolol, bisoprolol Technically, a diuretic o Enhanced Na and H2O excretion is so small as to be relatively unimportant as a diuretic As a diuretic o Inhibits aldosterone effects on the collecting ducts o Decreases Na/K exchange § Promotes hyperkalemia, but this is usually slight if no other o Diuretics • • • Beta blockers • • • • Aldosterone antagonists (spironolactone) • • • factors are present Hyperkalemia can be pronounced when coupled with an ACE inhibitor Recently demonstrated to improve mortality and morbidity in patients with severe (Class IV) HF Lends support to hypothesis that aldosterone effects on the heart are a major contributor to tissue remodeling MOA o Via receptor binding to guanylate cyclase-A and cGMP production § NO like (vasodilator) Hemodynamics o ¯ preload o ¯ afterload o ­ contractility and no ­ HR IV bolus and then IV infusion Elevated lab values in HF patients § • • Naturetic peptide- BNP • • • • POSITIVE INOTROPIC DRUGS Bi-dil New agents Cardiac glycosides (digoxin) • MOA o o o o • • • Inhibits cell membrane NA/K-ATPase § Relatively selective for cardiac enzyme Binds preferentially to and stabilizes the phosphorylated form of the enzyme An inverse relationship exists between extracellular K+ regulates and phosphorylation of the enzyme § Elevated K+ ¯ es the affinity of ATPase for cardiac glycosides § Low levels of K+ ­ es the affinity of ATPase for cardiac glycosides Inhibition of the Na/K-ATPase leads to enhanced Ca++ inside the cell § Higher Ca+2 concentrations lead to enhanced contractility Oral Mechanical Effects of Glycosides on the Heart o Due to ­ ed intensity of actin-myosin interaction § ­ ed myocardial contractile force (+ inotropic effect) § ­ ed velocity of contraction (+ dromotropic) § ¯ ed duration of systole (small effect) Electrical Effects of Glycosides on the Heart o Sinoatrial node § Slowing of the sinus rate § Through indirect (vagal) effects o AV node (antiarrhythmic effect) § Indirect effects (predominant) • ­ in ERP • ¯ in conduction velocity § Direct effects • Same as indirect • In combination (indirect + direct) get a high likelihood of AV block if the dose is too high o Purkinje fibers, ventricle § Indirect effects (negligible) § Direct effects (high doses) • • • • Toxicity o GI Anorexia, nausea, vomiting-excitation of chemoreceptor trigger zone (CTZ) § Diarrhea, abdominal discomfort--direct irritant o Headache, fatigue, malaise and drowsiness § Occur early in digitalis intoxication o Mental symptoms § Disorientation, confusion, delirium, hallucinations (“digitalis delirium”), nightmares, depression (elderly) o Vision § Blurred vision § White vision: white halos on dark object § Color vision: yellow and green common Dobutamine o MOA § ­ in cardiac output § ¯ in ventricular filling pressure § Beta1 (predominant) and beta2 agonist effects o Indications § Short-term support of cardiac output in advanced HF § Tolerance prohibits long-term use o Adverse Effects § Tachycardia with possible ­ in myocardial oxygen consumption (angina) Dopamine o MOA § Agonist effects at beta1 and dopamine1 receptors o Indications § Short-term therapy only § Especially useful to ­ splanchnic and renal blood flow o Adverse Effects § Tachycardia (worse than dobutamine) § At higher doses, ­ in SVR* • Mechanism is alpha agonist • Limits CO and worsens congestion § Dobutamine is generally a better choice MOA o ­ inward calcium flux in the heart & o Inhibition of cAMP phosphodiesterase à ­ cAMP § In heart: ­ cardiac output § In vasculature: ¯ SVR, decrease pulmonary capillary wedge pressure § Net result: improved hemodynamics Inotropic Vasodilatory o Some patients don’t tolerate due to hypotension Half-life = 2-3 hours § Adrenoreceptor agonists • • Phosphodiestera se inhibitors (milrinone) • • • • ¯ in ERP ¯ action potential duration ­ in conduction velocity • • Short-term therapy o PDE inhibitor of choice for short-term tx of acute failure o Parenteral administration Adverse Effects o Short Term § Fewer than inamrinone (removed from US), which reported nausea/vomiting, thrombocytopenia, and liver damage in significant number of patients o Long Term § ­ ed mortality* § Arrhythmias § Usually for PHTN ANTIARRHYTHMICS Drug CLASS 1 (Na+ Channel Blockers) • • • • Drug Specifics Act on fast response cells Reduce membrane responsiveness Reduce Vmax (depress conduction velocity) Prolong effective refractory period (ERP) o If RP is too long à asystole quinidine • Class 1A Drugs (Quinidine)-EP Effects procainamide • Moderate phase 0 depolarization and slowed conduction (2+) propafenone • Prolong repolarization • Direct Effects o Decrease Vmax o Increase ERP (effective refractory period) • Indirect Effects o Blocks K+ channels à after depolarizations • Use o Atrial flutter or fibrillation o Prevent V-tach and fibrillation • Quinidine Side Effects o Variable therapeutic concentration o Severe GI effects – anticholinergic o Metabolized in liver o Inhibits P450 system (metabolism of narcotics) lidocaine • Class 1B mexiletine • Minimal phase 0 depression and slowed conduction (0-1+) • Shortens repolarization • Direct Effects o Increases Block of Na+ channels (¯ Vmax) at high HR or in depolarized cell o Decreases AP duration o Increases ERP o Dissociates rapidly at resting Em • Side Effects o Dizziness o Seizures o Can cause dysrhythmias (Na channel blockade) • Use o V-tach o Digitals-induced arrhythmias o Regional or antiarrhythmic drug (Na channel blockade) flecainide • Class 1C • Marked phase 0 depression and slowed conduction (4+) • Little effect on repolarization • Direct Effects o Decreases Vmax (conduction velocity o Variable effects on ERP o Dissociates from Na+ channel slowly § Daily dosing § Hard to treat dysrhythmias • Side Effects o Pro-arrhythmic • CLASS 2 (Beta Adrenergic Blockers) atenolol esmolol metoprolol • • • • • • • CLASS 3 (K+ Channel Blockers) amiodarone dofetilide dronedarone sotalol ibutilide • • • • CLASS 4 (Ca+2 Channel Blockers) verapamil diltiazem • • • • Use o Atrial and ventricular arrhythmias resistant to other drugs (afib and SVT) Bind to ß-adrenergic receptors on cardiac cell membranes to competitively inhibit norepinephrine binding No effect in absence of catecholamines In the presence of catecholamines, the main action of Class II agents is to decrease diastolic depolarization o Takes a longer time to reach threshold, but doesn’t change threshold potential Uses o Used for all atrial arrhythmias, ventricular tachycardia and fibrillation Major side effects are negative inotropic effect, and bronchospasm Esmolol o Short acting IV Metoprolol o Long acting oral Very heterogeneous group Na+ channel blocking properties (amiodarone) ß-Adrenergic blocking properties (sotalol) Amiodarone o Very heterogenous o Potent K+ channel blocker* o Modest Na+ channel blocker o Modest Ca2+ channel blocker o Modest a and ß adrenergic receptor blocker o Uses § Used for all arrhythmias (V Tach) o Side effects § Pulmonary fibrosis § Altered thyroid function (inhibits conversion of T4 to T3) Acts primarily on slow response cells (SA & AV node), which are dependent on Ca2+ influx for Phase 0 of the action potential Major EP Effects of Ca+2 Channel Blockers o Depress phase 4 depolarization o Depress Vmax o Depress conduction velocity Uses o Paroxysmal atrial tachycardia o Atrial flutter Major Side Effects o Negative chronotropic effect § Decreases automaticity of SA node à can cause heart block o Negative inotropic effect § Decreases Ca2+ influx during plateau phase of ventricular action potential o Hypotension § Decreases Ca2+ influx into vascular smooth muscle cells o Peripheral edema o Constipation § Decreases Ca2+ influx into GI smooth muscle cells o Interacts with digitalis to slow conduction velocity in the AV node à heart block OTHERS adenosine • • digitalis magnesium • • • • • • • Activates K+ channels to increase ERP especially at the AV node o Inward K+ current and inhibition of Ca+2 current o Results in hyperpolarization and suppression of calcium dependent AP Blocks Ca2+ channels at the AV node o Can cause the heart to stop Indicated for supraventricular tachycardia Purinergic (P1) receptor “Chemical cardioversion” Enhances vagal parasympathetic activity to slow conduction at the AV node o CN X Indicated for atrial fibrillation and SVT to control ventricular response rate Indicated for torsade’s de pointes* Mechanism of action is unknown ACUTE CORONARY SYNDROME Drug ORGANIC NITRATES • • • • • • Drug Specifics Pharmacodynamic effects o Relax vascular smooth muscle o Mainly relaxation of large veins à ¯ venous return à ¯ preload à ¯ O2 demand (major effect) o Smaller ¯ in afterload § Too much = ¯ coronary perfusion o In oxygen supply (transient), effective in prevention of coronary vasospasm MOA o In healthy subjects, NO dilates coronary arteries § Hypothesis was that NO improved perfusion to hypoxic areas of heart § This hypothesis has been expanded o In angina of effort, § Direct infusion of NTG into heart does not relieve angina, but sublingual NTG does (mainly works on ¯ preload/ venous) Therapeutic Indications o Angina o CHF § CO o After MI § ¯ work of heart § ¯ platelet aggregation • ­ flow= less turbulent flow/ more smooth laminar flow o Raynaud’s disease Adverse Effects/ Limitations o Headaches, dizziness o Orthostatic hypotension o Tolerance § Dose/frequency dependent • 8-hr drug-free/day § Mechanism unknown o Drug holidays can alleviate Drug Interactions o Sildenafil § Inhibits phosphodiesterase-5 enzymes § Leads to reduced breakdown of cyclic GMP § Nitrates enhance production of cyclic GMP § = lots of cGMP= dramatically enhanced vascular effects, including severe hypotension Nitrate therapy in chronic stable angina o Short-acting § Relief during acute episodes § Prophylaxis of acute episodes o Long-acting § Monotherapy for mild angina § Adjunctive for more severe angina § Mainly as prophylaxis as chronic use o Limitations § Side-effects § Tolerance nitroglycerin isosorbide mononitrate BETA BLOCKERS isosorbide dinitrate Non-selective (if they can tolerate B2 blockade): • • • • • • • propranolol Beta 1 selective: metoprolol atenolol • • Ca+2 CHANNEL BLOCKERS (cardio selective) Ca+2 CHANNEL BLOCKERS (vascular) diltiazem verapamil nifedipine amlodipine felodipine • • • • • Large first-pass effect if taken PO Sublingual = short onset, short-acting Slower, less potent than NTG Short and long-acting preparations Less subject to first pass effect Will have profound hypotension in the ORà treatment is vasopressor, not inotropic agent or chronotropic agent MOA o Acute beta blockade § ¯ heart rate (major effect); and also ¯ contractility (lesser effect) à ¯ cardiac work à ¯ O2 demand o ¯ peripheral resistance (block renin release) – longer term effect – which à ¯ O2 demand o No effect on O2 supply Indications for Chronic Stable Angina o Monotherapy for mild to moderate angina of effort (not for Prinzmetal’s) o Combination therapy (angina of effort) o After MI Limitations o Bradyarrhythmias o CHF o Extracardiac effects Pharmacodynamics o Block Ca entry through L-type channels § à relaxation of arteriolar smooth muscle § à afterload à ¯ O2 demand § Also, supply due to dilation of coronaries* Calcium Role in Vascular Smooth Muscle Contraction o Intracellular Ca+2 ­es by 3 mechanisms § 1. Voltage Gated Channels • L, N and T § 2. Receptor Mediated Activation of Internal Stores (e.g., alpha1) § 3. Receptor Mediated Influx of Ca+2 o All mechanisms lead to cell contraction Block L-type Ca++ Channels “Pines” bind to a slightly different region than verapamil/diltiazem o Presumably accounts for different spectrum of vascular vs. cardiac effects Mechanism of Beneficial Effects of Ca+2 Channel Blockers in Angina o ¯ excitability of vascular smooth muscle § ¯ propensity of arteries to spasm (helpful in Prinzmetal’s) o ¯ tone of vascular smooth muscle § ¯ afterload (helpful in angina of effort) • Helpful in LV ischemia • Too much= not enough pressure to perfuse coronaries o In addition to their vascular effects, verapamil and diltiazem ¯ SA and AV node function • Can cause profound bradycardia à ¯ coronary perfusion § ¯ Cardiac contractility o Both effects lead to less cardiac work (useful in angina of effort) As Monotherapy (chronic phase) o 1. Angina with historical features suggesting dynamic coronary vasoconstriction (Prinzmetal’s) o 2. Patients with sinus bradycardia, AV dysfunction – use a “pine” o 3. Patients with atrial fib/flutter – use verapamil o 4. Patients resistant/tolerant to nitrates or b blockers Combination therapy with beta blocker o More effective than either individually for angina of effort o Factors influencing combination of Ca channel blocker and b blocker § Choice of calcium channel blocker § Presence of antecedent LV dysfunction or conduction system abnormalities § Other drug interactions (e.g., digoxin, alpha adrenergic blockers, nitrates) Does not impact heart rate and blood pressure Improves metabolism of the ischemic myocardial cells 325 mg chewed Clearly demonstrated to ¯ mortality in patients with unstable angina, reducing incidence of MI and death ¯ incidence of MI in chronic stable angina Effect due to inhibition of platelet aggregation Similar effect seen with heparin § • • Na+ CHANNEL ANTAGONISTS ANTICOAGULANTS ranolazine (Ranexa) aspirin • • • • • • • clopiogrel (Plavix) GP IIb/ IIIa inhibitors ANTICOAGULANTS, ANTIPLATELETS, FIBRINOLYTICS, & REVERSAL AGENTS ANTIPLATELET Drug Drug Specifics aspirin • • cilostrazol (Pletal) dipyridamole (Persantine) abciximab eptifibatide & tirofiban clopidogrel (Plavix) prasugrel (Effient) • • • • • • • • • • • • • • ticagrelor (Brillinta) ticlopidine (Ticlid) • • • • Antiplatelet Effects o Aspirin, at very low doses, irreversibly* inhibits cyclooxygenase o Since platelets cannot synthesize new enzyme, aspirin inhibits TXA2 formation and platelet aggregation for the life of the platelet (7-10 days) § Can’t reverse, can only give products as treatment § Patients need to DC 7-10 days before surgery o Only low doses* are required to inhibit cyclooxygenase o Higher doses inhibit the enzyme in endothelial cells and prevent the formation of prostacyclin (PGI2), a compound that inhibits platelet secretion and stimulates vasodilation Therapeutic Uses o Should be administered routinely to virtually all patients with myocardial infarction* o Secondary prevention of MI and stroke o Primary prevention of cardiovascular disease (benefits less clear) o Reduction of thromboembolic complications in patient with artificial heart valves, hemodialysis, coronary bypass grafts Inhibits PDE III (­ cyclic AMP) Inhibits platelet aggregation Stimulates vasodilation Indicated for reduction of symptoms of intermittent claudication Contraindicated in patients with CHF Inhibits platelet aggregation & weak vasodilator May be useful in secondary prevention of MI and stroke, but disappointing clinical trial Monoclonal antibody Prevents fibrinogen binding to glycoprotein GP IIb-IIIa à inhibiting platelet aggregation Greater antithrombotic activity than aspirin or heparin Approved as antithrombotic during angioplasty Approved for acute coronary syndromes Approved for the prophylaxis of stroke, MI, peripheral arterial disease, and acute coronary syndrome Clopidogrel and prasugrel irreversibly inhibits the platelet adenosine diphosphate (ADP-P2Y12) receptor and thus blocks the subsequent ADPmediated activation of the glycoprotein GPIIb/IIIa complex o This inhibits fibrinogen binding and platelet aggregation o Platelets exposed to clopidogrel are affected for the remainder of their lifespan (7-10 days) Ticagrelor reversibly inhibits the ADP-P2Y12 receptor Inhibits fibrinogen binding to platelets and blocks platelet aggregation and clot retraction Approved for prevention of thrombotic stroke in patients who have experienced TIAs o Better for cerebral vasculature* Adverse side effects limit its use pentoxifylline (Trental) • • ANTICOAGULANTS heparin • • • • • • Hemorheological agent = improves blood flow o Mechanism is unclear, but appears to enhance RBC flexibility, ¯ es blood viscosity o May ¯ TXA 2 levels and ­ PGI2 levels Indications o Intermittent claudication, chronic occlusive arterial disease of the limbs o Failed bypass or stent placement Heparin is the drug of choice for parenteral anticoagulant therapy MOA: o Heparin binds to antithrombin III o Heparin-antithrombin complex binds to and inactivates coagulation factors of common and intrinsic pathways: thrombin, Xa, IXa, XIa, XIIa o Heparin prolongs both the aPTT and the thrombin time (PTT) o At higher doses can also prolong the PT time o Routes of Administration § Continuous IV (often preceded by IV bolus) § Intermittent IV (not recommended) * § Subcutaneous Minidose § For post-surgery prophylaxis § NOT GIVEN IM OR ORAL Pharmacokinetics o Onset § IV= Immediate anticoagulant § SC= Begins in 20 - 30 minutes § Continuous IV infusion= 2-3-hour delay • Unless an initial bolus injection is given o Duration (of a single dose) § IV= 1 - 3 hours § SQ= 12-24 hours § Plasma (t1/2 is dose-dependent) = 1 -2.5 hours o Termination § Metabolized in liver or excreted unchanged Indications for Heparin Therapy o Prophylaxis of postoperative thrombosis= SQ o Myocardial infarction and unstable angina o Deep venous thrombosis and pulmonary embolism o Extracorpeal circulation (hemodialysis or heart-lung machine o Disseminated Intravascular Coagulation (DIC) o TIA= probably effective, but very risky § Not used if stoke-in-progress Therapeutic Use o Heparin is used when rapid onset of anticoagulation is required o Small doses to prevent thromboembolism o Medium doses to prevent propagation of thrombus o Large doses to inhibit established pulmonary embolus o If prolonged anticoagulation is necessary, the initial heparin therapy is overlapped with and then replaced with oral anticoagulant, i.e., warfarin Toxicity o Hemorrhage: from inadvertent overdose or from undiagnosed disease site Hematoma at site of injection Less common side effects: platelet aggregation, thrombocytopenia (heparin-induced thrombocytopenia or HIT), acute hypersensitivity, alopecia, osteoporosis, priapism Heparin-Induced Thrombocytopenia (HIT) o HIT-Type II § Delayed onset (5-14 days) § Severe thrombocytopenia (platelet counts< 100,000) • Functional platelets may be < actual count § This is an immune-mediated reaction, a heparinantibody complex caused significant platelet aggregation § Recovery can be delayed and consequences of peripheral thrombosis can be severe, including stroke, acute MI, skin necrosis. Amputation is necessary in up to 25% of patients and mortality approaches 25% § Incidence of Type II HIT is about 3% of all treated o HIT-Type I § Transient, reversible clumping of platelets § Platelet count >100,000 § Usually occurs within first few days of therapy § Usually asymptomatic and recover OK even if heparin continued Contraindications o Any site of active or potential bleeding o Severe hypertension or known vascular aneurysm o Recent head, eye, or spinal cord surgery o Head trauma o Lumbar puncture or regional anesthetic block o Tuberculosis, visceral carcinoma, GI ulcers Monitoring for Heparin Therapy o aPTT tested prior to starting therapy o aPTT of 1.5 -2.0 times control is the typical therapeutic goal o ACT intraoperatively Treatment of Heparin Overdose o Stop administration o Protamine sulfate § Binds to and inactivates heparin § Must be given slowly IV o Infusion of fresh-frozen plasma Smaller, active pieces of regular heparin Greater anti-Xa activity Less anti-platelet activity Used (SQ injection) for prophylaxis of DVT associated with hip, knee, and abdominal surgery Longer duration, simpler kinetics, clotting tests not usually required MOA: o Inhibits vitamin K epoxide reductase o Inhibits vitamin K-dependent post translation modification of clotting factors: thrombin, VII, IX, X, Protein C and S o o • • • • ANTICOAGULANTS: LOW MOLECULAR WEIGHT HEPARIN enoxaparin dalteparin ardeparin danaparoid ORAL ANTICOAGULANTS Warfarin (Coumadin) • • • • • • Without addition of the g carboxyglutamic acid residue the clotting factors cannot bind Ca+2 and are inactive Pharmacokinetics o Onset: considerably delayed (36 - 72 hours) § Delay in onset is due to long t1/2 of warfarin and the fact that pre-existing clotting factors are slowly cleared from the blood (t1/2 for VII = 6 hours) o Duration: prolonged § Proportional to the elimination t1/2 (25-60 hours) o Distribution § Rapid and complete absorption § Highly fat-soluble § 99% bound to plasma albumin o Termination: delayed (2 -5 days) § Liver and kidney metabolism § Long elimination t1/2 § New, active clotting factor must be synthesized Toxicities and Contraindications o Hemorrhage o Anorexia, nausea, vomiting, diarrhea o Skin necrosis o Contraindications § Pregnant patients: congenital abnormalities § Unreliable patient § Any recent bleeding § Recent eye, brain, or spinal cord surgery; head injury § Severe hypertension or known vascular aneurysm Indications o Overlap with heparin therapy to avoid long delay in onset of action* (bridge therpay) o Deep venous thrombosis o Pulmonary embolism o Atrial fibrillation (prevents arterial clots) o Rheumatic heart disease o Mechanical and prosthetic heart valves Therapeutic Guidelines o Warfarin is only given orally o Initial doses followed by maintenance doses § Adjust according to PT time (INR) o Determine PT time (INR) prior to starting therapy, daily until response stabilized, weekly until maintenance dose established o Warfarin is often administered concurrently with heparin until target INR is achieved and then patient is maintained on warfarin Patient Variability o Individual patient variation is very high* o Due to differences in absorption, elimination, liver function, and drug-drug interactions § BBWà VKOR 1 gene testing needed o Noncompliant and unreliable patients are not good candidates for warfarin therapy o Potential drug-drug interactions are numerous o • • • • • • ANTICOAGULANTS ANTICOAGULANTS: DIRECT THROMBIN INHIBITORS REVERSING AGENTS Drug Interactions o Warfarin is a classic example* for many types of drug-drug interaction o Inhibition or acceleration of warfarin metabolism o Displacement from plasma protein binding sites o Interference with mechanism of action o Interference with absorption • Overdose Treatment o Vitamin K o KCentra® Prothrombin Complex Concentrate (Human) o Data demonstrated with INR >3 prior to infusion decreased to INR of 1.2 by 30-minute time point rivaroxaban • Approved for the treatment of venous thrombosis, pulmonary embolism, (Xarelto) prevention of stroke with atrial fibrillation and acute coronary syndrome • Binds to the active site of factor Xa and inhibits its enzymatic action apixaban • Rivaroxaban is eliminated 66% via metabolism in the liver and 33% (Eliqus) unchanged drug in the urine • Apixaban is metabolized by the CYP450 system in the liver and excreted edoxaban by renal and GI system (Savaysa) • Since these factor Xa inhibitors prevent thrombin generation, via the intrinsic and extrinsic coagulation pathways they can (usually don’t) prolong both aPTT and PT times o Therefore, no routine monitoring of these laboratory parameters • Direct Xa Inhibitor Overdose Treatment o Coagulation Factor Xa-recombinant and inactivate-(Andexxa) • These agents all bind directly to thrombin • Highly selectively for thrombin • Do not required other proteins such as antithrombin III for activity • Expensive • These agents are approved for use in patients with thrombosis related to heparin-induced thrombocytopenia (HIT) and during coronary angioplasty hirudin & • An irreversible thrombin inhibitor produced by medicinal leeches now iepirudin available as the recombinant protein, lepirudin bivalirudin • Short-acting, synthetic thrombin inhibitor argatroban • Short-acting, synthetic thrombin inhibitor aabigatran • Overdose treatment= idarucizumab (PraxBind) (Pradaxa) vitamin K • Warfarin (Coumadin) overdose treatment • Vitamin K to overcome antagonism and maintain Vitamin K clotting factor formation (not immediate) Prothrombin complex concentratehuman (KCENTRA) protamine sulfate • • Warfarin (Coumadin) overdose treatment Contains Factor II, VII, IX-potency, Protein C and S (~ 30-minute onset) • • • Heparin overdose treatment Binds to and inactivates heparin Must be given slowly IV o Risk factors for protamine reaction idarucizumab (PraxBind) THROMBOLYTIC DRUGS • • § Previous exposure § Insulin therpay § Men with vasectomies aabigatran (Pradaxa) Overdose Treatment An antibody fragment that binds free and thrombin-bound dabigatran and neutralizes the dabigatran activity Direct Xa Inhibitor Overdose Treatment coag facor Xa- • inactivated zhso (Andexxa) • Thrombolytic= fibrinolytic • Normal fibrinolysis o Clots are dissolved by the action of the protease plasmin o Plasmin is formed from inactive plasminogen by tissue plasminogen activator (tPA) o Fibrinolysis is controlled by fast clearance of tPA, by a circulating inhibitor of tPA, and by the fact that tPA has much higher activity against fibrinogen bound to clots than free fibrinogen in circulation • Thrombolytic Therapy o Objective § Dissolve pathological blood clots by injecting a fibrinolytic enzyme or an activator of endogenous fibrinolysis without causing uncontrolled bleeding. o Indications § Acute myocardial infarction § Pulmonary embolism § Deep venous thrombosis § Ischemic stroke (special circumstances only) • CAT scan, MRI first tPA • Recombinant tissue plasminogen activator alteplase • Produced by genetic engineering activase • t1/2 = 3 min • IV bolus followed by IV infusion • Adverse effects o Serious hemorrhage • Expensive • Advantages over less expensive streptokinase difficult to demonstrate reteplase • A shorter, genetically engineered form of r-TPA • Diffuses more freely into clot than alteplase • Shorter half-life than alteplase streptokinase • A nonenzymatic activator of plasminogen extracted from hemolytic streptococci o Bacteria à can have serious reactions • A loading dose of streptokinase used to saturate pre-existing antibodies o Have to overcome intrinsic antibody activity • Serious hemorrhage is a potential side effect urokinase