Pharm 4: Cardiovascular drugs

Re-entrant circuits

Abnormalities in Impulse Conduction Normal impulses are conducted down bifurcated pathways to activate entire ventricular surface Re-entry = if unidirectional block results in abnormal conduction pathway Re-entry is the most common cause of arrhythmias Effects of drugs on re-entrant circuits Antiarrhythmics prevent re-entry by: • slowing conduction and / or • increasing the refractory period ie: unidirectional block is converted into bidirectional block

Carbonic Anhydrase Inhibitors

Acetazolamide • Act mainly in proximal tubular epithelial cells • Less efficacious than other diuretics • Often used for other pharmacological properties Clinical applications: • glaucoma (reduce elevated intraocular pressure) • epilepsy (used alone or with other antiepileptics) Clinical applications continued: • mountain sickness prophylaxis • metabolic alkalosis MOA • Inhibits intracellular carbonic anhydrase • Decreases ability to exchange Na+ for K+ (diuresis) • HCO3- is retained in lumen (increasing urinary pH) PK • Oral & well absorbed • t1/2 = 3-6 h. • Increase urine pH AE • Metabolic acidosis • Hyponatremia • Hypokalemia • Crystalluria • Malaise, fatigue, depression, headache, GI disturbances, drowsiness, paresthesia Summary: Increased urinary excretion of Na, K, HCO3, Urine volume

K+ sparing diuretics, spironolactone, eplerenone

Aldosterone antagonists- spironolactone, eplerenone Blocks aldosterone receptors • Used alone when there is excess aldosterone • Potassium levels must be closely monitored • Act mainly in collecting tubule Clinical applications: • heart failure (to treat refractory edema or as adjunct to standard therapy) • hypertension (adjunct to standard therapy) Clinical applications continued: • primary hyperaldosteronism (diagnosis & treatment) • edema (associated with excessive aldosterone excretion) • Oral & strongly protein bound (t1/2 = 2-3 days) • Spironolactone has an active metabolite (canrenone) AE: • Gastric upset & peptic ulcers • Endocrine effects (antiandrogen) • Hyperkalemia • Nausea, lethargy, mental confusion (rare) Summary: decreased urinary excretino of K, increased urinary excretion Na and urine volume.

Mechanism of Arrhythmias

All arrhythmias result from either: (a) disturbances in impulse formation (b) disturbances in impulse conduction (c) a combination of (a) and (b) Cardiac arrhythmias can cause the heart to: (a) beat too slowly (bradycardia) (b) beat too rapidly (tachycardia) (c) beat regularly (sinus tachycardia or sinus bradycardia) (d) beat irregularly (atrial fibrillation) Arrhythmias can be classed as either: • supraventricular (atrial or AV junctional) or, • ventricular Factors that can palpitate arrhythmias -ischemia • hypoxia • acidosis or alkalosis • electrolyte abnormalities • excessive catecholamine exposure • autonomic influences • drug toxicity (esp. antiarrhythmics)**** Causes of Arrhythmias Most arrhythmias arise either from abnormal automaticity or from a defect in impulse conduction Common causes of arrhythmias: • abnormal automaticity • re-entrant circuits • afterdepolarizations • accessory tract pathways

HF treatment conclusions

All patients with HF & systolic dysfunction (LVEF <40%) should take (unless a specific contraindication): ACE inhibitor and a β-blocker & a diuretic (if volume overloaded) • ARBS - patients who cannot tolerate an ACEI • Aldosterone antagonist - addition can be beneficial for patients with moderately-severe to severe HF or patients with LV dysfunction after an MI • Hydralazine/isosorbide dinitrate - addition can be beneficial • Digoxin - addition can decrease symptoms but not increase survival

Class II Antiarrhythmics

Beta Blockers • Reduce both heart rate & myocardial contractility (β1) • Slow conduction of impulses through myocardial conducting system • Reduce rate of spontaneous depolarization in cells with pacemaker activity (block of adrenergic release) • Little effect on action potential in most myocardial cells AE • Bradycardia, hypotension, CNS effects etc. • Contraindicated in CHF, severe bradycardia or heart block and severe hyperactive airway disease Kaplan: Decreased SA and AV node activity Decreased slope of phase 4 Drugs: -nonselective- propranolol and selective- acebutolol, esmolol -uses- prophylaxis post-MI, supraventricular tachyarrhythmias (SVTs), and esmolol (IV) is used in acute SVTs

ACE inhibitors diagram kaplan

Beta blockers can also block renin release

Class IV antiarrhythmics

Calcium channel blockers • Block Ca2+ channels • Decrease inward Ca2+ current leads to decreased rate of Phase 4 spontaneous depolarization • Slow conduction in tissues dependent on Ca2+ current (SA & AV nodes) • Major effects on both vascular smooth muscle & heart Kaplan: Block slow cardiac Ca channels Decrease phase 0, decrease phase IV decrease SA, decrease AV nodal activity Verapamil and diltiazem Uses- supraventricular tachycardias side effects- constipation (verapamil), AV block, dizziness, flushing, hypotension Drug interaction -additive AV block with beta blockers, digoxin. -verapamil displaces digoxin from tissue binding sites

Chronic Stable vs. unstable angina

Chronic Stable Angina Relative ischemia occurs when oxygen demand increases. Pain is usually associated with a predictable threshold of physical activity. LAD, RCA, Circumflex. Unstable Angina Clots often form in response to plaque rupture in atherosclerotic coronary arteries; however can also form because diseased coronary artery endothelium is unable to produce NO and prostacyclin that inhibit platelet aggregation and clot formation Variant Angina Enhanced sympathetic activity (eg, emotional stress) especially when coupled with a dysfunctional coronary vascular endothelium (reduced NO) can precipitate vasospastic angina

MOA of Beta Blockers

Clinical Applications • Recommended in all patients (unless contraindicated) with stable angina who have had an ACS or who have left ventricular dysfunction AE: • Bradycardia • Conduction disturbances • Bronchoconstriction • Worsening of symptoms of peripheral vascular disease • Fatigue, • CNS effects • Impotence etc.

Ca2+ channel blockers

Clinical applications Hypertension (equally effective in black & white patients) • Have intrinsic natriuretic effect (no need for diuretic) • Useful in patients with asthma, diabetes, peripheral vascular disease PK • High-doses of short-acting dihydropyridine Ca2+- channel blockers can increase risk of MI (excessive vasodilation & reflex cardiac stimulation) • Sustained release preparations are preferred AE • Verapamil constipation (~7 %), should be avoided in patients with congestive HF (-ve inotropic effects) • Dihydropyridines hypotension, dizziness, headache, fatigue, peripheral edema (esp. feet & ankles), bradycardia, heart block reflex tachycardia can occur, especially in short-acting preparations Kaplan: block L-type Ca channels in heart and blood vessels. REsults in decreased intracellular Ca+, causes decreased CO (verapamil and diltiazem), decreased TPR (all CCBs). Drugs: verapamil, diltiazem and dihydropyridines 'dipines', prototype = nifedipine

alpha blockers

Clinical applications • Hypertension (due to side-effect profile, development of tolerance & advent of safer antihypertensives, α- blockers are seldom used in treatment of hypertension) • Reserved as alternative agents for unique situations, such as men with benign prostatic hyperplasia • Have been used in heart failure (but not commonly) AE • Orthostatic hypotension (which may lead to syncope) upon first-dose or large increases in dose • Concomitant use of a β-blocker may be necessary to blunt short-term effect of reflex tachycardia • Dizziness, drowsiness, headache, lack of energy, nausea, and palpitations, • Doxazosin shown to increase rate of congestive HF Kaplan alpha 1 blockers Decrease arteriolar and venous resistance reflex tachycardia drugs: prazosin, doxazosin, terazosin uses- htn, BPH (decrease tone of urinary sphincters) **side effects: first dose syncope, orthostatic hypotension, URINARY incontinence! Advantage; good effect on lipid profile

Calcium Channel Blockers- MOA

Clinical applications: • Used in combination with β-blockers when initial treatment with β-blocker is not successful or, as a β- blocker substitute when β-blockers are contraindicated • Relieve symptoms of variant angina

ADH Antagonists

Conivaptan Clinical applications : • euvolemic and hypervolemic hyponatremia • SIADH (syndrome of inappropriate ADH secretion) • heart failure (only when benefits outweigh risks - safety not established) • IV only • Metabolized by & potent inhibitor of CYP 3A4 AE: • Infusion site reactions • Thirst • Atrial fibrillation • GI & electrolyte disturbances • Nephrogenic diabetes insipidus Contraindications • Hypovolemic hyponatremia • Renal failure

Allergies to Sulfonamide Containing Drugs

Cross allergenicity with: -Carbonic anhydrase inhibitors -All loop diuretics, *****except ethacrynic acid***** -Thiazides -Sulfa antibiotics -Celecoxib Sulfa is very lipid soluble. Added to things for better absorption, but with lipid solubility, comes protein binding. And if its able to act as a hapten, once protein bound, can trigger an allergic response.

Sodium Nitroprusside

Direct NO donor = very effective, immediate vasodilator --Clinical Applications • ICU & emergency settings • used to treat severe hypertensive emergencies & severe heart failure --Pharmacokinetics • IV only (t1/2 < 3min) • continuous infusion is required AE: • Severe nausea • Vomiting • Headache etc • High doses = cyanide intoxification (nitroprusside releases cyanide along with NO)

Inotropic Agents

Disadvantages to Digoxin • narrow therapeutic margin • unfavourable, complicated pharmacokinetics • drug sensitivity varies between patients • drug sensitivity may change during therapy • severe, potentially lethal adverse effects

Treatement of Diastolic HF

Diuretics Can be used to treat any resulting pulmonary edema; must be used cautiously (do not want stroke volume to decrease) Calcium-channel blockers In diastolic failure inotropy can be normal so Ca2+- channel blockers do not impair stroke volume. Shown to be beneficial in improving ventricular relaxation and reducing heart rate β-blockers Similar beneficial effects to Ca2+-channel blockers Agents NOT used • Positive inotropes (increasing inotropy can lead to increased outflow obstruction)

Drugs causing Torsades

Drugs causing torsades include: -potassium channel blockers -antipsychotics (thioridazine) -tricyclic antidepressants

Class IC Antiarrhythmics

Flecainide, Propafenone • Markedly depress Phase 0 of action potential > marked slowing of conduction of action potential but, little effect on duration or ventricular effective refractory period • Associate and re-associate slowly with Na+ channels • Show prominent effects even at normal heart rates Kaplan: Block fast Na channels, esp His-purkinje tissue no effect on APD No ANS effects

Preload and Afterload

Force against which ventricles must act. • Dependent on vascular resistance (aortic BP)

Cardiac Muscle Contraction

Force of cardiac muscle contraction is directly related to [Ca2+]i Sources of [Ca2+]i • voltage-sensitive Ca2+ channels • exchange with Na+ • released from sarcoplasmic reticulum Removal of [Ca2+]i • Na+/Ca2+ exchange • uptake by sarcoplasmic reticulum

Loop Diuretics

Furosemide, torsemide, ethacrynic acid • aka 'High-Ceiling' diuretics • Highest efficacy in removing Na+ & Cl- from body • Act on ascending limb of Loop of Henle Clinical applications: • diuretics of choice for reducing acute pulmonary edema associated with heart failure and hepatic or renal disease******** • hypertension K: can use for anion overdose, hypercalcemic states, hypertension, refractory edemas They vasodilate by increasing PGLs. NSAIDs can cancel or diminish the anti-hypertensive effect of loop diuretics.

Treatment Strategies

Goal is to reduce CV & renal morbidity and mortality • Stage 1 hypertension ---often controlled with single drug • Stage 2 hypertension ---often requires multiple drugs • Initiate therapy with a single drug • ACE-inhibitor, ARB blocker, calcium channel blocker or thiazide diuretic • If BP not controlled then add another drug • selected on minimizing adverse effects • If BP still not controlled a third drug can be added • usually vasodilator • First-line agents • ACE-inhibitors, ARBs, calcium channel blockers, thiazide diuretics • Second-line agents • β-blockers, aldosterone antagonists • Other agents • loop diuretics, α-blockers, direct vasodilators, central α2-agonists, renin inhibitors

Pathophysiology of heart failure

Heart failure Symptoms When cardiac output is inadequate to provide O2 needed by the body Tachycardia, decreased exercise tolerance, dyspnea, peripheral & pulmonary edema, cardiomegaly Most common cause in US Coronary artery disease and hypertension Two types of failure (impaired ability to adequately fill and/or eject blood): -Systolic failure Mechanical pumping action (contractility) and the ejection fraction of the heart are reduced -Diastolic failure Stiffening and loss of adequate relaxation > abnormal ventricular filling, resulting in a reduction in cardiac output (ejection fraction may be normal) Congestive Heart Failure (CHF) Abnormal increases in blood volume & interstitial fluid. Symptoms include dyspnea from pulmonary congestion in left HF, and peripheral edema in right HF Role of Physiologic Compensatory Mechanisms in HF Chronic activation of SNS & renin-angiotensin- aldosterone pathway is associated with cardiac tissue remodeling. This prompts additional neurohumoral activationvicious cycledeath

Therapeutic strategies

Heart failure is a progressive disease, characterized by gradual reduction in cardiac performance & episodes of acute decompensation Treatment is directed at both: (1) reducing symptoms & slowing progression of disease and (2) managing acute episodes Chronic HF • light aerobic exercise • low dietary intake of Na+ (2g sodium diet) • smoking cessation • achieving ideal weight • 2L fluid restriction • treatment of comorbid conditions • use of ACE-inhibitors, diuretics, & inotropic agents • NSAIDS, alcohol, Ca2+-channel blockers should be avoided if possible (may exacerbate HF)

Categories of HTN

Hypertension: • Sustained systolic BP > 140 mmHg or, • Sustained diastolic BP > 90 mmHg Results from: increased peripheral vascular smooth muscle tone > increased arteriolar resistance & reduced capacitance of venous system In most cases cause is unknown

Treatment rationale of angina

Increase oxygen delivery • coronary vasodilators • anti-thrombotic drugs Decrease oxygen demand • vasodilators (reduce afterload & preload) • cardiac depressants (reduce heart rate & contractility)

Phentolamine, esmolol, hydralazine

Kaplan: Hydralazine decrease TPR via arteriolar dilation use- moderate - severe hypertensino side effects: -sle like syndrome and slow acetylators -edema -reflex tachycardia also used in pregnancy

Class IB Antiarrhythmics

Lidocaine, mexiletine, tocainide • Slows Phase 0 & decreases slope of Phase 4 • Shortens Phase 3 repolarization • Little effect on depolarization phase of action potential in normal cells • Decrease duration of action potential by shortening repolarization • Rapidly associate and dissociate with Na+ channels Kap: Block fast Na+ channels (decrease Ina channels0 BLock inactivated channels (slow conduction in hypoxic and ischemic heart) Decreases Action Potential Duration due to the block of the slow Na+ 'window' currents

Kaplan Loop Diuretics

Loop diuretics work on the Cl, Na, K symport K leaks back out. Then you get a positively charged luminal membrane, which repels the cations to go through the tubule. Loop diuretic will cause hypoEVERY ion in the body.

Angiotensin receptor blockers (ARB's)

Losartan, valsartan Alternatives to ACEI's Block angiotensin-2 type 1 receptors decreases BP by causing arteriolar and venous dilation Block aldosterone secretion > decrease Na+ and H2O retention. Decreased diabetc nephrotoxicity Do NOT INCREASE BRADYKININ LEVELS AE • Similar to those of ACE inhibitors • Dry cough does not occur (due to no effect on bradykinin levels) • Angioedema risk is significantly lower than with ACEI's Contraindications • Pregnancy • Patients with bilateral renal artery stenosis ARBs: losartan and other -sartans block AT1 receptors same results as ACEIs on BP mechanisms do not interfere with bradykinin degradation

HTN treatment for patients with compelling indications

MI -- Beta blocker then add ACEI/ARB -- Aldosterone antagonist Prior ischemic stroke -- ACEI/ARB + thiazide diuretic

MOA of Digoxin

MOA: Positively inotropic- increases force of heart contraction Negatively chronotropic- decreases heart rate • Inotropic action : increased cytoplasmic Ca2+ concentration that enhances contractility of cardiac muscle and > increases cardiac output • also • reduced sympathetic activity • reduced peripheral resistance > decreases HR •vagal tone also enhanced > decreased myocardial O2 demand • [Ca2+]i must be lowered for cardiac muscle to relax • Na+/Ca2+ exchanger extrudes Ca2+ from myocyte • concentration gradient determines net ion movement • inhibiting active transport of Na+ decreases Na+ concentration gradient & ability for Ca2+ to leave cell • increased cellular Na+ is exchanged for Ca2+ • Ca2+ is retained intracellularly > increased [Ca2+]i • if Na+/K+ ATPase is extensively inhibited > dysrhythmias Effects of digoxin result from direct action on cardiac muscle as well as indirect actions (autonomic effects): • increases force and velocity of myocardial systolic contraction (+ve inotropic action) • decreases in the degree of activation of SNS & renin- angiotensin system • slowing of the HR & decreases conduction velocity through AV node

Verapamill, Diltiazem

MOA: • Inhibit voltage-sensitive Ca2+ channels decrease in slow inward current that triggers cardiac contraction • Bind only to open, depolarized channels, preventing repolarization before drug dissociates • Use/state-dependent • Slow conduction & prolong effective refractory period Clinical Applications More effective against atrial than ventricular arrhythmias • Supraventricular tachycardia is major arrhythmia indication • Reduction of ventricular rate in atrial fibrillation & flutter • Hypertension, angina AE: • Negative inotropes • Transient decrease in BP • CNS effects (headache, fatigue, dizziness) • GI effects (constipation, nausea) Contraindications Verapamil can increase the concentrations of other cardiovascular drugs such as digoxin, dofetilide, simvastatin, & lovastatin

Class I antiarrhythmics

Na+ Channel Blockers • Block fast inward Na+ channels • Decreased Na+ entry slows rate of rise of Phase 0 depolarization • Cause decrease in excitability and conduction velocity • Different properties depending on their affinity for Na+ channel • Use / state-dependent Use/state dependent • Drugs bind more rapidly to open or inactivated Na+ channels • Drugs have greater effect in tissues more freq. depolarizing = use/state dependence (cells discharging at abnormally high frequency are preferentially blocked)

MOA of Nitrates

Nitrates mimic the actions of endogenous NO Rapid reduction in myocardial O2 demand (systemic vasodilatation) & relief of symptoms • In CV system, nitrous oxide (NO) is primarily produced by vascular endothelial cells • NO functions: --• vasodilation --• anti-thrombotic --• anti-inflammatory (all involve NO-stimulated formation of cGMP)

Procainamide

PK • Oral • Metabolized by CYP 2D6 (N-acetyltransferase), so know about slow/fast metabolizers because its a good hapten. • Partly acetylated to N-acetylprocainamide (NAPA) which prolongs duration of action potential (class III) AE: Chronic use = high incidence of AE • reversible lupus-like syndrome (25-30%) SLE-like syndrome • toxic doses: asystole, induction of ventricular arrhythmias • CNS effects (depression, hallucination, psychosis) • weak anticholingeric effects • hypotension Hematotoxicity, CV effects (torsades) Contraindications • Hypersensitivity • Complete heart block • 2nd degree AV block • Systemic lupus erythematosus (SLE) • Torsades de Pointes • Heart failure & hypertension (use with caution)

Spironolactone

Patients with advanced heart disease have elevated aldosterone levels due to: --• angiotensin stimulation --• reduced hepatic clearance MOA Aldosterone antagonist > prevents Na+ retention, myocardial hypertrophy & hypokalemia Clinical Application in HF + ACE inhibitors are shown to decrease morbidity & mortality in patients with severe heart failure Adverse Effects Hyperkalemia (esp. in patients taking ACEIs/ARBs, K+ supplements or who have renal failure) GI disturbances (gastritis, peptic ulcer) CNS effects (lethargy, confusion) Endocrine abnormalities (gynecomastia, decreased libido, menstrual irregularities)

Na+ Channel Blockers PK/AE

Pharmacokinetics • Metabolized by CYP 3A4 Adverse Effects • QT interval prolongation (main concern with this new drug) • Nausea • constipation • dizziness

Pacemaker Cell

Phosphorylation with beta 1 stimulation by NE causes Na and Ca to open, K+ channels to close. M2 is Gi coupled, and if stimulated causes dephosporylation of all channels and the opposite effect.

Therapy of cardiac arrhythmias

Principles: (1) eliminate or minimize precipitating factors (2) define precisely the type of arrhythmia (3) remember that most antiarrhythmic drugs can also cause arrhythmias >minimize risks of drug therapy Goals: (1) termination of ongoing arrhythmia (2) prevention of recurrent arrhythmias Tachyarrhythmias: • antiarrhythmic drugs • external electrical cardioversion • ablation of arrhythmic pathways & implantable cardioverter-defibrillators have increasing role Bradyarrhythmias: • cardiac pacing is treatment of choice • atropine & sympathomimetics have been used Non-pharmacological therapy • pacemakers • cardioversion • catheter ablation • surgery

Drugs that cause SLE-like syndrome

Procainamide Hydralazine Isoniazid +ANA +AntiHistone- classic for drug induced SLE

Wolffe-Parkinson-White Syndrome

Quinidine blocks IA pathway. Also antimuscarinic effect. Will also decrease action potential by blocking phase 0. DO NOT slow AV conduction!!!!

Class IA Antiarrhythmics

Quinidine, procainamide, disopyramide • Slow rate of change of phase 0 ---• slowing conduction, prolonging action potential & increasing ventricular effective refractory period • Prolong phase 3 by an inhibiting K+ channels • Intermediate speed of association with activated / inactivated Na+ channels & intermediate rate of dissociation

ACE inhibitors flowchart

Recommended for all patients with: -symptomatic heart failure -asymptonmatic patients with decreased LVEF or history of MI Suggested for patients: -at high risk for developing heart failure due to atherosclerotic disease, obesity, diabetes mellitus or hypertension Adverse E • Hypotension, • Persistent dry cough • Teratogenic****** • Renal insufficiency • Hyperkalemia • Angioedema

Beta-blockers MOA and HF

Recommended in addition to an ACEI for patients with: - symptomatic heart failure - asymptomatic patients with a decreased LVEF or history of MI AE: • Same as all β-blockers • Use cautiously in asthmatics and patients with severe bradycardia • Fluid retention (upon initial treatment) - an increasing dose of concurrent diuretic may help Kaplan: Side effects: -cardiovascular depression -fatigue -sexual dysfunction -increase LDLs and TGs. Cautions in use: asthma, vasospastic disorders, diabetes (mask hypoglycemia)

Drugs interfering with storage vesicles

Reserpine (destroys vesicles) -decreases CO and decreases TPR (decreases NE in periphery) -decreases NE, decreased Dopamine, decreases serotonin in CNS Side effects: -depression (often severe)- suicide -edema -increased gastrointestinal secretions

Kaplan K+ sparing agents

Spironolactone uses- hyperaldosteronic state, adjunct to K+ wasting diuretics, antiandrogenic uses, congestive heart failure. Side effects: hyperkalemia and acidosis, antiandrogen Amiloride and triamterene: Na+ channel blockers use- adjunct to K+ wasting diuretics, lithium induced nephrogenic diabetes insipidus Side effects: hyperkalemia, acidosis Note: eplerenone is a selective aldosterone-receptor blocker devoid of antiandrogenic effect

Electrolyte disturbances and drugs 1

Start with Potassium... retained? then sparing. Then look at bicarbonate for CA inhibitors. Then look at calcium- thiazides

Dihydropyridines

Strongest direct acting.

Nitrates and their action on the cardiovascular system

Systemic Vasculature --• vasodilation (venous dilation > arterial dilation) --• decreased venous pressure --• decreased arterial pressure (small effect) Cardiac --• reduced preload & afterload (decreased wall stress) --• decreased oxygen demand Coronary --• prevents/reverses vasospasm --• vasodilation --• improves subendocardial perfusion --• increased oxygen delivery

Abnormal Automaticity

The SA node sets pace of myocardium contraction however, if other cardiac sites show enhanced automaticity they may generate competing stimuli leading to arrhythmias ie: abnormal automaticity Most antiarrhythmics suppress automaticity by blocking either Na+ or Ca2+ channels to reduce ratio of these to K+ to • decrease slope of phase 4 depolarization, and/or, • raise threshold of discharge to less negative voltage > decreased frequency of discharge

M and h gates

The inactivated sodium channel is the reason that another action potential can't start. Class Ia Na channel blocks the open/active sodium channel. Ib Na channel blocker blocks the inactive channel. Ic blocks all 3 channels. Hypoxic tissue tends to be depolarized tissue

Diuretics

Thiazides Clinical applications Counteract Na+ & H20 retention caused by other antihypertensive drugsuseful in combination therapy • Particularly useful in black & elderly (with normal renal & cardiac function) AE of thiazides • Hypokalemia • Hyperuricemia • Hyperglycemia • Hypomagnesemia • Hypercholesterolemia

Kaplan Beta blockers and Carvedilol

Use in angina of effort Beta blockers are CONTRAINDICATED in vasospastic angina!!!! Can WORSEN in pts with Prinzemetal. Carvedilol is clinical equivalent to isosorbide in angina of effort.

Calcium Channel Blockers CCBs kaplan

Uses: -htn, angina, antiarrhythmics (verapamil, diltiazem) Side effects: -reflex tachycardia -dipines -gingival hyperplasia - dipines -constipation- verapamil

Kaplan Thiazides

Weak action because less than 10% of the Na is absorbed in the distal tubule. Thiazides work on the Na/Cl symport. Gs coupled receptor on the basolateral membrane increases cAMP which makes PKA which phosphorylates the Calcium cannel (PTH dependent channel) on the luminal membrane. When blocking the symport, you have lower sodium inside the cell which should help the sodium calcium exchange There should be an increase in reabsorption of calcium in the kidney causing HYPERcalcemia (as opposed to the loop diuretics causing HYPOcalcemia)

Afterdepolarizations

When a normal action potential triggers extra abnormal depolarizations / oscillations > arrhythmias • early afterdepolarizations • delayed afterdpolarization

Renin Inhibitor

aliskiren blocks formatino of angiotensin I same results as ACEIs on BP mechanisms Aliskiren does not interfere with bradykinin degradation

Antiarrhythmics and action potential

antiarrhythmics- slow hr, stretching the action potential out. Increasing APD would increase ERP.

Ace inhibitors

catopril, enalapril, lisinopril • First-line agents • Decrease BP by decreasing peripheral vascular resistance • INHIBIT ACE (angiotensin converting enzyme) that cleaves angiotensin I to form angiotensin II • DECREASE Na+ & H20 retention • INCREASE BRADYKININ levels • DO NOT reflexively increase cardiac output, rate or contractility Clinical applications • Hypertension (most effective in white, young patients) + diuretic = effectiveness similar in white and black • Preserve renal function in patients with either diabetic or non-diabetic nephropathy • Effective in treatment of chronic HF • Standard of care for patients following MI (started 24h after end of infarction) AE • Hyperkalemia • Hypotension • Dry cough • Angioedema (rare but life-threatening) • Acute renal failure (patients with bilateral renal artery stenosis) • Rash, fever, altered taste Contraindications • Pregnancy During 1st trimester due to risk of congenital malformations and during 2nd and 3rd trimesters because of risk of fetal hypotension, anuria & renal failure • Patients with bilateral renal artery stenosis Captopril and other -prils -block formation of angiotensin II -result in prevention of AT1-receptor stimulation -decreases aldosterone, vasodilation -prevent bradykinin degradation

Propranolol, metoprolol

clinical applications • Reduce incidence of sudden arrhythmic death after MI • Control of supraventricular tachycardias (atrial fibrillation & flutter, AV nodal re-entrant tachycardias) • Ventricular tachycardias (catecholamine-induced arrhythmias, )

Esmolol

clinical applications • Short-acting β1-selective antagonist •t1/2 =~9min • Used IV for treatment of acute arrhythmias occurring during surgery or in emergency situations

causes gingival hyperplasia

dipines and phenytoin

Thiazides- MOA, clinical applications

hydrochlorothiazide, chlorthalidone, metolazone, indapamide • aka. 'ceiling diuretics' • Act on distal tubule - all have equal maximum effects Clinical applications: • hypertension (either alone or with other antihypertensives such as ACE inhibitors or β- blockers) HTN: also ATP dependent K+ channel openers. like minoxidil, diazoxide. • heart failure (mild-moderate) Nephrolithiasis (calcium stones) nephrogenic diabetes insipidus Clinical applications continued: • hypercalciuria (inhibit Ca2+ excretion, particularly useful for kidney stones) • diabetes insipidus (produce hyperosmolar urine) • premenstrual edema

Angiotensin converting inhibitors and ARBs uses, side effects, kaplan

hyperkalemia because of lack of aldosterone. Pp with renal artery stenosis suffer from renovascular hypertension

Use of antihypertensive drugs in comorbid conditions

hypertension is the first Nodular glomerulosclerosis- kimmelsteil and wilson. Hyaline arteriosclerosis > nodular/diffuse glomerulosclerosis. use ace inhibitors- to decrease the likelihood of glomerulosclerosis by improving blood supply- ACEIs and ARBs

Altitude- kaplan

hypoxia causes vasoconstriction in the lung!!! This changes the resistance to flow in the lung- increases capillary pressure.

Osmotic diuretics

mannitol- inhibits water reabsoprtion throughout the tubule. Increases urine volume. Clinical applications : • increase urine flow in patients with acute renal failure • reduce increased intracranial pressure & treatment of cerebral edema • promote excretion of toxic substances Decreases IOP in glaucoma- acute attack of narrow angle glaucoma Decreases Intracerebral pressure Oliguric states (eg rhabdomyolysis- related to statins, related to myoglobin toxicity, increase its clearance by using Mannitol) Side effect: acute hypovolemia. PK: • IV (only small amount absorbed from GI tract) AE: • Extracellular water expansion (can lead to hyponatremia) • Tissue dehydration

2 drugs for pre-eclampsia

mild-moderate HTN: alpha methyldopa moderate-severe: hydralazine

Drugs that need digitizing

used with digoxin: Quinidine and verapamil

Heart failure

• 5.8 million patients in US (23 million worldwide) • Annual inpatient and outpatient costs in the US > 10 billion $US • Leading cause of hospitalization in the > 65 y age group • Mortality rate @ 5 y = ~ 50% Risk factors: • Myocardial infarction • Hypertension • Coronary artery disease • Diabetes mellitus • Family history of cardiomyopathy • Use of cardiotoxins • Obesity

Etiology and pathophys of HTN

• > 90 % patients have essential hypertension (unknown origin) Risk Factors: • family history • obesity / high dietary intake of sodium • age • stress • smoking • 4 x more likely in black compared to white people • more common in middle-aged males than females • Affects ~ 29 % of US population over 18 (~ 89 million people) • Can lead to strokes, congestive HF, MI and renal damage • Mortality & morbidity is sig. decreased if hypertension is treated early and effectively

Loop diuretics

• Act promptly in patients with poor renal function or heart failure • More potent at inducing diuresis & can cause more side effects • Used primarily in patients who do not respond to thiazide therapy adequately • Cause increased renal vascular resistance & decreased renal blood flow

Pulmonary Hypertension

• An increase in blood pressure in the pulmonary artery, pulmonary vein or pulmonary capillaries Treatments • Prostaglandins (epoprostenol) • Inhibitors of endothelin synthesis and action (bosentan) **PGI2 is contraindicated in pregnancy Type V PDE is in arteries and corpora cavernosum

Pathophysiology of Angina

• Angina pectoris is the principal clinical manifestation of CAD • Characterized by pre-cordial pressure-like discomfort resulting from myocardial ischemia • Immediate cause of angina pectoris = imbalance between myocardial O2 supply and demand • Transient episodes that don't cause cellular death (MI) & last ~15 s > ~15 min) Kaplan: drug strategies -increase oxygen delivery by decreasing vasospasm (nitrates and CCBs) -decrease oxygen requirement by decreasing TPR, CO or both (nitrates, CCBs, and beta blockers

BP Control

• Arterial BP directly proportional to cardiac output & peripheral vascular resistance • Cardiac output & peripheral resistance controlled by baroreflexes, which are mediated by SNS and renin-angiotensin-aldosterone system Antihypertensives: decreased cardiac output and/or decreased peripheral resistance

Amiloride and triamterene

• Block Na+ transport channels ( Na+/K+ exchange) • Do not rely on presence of aldosterone • Usually used in combination (not very efficacious) • Can prevent K+ loss associated with thiazides & furosemide • Hyperkalemia • Hyponatremia • Leg cramps • GI upset • Dizziness, pruritus, headache & minor visual changes Summary: decreased urinary excretino of K, increased urinary excretion Na and urine volume.

Class III Antiarrhythmics

• Block repolarizing K+ channels • Prolong action potential (and QT interval) without altering Phase 0 or resting membrane potential • Prolong effective refractory period • All have potential to induce arrhythmias***** K+ channel blockers Kaplan: Decreases Ik, slowing phase 3 Increases APD and ERP

Na+ Channel Blockers- MOA, clinical

• Blockade of Na+ current that facilitates Ca2+ entry via Na+/Ca2+ exchanger • Decreased intracellular Ca2+ reduces ventricular tension & myocardial O2 demand • Thought to also produce myocardial relaxation • May modify fatty acid oxidation Clinical applications Option for patients who have failed all other antianginal therapies 3 classes: Class 1A: -block fast Na+ channels (decreases INa) -preferrentially in teh open or activated state -increases APD and ERP -also blocks K+ channel (prolongs repolarization)

Minoxidil

• Causes direct peripheral vasodilatation of arterioles • Oral treatment for severe-malignant hypertension (refractory to other treatments) AE: • Causes direct peripheral vasodilatation of arterioles • Oral treatment for severe-malignant hypertension (refractory to other treatments) Kaplan: Drugs acting to open ATP dependent potassium channels: Minoxidil and Diazoxide -open K channel, causing hyperpolarization of smooth muscle. Results in arteriolar vasodilation (selective) Uses: hypertensive emergencies (diazoxide) severe hypertension (minoxidil) baldness (topical minoxidil) ATP dependent potassium channels are found in 2 tissues: arterioles and beta cells of the pancreas. AE: hypertrichosis (minoxidil) hyperglycemia- decrease insulin release (Diazoxide)- has been used in the treatment of insulinoma edema reflex tachycardia

Hypertensive crises

• Clinical symptoms characterized by severe (typically acute) elevations in BP (generally diastolic BP >120mmHg) > vascular injury & organ damage • Divided into two general categories: --• Hypertensive Emergencies --• Hypertensive Urgencies

Atrial Fibrillation

• Commonest arrhythmia encountered clinically • Can be paroxysmal (intermittent) or persistent (chronic) • For most patients is not immediately life-threatening, management is focused mainly on symptom control & prevention of long-term morbidity & mortality Treatment Approaches: • Rhythm control (restore and maintain sinus rhythm) • Rate control (control of ventricular rate while allowing atrial fibrillation to continue)

Quinidine

• Concomitant Class III activity (block K+ channels) • Can precipitate arrhythmias • Due to toxicity is being replaced by Ca2+ antagonists Clinical Applications • Conversion and prevention of relapse into atrial fibrillation +/or flutter • Suppression of ventricular arrhythmias Replaced by more effective/safer antiarrhythmic agents MOA/PK • Prevents Na+ influx • Slows Phase 0 • Decreases slope of Phase 4 • Inhibits K+ channels Pharmacokinetics • Quinidine sulfate = rapid oral absorption • Forms active metabolites (CYP 3A4) • Inhibits CYP 2D6, 3A4 & P-glycoprotein AE • Arrhythmias (torsades de pointes)! due to anti-muscarinic actions. Can lead to vfib. • SA & AV block or asystole • Nausea, vomiting & diarrhea (30-50%) • Thrombocytopenic purpura • Toxic doses - ventricular tachycardia (exacerbated by hyperkalemia) • Cinchonism (blurred vision, tinnitus, headache, psychosis) • Mixed α-adrenergic block & antimuscarinic properties • Can increase [digoxin] by decreasing renal clearance Contraindications Do not use in patients with: • complete heart block (note interactions from kaplan slide) Use with extreme caution in patients with: • prolonged QT interval • history of Torsades de Pointes • incomplete heart block • uncompensated heart failure • myocarditis • severe myocardial damage

Direct vasodilators

• Concurrent use of hydralazine & isosorbide dinitrate recommended for use in patients: • who cannot tolerate ACEI or ARB or, • in black patients with advanced heart failure as an adjunct to standard therapy AE: Hydralazine Headache, dizziness Hydralazine & isosorbide dinitrate Tachycardia, peripheral neuritis, lupus-like syndrome

Flecainide

• Decreases rate of rise of Phase 0 depolarization without affecting duration of action potential • Causes slight prolongation of refractory periods • Automaticity reduced by an increase in threshold potential of ventricle rather than decrease in slope of Phase 4 Limited use b/c of its proarrhythmogenic effects leading to sudden death Clinical Applications • Severe symptomatic ventricular arrhythmias (life- threatening only), premature ventricular contraction or ventricular tachycardia resistant to other therapy • Severe symptomatic supraventricular arrhythmias & prevention of paroxysmal atrial fibrillation • 'Flecainide increased mortality more than two-fold in post MI patients treated for premature contractions' (CAST, Cardiac arrhythmia suppression trial) AE: • Aggravates CHF (negative inotropic effect) • CNS effects: dizziness, blurred vision, headache • GI effects: nausea, vomiting, diarrhea • Life-threatening arrhythmias & ventricular tachycardia

Propafenone

• Decreases rate of rise of Phase 0 depolarization without affecting duration of action potential • Prolongs conduction & refractoriness in all areas of the myocardium • Prolongs effective refractory period & reduces spontaneous automaticity Clinical applications • Used for treatment of life-threatening ventricular arrhythmias and the maintenance of normal sinus rhythm in patients with symptomatic atrial fibrillation Adverse Effects • Similar to flecainide

Drugs used to treat systolic HF

• Diuretics • Spironolactone • Inhibitors of angiotensin (ACE-inhibitors / ARBs) • Direct vasodilators • β-adrenoceptor antagonists (β-blockers) • Inotropic agents

Drugs used to treat Diastolic HF

• Diuretics • β-adrenoceptor antagonists (β-blockers) • Calcium-channel antagonists

Variant (Prinzmetal's Angina)

• Episodic angina due to coronary artery spasm. Unrelated to activity, HR or BP. • Symptoms respond to nitroglycerin & Ca2+ channel blockers • All available Ca2+ channel blockers appear to be equally effective. • Choice of drug is based on each individual patient

Magnesium and arrhythmia

• Functional Ca2+ antagonist Used for treatment of: • torsades de pointes • digitalis-induced arrhythmia • prophylaxis of arrhythmia in acute MI Use: Torsades Drugs causing torsades include: -potassium channel blockers -antipsychotics (thioridazine) -tricyclic antidepressants

Digoxin clinical applications and contraindications, PK

• HF with atrial fibrillation (main application) • Can be used (in addition to ACEI & β-blocker) to decrease symptoms, increase exercise tolerance & decrease rate of hospitalization Contraindications: • In patients with diastolic or right-sided HF • In presence of uncontrolled hypertension • In presence of bradyarrhythmias • In non-responders or intolerance PK • Very potent (narrow safety margin) • Widely distributed (including CSF) • t 1⁄2 = ~36-40 h • Accumulates in muscle large Vd (loading dose required) Kaplan: inamrinone and milrinone are phosphodiesterase inhibitors, so it leaves the Ca channel phosphorylated longer.

AE and tolerance of Nitrates

• Headache (cerebral vasodilation) • High doses = postural hypotension, facial flushing, reflex tachycardia Contraindications • Sildenafil Tolerance: • Develops rapidly (vessels desensitize to vasodilation)- acute tolerance (tachyphylaxis) • Can be overcome by daily 'nitrate-free interval' (10-12h) eg, nitroglycerin patches: 'on' for 12 h, 'off' for 12 h

Non-edematous states

• Hypertension • Hypercalcemia • Diabetes insipidus (polyuria & polydipsia)

Thiazides- actions, pk, ae, summary

• Increased Na+ & Cl- excretion • Increased K+ excretion • Increased Mg2+ excretion • Decreased urinary Ca2+ excretion • Decreased peripheral vascular resistance • due to decrease in blood volume. With continued therapy, volume recovery occurs although hypotensive effects remain PK • Orally effective • t1/2 = 40h (take 1-3 wks to produce stable effect) Related Compounds: • Chlorthalidone long duration of action: t1/2 = 40-60 h (used to treat hypertension once daily). • Metolazone most potent, causes Na+ excretion in advance kidney failure. AE Sulfonamide hypersensitivity • Hypokalemia and alkalosis • Hyponatremia • Hyperuricemia Hypercalcemia • Volume depletion • Hyperglycemia- decreases insulin release • Hyperlipidemia • Hypersensitivity Drug interactions and cautions: Digoxin increases toxicity due to electrolyte disturbances Avoid in pts with diabetes mellitus

Edematous states

• Increased NaCl reabsorption water retention & blood volume Examples: • Heart failure (kidneys respond as if there was hypovolemia, increasing blood volume) • Hepatic ascites (increased portal BP & secondary hyperaldosteronism) • Nephrotic syndrome (damaged glomerular membranes allow leakage of plasma proteins, reducing osmotic pressure. Low plasma volume stimulates aldosterone secretion) • Premenstrual edema (hormone imbalances)

Classes of antihypertensive

• Inhibitors of angiotensin (ACE-inhibitors / ARBs / renin inhibitors) • Calcium-channel blockers • Diuretics • β-adrenoceptor antagonists • α-adrenoceptor antagonists • Central α2 agonists • Direct vasodilators

Diuretics

• Inhibitors of renal ion transporters that decrease the reabsorption of Na+ at different sites in the nephron • Major clinical uses: • managing abnormal fluid retention (edema) or, • treating hypertension (reduce blood volume) Loop Diuretics: • furosemide, torsemide, ethacrynic acid Thiazides: • hydrochlorothiazide, chlorthalidone, metolazone, indapamide Potassium-Sparing Diuretics: • spironolactone, eplerenone, triamterene, amiloride Carbonic Anhydrase Inhibitors: • acetazolamide Osmotic: • mannitol Antidiuretic Hormone (ADH) Antagonists: • conivaptan

Lidocaine

• Local anesthetic • Rapidly associates & dissociates from Na+ channels*** • More effect on ischemic or diseased tissue • Particularly useful in treating ventricular arrhythmias • LITTLE EFFECT on K+ channels Pharmacokinetics • IV only (extensive first-pass metabolism) Clinical applications • Drug of choice for termination of ventricular tachycardia and prevention of ventricular fibrillation after cardioversion in the setting of acute ischemia • Little effect on atrial or AV junction arrhythmias AE • Wide toxic-therapeutic ratio • CNS effects (drowsiness, slurred speech, agitation etc.) • Little impairment of left ventricular function • NO negative inotropic effect • Cardiac arrhythmias (<10%) • Toxic doses: convulsions, coma Kaplan Post-MI Open heart surgery Digoxin toxicity AE CNS toxicity (seizures); least cardiotoxic of conventional anti-arrhythmics IV use- first pass metabolism.

Isosorbide Mononitrate- PK

• Longer onset of action & duration of action than nitroglycerin (more useful for long-term prophylaxis) • Isosorbide mononitrate = >1 h (time to onset of action) & nearly 100 % oral bioavailability • Metabolites have longer t1/2's and significant activity

Felodipine, amlodipine- MOA/AE

• Minimal effect on cardiac conduction or HR • Short-acting dihydropyridines should be avoided unless combined with β-blocker (increased mortality) Adverse Effects • Flushing • Headache • Hypotension • Peripheral edema (eg, pedal edema) • Constipation

Adenosine and Arrhythmias

• Naturally occurring nucleoside (P1 receptor agonist) • high doses = decreases conduction velocity & prolongs refractory period as well as decreasing automaticity in AV node • Very short t1/2 (15 s) MOA • Enhances K+ conductance • Inhibits cAMP-mediated Ca2+ influx • Leads to hyperpolarization esp. in AV node Clinical Applications • IV adenosine = drug of choice for abolishing acute supraventricular tachycardia AE Low toxicity • flushing • burning • chest pain • hypotension • bronchoconstriction in asthmatics (may persist up to 30 min) Kaplan: Adenosine -causes Gi coupled decrease in cAMP decreases SA and AV nodal activity uses: DOC for paroxysmal supraventricular tachycardias and AV nodal arrhythmias IV- T1/2 < 10 seconds Side effects: flushing, sedation, dyspnea Adenosine is antagonized by methylxanthines (theophylline and caffeine)

Mexiletine, tocainide

• Orally active derivatives of lidocaine • Can be used both orally and IV Clinical Applications Mexiletine : management of severe ventricular arrhythmias Tocainide: treatment of ventricular tachyarrhythmias AE: Mexiletine : mainly CNS & GI Tocainide : severe hematological & pulmonary toxicity (limits use)

Dofetilide

• Potent and pure K+ channel blocker Clinical Applications • Maintenance of normal sinus rhythm in patients with chronic atrial fibrillation / flutter of longer than one week duration who have been converted to normal sinus rhythm • Conversion of atrial fibrillation / flutter to normal sinus rhythm Pharmacokinetics • Excreted in urine (~80 % unchanged) Adverse Effects • Headache, chest pain, dizziness, ventricular tachycardia • Torsade de Pointes (prolongs QT interval)

Sotalol

• Potent non-selective β-blocker • Inhibits rapid outward K+ current • Prolongs repolarization & duration of action potential • Lengthens refractory period Clinical applications • Treatment of life-threatening ventricular arrhythmias • Maintenance of sinus rhythm in patients with atrial fibrillation & flutter who are currently in sinus rhythm • Due to pro-arrhythmic effects - do not use for asymptomatic arrhythmias AE: • As for β-blockers • Lowest rate (of antiarrhythmics) of acute or long-term adverse effects • Torsades de pointes (prolongs QT interval) • Use with caution in patients with renal impairment Kaplan: decreases Ik, slowing phase III Beta1 blockade, leading to decreased HR , decreased AV conduction Use: life-threatening ventricular arrhythmia

Disopyramide

• Pronounced negative inotropic effects • Severe antimuscarinic effects (dry-mouth, urinary retention, blurred vision, constipation) • May induce hypotension & cardiac failure without pre- existing myocardial dysfunction

Beta-blockers

• Propranolol non-selective β1 & β2 receptor antagonist • Metoprolol & atenolol (most widely used) selective β1 receptor antagonists • Pindolol non-selective β1 & β2 partial agonist with intrinsic sympathomimetic activity (preferred β-blocker in pregnancy)

Diuretics and congestive heart failure

• Relieve pulmonary congestion & peripheral edema • Reduce symptoms of volume overload (eg, orthopnea) • decreased plasma > decreased volume venous return to the heart (preload) > decreased cardiac workload & O2 demand • also afterload (reducing plasma volume > BP) Clinical applications: • Integral component of treatment for congestive symptoms and/or intravascular volume overload • No evidence of a mortality benefit with thiazide or loop diuretics alone Loop diuretics : more effective diuretics than thiazides Thiazide diuretics : patients with hypertensive heart disease (with congestive symptoms). Often ineffective as monotherapy due to weak diuretic effect

Hypertensive emergency

• Severe hypertension with signs of damage to target organs (brain, CV system, kidneys) • Immediate BP reduction is required with IV drugs Causes of HTN emergency • Essential hypertension • Renal parenchymal disease • Renovascular disease • Pregnancy (eclampsia) • Endocrine, eg. Pheocromocytoma, Cushing's, renin- producing tumors • Drugs eg, cocaine, crack, sympathomimetics, amphetamines, MAO-inhibitors, tyramine • Drug withdrawal eg, clonidine, nifedipine etc. • CNS disorders eg, injury, stroke, tumor • Autonomic hyperreactivity

Miscellaneous- Digoxin

• Shortens refractory period in atrial & ventricular myocardial cells • Prolongs effective refractory period & diminishes conduction velocity in AV node Clinical Applications • Control of ventricular response rate in atrial fibrillation & flutter with impaired left ventricular function or heart failure MOA Heart Failure • positive inotrope (increases intracellular [Ca2+]i) Arrhythmias • direct AV node blocking effects & vagomimetic properties: • inhibition of Ca2+ currents in AV node • activation of Ach-mediated K+ currents in atrium Major indirect actions • hyperpolarization • shortening of atrial action potentials • increases in AV nodal refractoriness (1) Slows AV conduction, and (2) Prolongs effective refractory period of the AV node thereby decreasing the fraction of atrial impulses that are conducted through the node ---> useful in treating atrial flutter / fibrillations (by controlling ventricular rate) Toxic doses • ectopic ventricular beats > ventricular tachycardia & fibrillation

Diltiazem- MOA/AE

• Similar effects to verapamil (slow AV conduction) • Decreases HR (lesser extent than verapamil) & BP Adverse Effects • Same as other Ca2+ channel blockers but incidence is low Contraindications • Same as verapamil

Verapamil- MOA/AE

• Slows AV conduction directly HR, contractility, BP & O2 demand • Has greater inotropic effects than dihydropyridines (weaker vasodilator) Adverse Effects • Same as other Ca2+ channel blockers • Constipation Contraindications • Preexisting depressed cardiac function or AV conduction abnormalities, • Use with caution in patients taking digoxin (increases digoxin levels)

Treatment of unstable angina

• The link between stable angina & MI. Chest pains occur more frequently & precipitated more easily. • Symptoms relieved by rest or nitroglycerin • In addition, therapy with nitroglycerin & β-blockers should be considered

PK of Nitroglycerin

• Undergoes sig. first-pass metabolism taken sublingually, transdermally, buccal, IV) • Fast-acting: 2-5 min to onset of action • Effect usually lasts ~ 30 min • Longer-acting (12-24 h) preparations are available (eg, transdermal patches)

Atropine and arrhythmias

• Used in bradyarrhythmias to decrease vagal tone

Clinical Applications of Nitrates

• Variant angina • Stable & unstable angina • IV nitroglycerin = unstable angina & acute heart failure • Nitroglycerin (sublingual or spray) = first-line therapy for treatment of acute anginal symptoms • Isosorbide mononitrate = orally for prophylaxis (sustained release preps available)

Angina Pectoris

• Vasospasm (transient constriction of coronary arteries) • Fixed stenosis (chronic narrowing of a coronary artery) • Coronary thrombosis (formation of blood clot within the vessel)

Hypertensive Urgency

• Very high BP without target-organ damage. Acute complications unlikely so immediate BP reduction not required • Patients should be started on 2-drug oral combination & close evaluation continued on an outpatient basis

Carbonic Anhydrase Inhibitors:

• acetazolamide enhances sodium excretion, water will follow. Bicarbonate will also be loss- bicarbonaturia. > Metabolic acidosis Kaplan: Acetazolamide and Dorzolamide. Mechanism: carbonic anhydrase inhibition -decreased H+ formation inside PCT cell -decreased Na/H antiport -increased Na and HCO3 in lumen -increased diuresis AE: HYPERchloremia *****can cause renal stones Ureases can increase pH of the urine > Struvite stones > renal stones. Sulfonamide hypersensitivity Uses: Glaucoma: acute mountain sickness, metabolic alkalosis Side effects: bicarbonaturia and acidosis, hypokalemia, hyperchloremia, paraesthesias, renal stones, sulfonamide hypersensitivity

Risk factors for CAD

• advanced age (> 55 y for men; > 65 y for women) • family history of premature cardiovascular disease • hypertension • cigarette Smoking • diabetes Mellitus • dyslipidemia • kidney disease • obesity • physical inactivity

Loop Diuretics:

• furosemide, torsemide, ethacrynic acid

Thiazides:

• hydrochlorothiazide, chlorthalidone, metolazone, indapamide

Potassium-Sparing Diuretics:

• spironolactone, eplerenone, triamterene, amiloride

Compensatory physiological responses

(a) Increased sympathetic activity (b) Activation of renin-angiotensin system Can ultimately result in further cardiac deterioration Myocardial Hypertrophy increased heart size (excess enlargement = decreased ability to pump) Systolic (inability to pump) or diastolic (heart muscles cannot relax) dysfunction Systolic Failure (reduced cardiac output & ejection fraction): typical of acute failure Diastolic Failure (reduced cardiac output, ejection fraction may be normal): does not usually respond to positive inotropic drugs

Management and treatment of hypertensive emergency

(a) Lower BP by no more than 25 % (within min - 1 h). Appropriate goal is 100-110 mmHg (DBP) (b) If stable, followed by further reduction towards goal of 160/100 mmHg (SBP/DBP) within 2-6 h and gradual reduction to normal over next 8-24 h Treatments • Sodium nitroprusside • Labetalol • Fenoldopam • Nicardipine • Nitroglycerin • Diazoxide • Phentolamine • Esmolol • Hydralazine

Amiodarone

*• Related structurally to thyroxine (contains iodine) *• Complex MOA showing Class I, II and III (& some IV) effects *• Dominant effect = K+ channel blockade. • Decreases AV conduction & sinus node function. • Blocks mostly inactivated* Na+ channels • Weak Ca2+ channel blocker • Inhibits adrenergic stimulation (α & β-blocking properties) • Antianginal & antiarrhythmic activity Clinical Applications • One of most commonly employed antiarrhythmics (despite side-effect profile) • Used in the management of ventricular & supraventricular arrhythmias • Low doses for maintaining normal sinus rhythm in patients with atrial fibrillation PK: • Oral (very well absorbed) • t1/2 = several weeks (extensively distributed in adipose tissue), loading dose required • Full clinical effects (& adverse effects) may take 6 weeks to achieve AE: • Long term use = > 50% patients show adverse effects severe enough for discontinuation • Many are dose-related and reversible on decreasing dose eg, interstital pulmonary fibrosis, GI intolerance, tremor, ataxia, dizziness, hyper- or hypothyroidism, liver toxicity, photosensitivity, neuropathy, muscle weakness, hypotension, bradycardia, AV block, arrhythmias • blue skin discoloration (iodine accumulation) Contraindications • Patients taking: • digoxin, theophylline, warfarin, quinidine • Patients with: • bradycardia • SA or AV block • severe hypotension • severe respiratory failure Kaplan: Mimics classes I, II, III and IV Increases APD and ERP in all cardiac tissues Uses: any arrhythmias t1/2 > 80 days High tissue protein binding- high Vd. Side effects: pulmonary fibrosis, blue pigmentation of the skin (smurf skin), phototoxicity, corneal deposits, hepatic necrosis, thyroid dysfunction

In diabetic patients, use ___ and ___ for hypertension, not ___

ACE inhibitors and ARBs. Do not use Thiazides

Loop diuretics- actions, pk, AE, summary

ACTIONS • Increased Ca2+ excretion • Increased Mg2+ excretion • Decreased renal vascular resistance • Increased renal blood flow • Increased prostaglandin synthesis PK • Oral & parenteral •t1/2 =2-4h Adverse: • Ototoxicity • Hyperuricemia • Acute hypovolemia • K+ depletion • Hypomagnesemia • Allergic reactions Hypokalemia and alkalosis Hypocalcemia, hypomagnesemia hyperuricemia- weak acids Ototoxicity (ethacrynic-irreversible > furosemide- reversible) Drug interactions: Aminoglycosides-Amikacin, Gentamicin, lithium, digoxin Summary: Increased urinary excretion of Na, K, Ca, urine volume

Central alpha 2 agonists- clonidine

AE • Drowsiness, dry mouth, dizziness, headache & sexual dysfunction occur commonly • Rebound hypertension may occur following abrupt withdrawal (avoid concomitant use with β-blockers) alpha 2 stimulation- decrease in sympathetic outflow (Gi), decrease in NE, decrease in TPR and HR. Used in mild-moderate htn, opiate withdrawal AE: CNS depression and edema. Interacts with tricyclic antidepressants which decrease antihtn effects of alpha 2 agonists

Central alpha 2 agonists- methyldopa

AE: Sedation, drowsiness, dizziness, nausea, headache, weakness, fatigue, sexual dysfunction • Nightmares, mental depression, vertigo (infrequent) • Development of positive Coombs test (10-20% patients on long-term treatment (>1 year)). Can result in hemolytic anemia, hepatitis & drug fever alpha 2 stimulation- decrease in sympathetic outflow (Gi), decrease in NE, decrease in TPR and HR. Used in mild-moderate htn, hypertensive management in pregnancy AE: positive coombs test, CNS depression and edema. Interacts with tricyclic antidepressants which decrease antihtn effects of alpha 2 agonists

Sodium Nitroprusside

AE: Adverse effects • Hypotension (overdose), goose bumps, abdominal cramping, nausea, vomiting, headache • Cyanide toxicity (rare)*** nitroprusside metabolism > cyanide ion Can be treated with sodium thiosulfate infusion > nontoxic thiocyanate Kaplan: decreases TPR via dilation of both arterioles and venules. Use: hypertensive emergencies, DOC used IV Side effect: cyanide toxicity (co-administered with nitrites and thiosulfate to decrease toxicity Can't use for more than 24/36 hrs or you get cyanide toxicity. Meth-hemoglobin serves as a carrier of cyanide. It doesn't block complex IV of the Electron Transport Chain.

Digoxin AE, interactions and toxicity

AE: Digoxin toxicity = one of the most common ADRs • Cardiac effects: arrhythmias, characterized by slowing of AV conduction (atrial arrhythmias) • GI effects: anorexia, nausea & vomiting • CNS effects: headache, fatigue, confusion, blurred vision, alteration of color perception, halos on dark objects Kaplan: anorexia, nausea, EKG changes, DISORIENTATION, visual effects (HALOS), cardiac arrhythmias Factors predisposing to digoxin toxicity • quinidine, verapamil & amiodarone can cause digoxin toxicity by displacement from tissue protein-binding sites & competition for renal excretion ([digoxin] can increase by 70-100%) Precipitating factors for adverse effects • hypokalemia*** would minimize the effects of digoxin. • drug accumulation / relative overdose • hypomagnesemia or hypercalcemia • hyperthyreosis • abnormal renal function • respiratory disease • acid-base imbalances • .... age above 65, low body weight, fever etc Factors predisposing to digoxin toxicity • K+-depleting diuretics • corticosteroids • hypothyroidism • hypoxia • renal failure • myocarditis Treatment of digoxin toxicity • Withdraw drug for some days and/or reduce dose • Monitor plasma digoxin and K+ levels, ECG • Adjust electrolyte status (K+ supplements) • Ventricular tachyarrhythmia: lidocaine, magnesium, adjust K+ to high normal Severe digoxin intoxication • Bradyarrhythmias, suppressed automaticity temporary cardiac pacemaker • Treat with digitalis antibodies (Digoxine immune fab, Digibind)

Hydralazine

AE: • Fluid retention & reflex tachycardia are common • Reversible lupus-like syndrome • Headache, nausea, sweating, flushing • Usually administered with β-blocker & thiazide

Mixed alpha and beta blocker

AE: Orthostatic hypotension may be a problem (first use or high doses)

Cinchonism

ANS side effects of a drug. For quinidine: Tinnitus, ocular dysfunction, CNS excitation, GI.