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Home , Thiazide

Drugs affecting the Cardiovascular System

(Tutorial) Therapeutic Classes

• Antianginal • Antiarrhythmic • Antihypertensive • Cardioinhibitory • Cardiostimulatory • • Pressor • Thrombolytic • Vasoconstrictor • Vasodilator Clinical Disorders

• Angina • Arrythmias • • Heart Failure • • • Drug Mechanism Classes • Adenosine receptor agonist • receptor antagonists • Alpha-agonists • Alpha-blockers • Angiotensin-converting enzyme (ACE inhibitors) • Angiotensin Receptor blockers (ARBs)

• Beta agonists • Beta blockers • Calcium-channel blockers • Centrally acting • Direct-acting vasodilators • Diuretics (loop,thiazide,-sparing)

• Endothelin receptor antagonists • Fibrinolytics • Ganglionic blockers • Muscarinic receptor antagonists • Cardiac glycosides • Natriuretic peptides • nitrodilators • Phosphodiesterase inhibitors • blockers • Potassium channel openers • Renin inhibitors • channel blockers • blockers (late sodium currents) • Sympathomimetics • Thrombolytics (fibrinolytics) • Vasopressin analogs

• Antianginal Drugs

• Therapeutic use & rationale

• Redn in O2 supply/demand ratio • Improve this ratio • Increase blood flow – increases O2 delivery & supply • Decrease O2 demand – decrease myocardial O2 consumption • Prevent vasospasm & clot formation • Classes of Drugs Used to Treat Angina

• Vasodialtors – dilate arteries & veins - blockers - Nitrodilators • Cardioinhibitory drugs – reduce heart rate & contractility - Beta blockers - Calcium channel blockers • Late soudium current blockers - • Anti-thrombotic drugs – prevent thrombus formation - Anticoagulants - Anti-platelet drugs • Calcium channel blockers (CCBs)

MoA

• Block calcium entry into cells of vascular sm, cardiac myocytes, cardiac nodal tissue • Cause vascular sm relaxation= vasodilation = decrease myocardial force generation = decrease heart rate = decreases conduction velocity in the heart Indications

• Hypertension • Angina • Arrythmias • Classes of Calcium-Channel Blockers

Dihydropyridines

- - - - - - - • smooth muscle selective • Mainly used to reduce systemic vascular resistance & arterial pressure • Mainly used to rx hypertension • Can lead to reflex cardiac stimulation (tachycardia & increased ionotropy) = increase myocardial O2 demand Non-dihydropyridines

• Phynylalkylamine – - reduces myocardial oxygen demand - reverses coronary vasospasm and arrhythmias. • Benzothiazepine - - Cardiac depressant properties - Vasodilator actions - Reduces arterial pressure without the reflex cardiac stimulation caused by dihydropyridines.

Side effects

• Flushing • Headache • Excessive hypotension • Edema • Reflex tachycardia • Antiarrhythmic Drugs

• Goal = to restore normal rhythm & conduction • Antiarrhythmic drugs are used to: • decrease or increase conduction velocity • alter the excitability of cardiac cells by changing the duration of the effective refractory period • suppress abnormal automaticity

• Antiarrhythmic Drug Classes • Class I – Sodium channel blockers • Class II – Beta blockers • Class II – Potassium Channel blockers • Class IV – calcium channel blockers • Miscellaneous – adenosine, electrolyte supplements (mg & K salts), cardiac glycosides, atropine (muscarinic ) Condition Drug Comments

Other underlying causes may need Sinus tachycardia Class II, IV treatment

Class IA, IC, II, III, IV Ventricular rate control is important Atrial fibrillation/flutter digitalis goal; anticoagulation required adenosine

Paroxysmal supraventricular Class IA, IC, II, III, IV tachycardia adenosine

AV block atropine Acute reversal

Ventricular tachycardia Class I, II, III

Class II, IV PVCs are often benign and not Premature ventricular complexes Mg++ salts treated

Class IB Digitalis toxicity Mg++ salts; KCl • Antihypertensive Drugs • Rationale for Pharmacologic Treatment of Hypertension

- Reduce cardiac output 1) reduce blood volume - reduces central venous pressure and cardiac output 2) reduce systemic vascular resistance –dilate systemic vasculature 3) reduce cardiac output by depressing heart rate and stroke volume - • Drugs Used to Treat Hypertension

Diuretics

- thiazide diuretics - Loop diuretics - Potassium sparing diuretics Vasodilators • Alpha blockers • Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors) • Angiotensin Receptor Blockers (ARBs) • Calcium-channel blockers • Direct acting arterial dilators • Ganglionic blockers • Nitrodilators • Potassium-channel openers • Renin inhibitors

Cardio-inhibitory Drugs

• Beta blockers • Calcium channel blockers Centrally Acting sympatholytics

• Mechanisms of drugs

• Diuretic drugs increase urine output by the = promote diuresis • altering how the kidney handles sodium • If the kidney excretes more sodium, then water excretion will also increase • Most diuretics inhibit the reabsorption of sodium at different segments of the renal tubular system Loop diuretics

• inhibit the sodium-potassium- co- transporter in the thick ascending limb • This transporter normally reabsorbs about 25% of the sodium load • inhibition of this pump can lead to a significant increase in the distal tubular concentration of sodium - reduced hypertonicity of the surrounding interstitium, and - less water reabsorption in the collecting duct = increased water loss = diuresis = increased sodium loss = natriuresis • Loop diuretics act on the thick ascending limb, which handles a significant fraction of sodium re-absorption • loop diuretics are very powerful diuretics. • These drugs also induce renal synthesis of prostaglandins, which contributes to their renal action including the increase in renal blood flow and redistribution of renal cortical blood flow. Thiazide diuretics

• the most commonly used diuretic, inhibit the sodium-chloride transporter in the distal tubule. • this transporter normally only reabsorbs about 5% of filtered sodium • these diuretics are less efficacious than loop diuretics in producing diuresis and natriuresis. • But are sufficiently powerful to satisfy most therapeutic needs requiring a diuretic. • Their mechanism depends on renal prostaglandin production. • loop and thiazide diuretics increase increases potassium loss (potentially causing ) because the increase in distal tubular sodium concentration stimulates the aldosterone-sensitive sodium pump to increase sodium re-absorption in exchange for potassium and hydrogen , which are lost to the urine. • Potassium-sparing Diuretics. • do not act directly on sodium transport • Some drugs in this class antagonize the actions of aldosterone (aldosterone receptor antagonists) • more sodium (and water) to pass into the collecting duct and be excreted in the urine. • They are called K+-sparing diuretics because they do not produce hypokalemia like the loop and thiazide diuretics • often used in conjunction with thiazide or loop diuretics to help prevent hypokalemia Carbonic anhydrase inhibitors

• inhibit the transport of bicarbonate out of the proximal convoluted tubule into the interstitium • leads to less sodium re-absorption • greater sodium, bicarbonate and water loss in the urine • the weakest of the diuretics and seldom used in cardiovascular disease. • Their main use is in the treatment of glaucoma. Cardiovascular effects of diuretics

• decrease blood volume and venous pressure • decreased cardiac filling (preload) • decreased ventricular stroke volume • Venodilation • Reduced systemic vascular resistance (long term use) THERAPEUTIC USES OF DIURETICS

• Hypertension • Heart Failure – reduces pulmonary & systemic congestion & edema

• Most patients in heart failure are prescribed Loop diuretics- are more effective in unloading sodium and water than thiazide diuretics. • In mild heart failure, a thiazide diuretic may be used. • Potassium-sparing, aldosterone-blocking diuretics (e.g., ) are being used increasingly in heart failure. Class Specific Drugs Comments Thiazide thiazide-like in chlorthalidone action, not structure prototypical drug; thiazide-like in action, not structure thiazide-like in action, not structure Loop

ethacrynic

acid

torsemide distal tubule Na+- K+-sparing channel inhibitor

aldosterone receptor antagonist; fewer side effects than spironolactone

aldosterone receptor spironolactone antagonist; side effect: gynecomastia

distal tubule Na+- channel inhibitor prototypical drug; not used in treating CA inhibitors hypertension or heart failure

not used in treating dichlorphenamide hypertension or heart failure

not used in treating methazolamide hypertension or heart failure • Adverse Side Effects and Contraindications

• Cardioinhibitory Drugs

• Cardioinhibitory drugs depress cardiac function by decreasing heart rate (chronotropy) and myocardial contractility (inotropy), which decreases cardiac output and arterial pressure • These cardiac changes reduce the work of the heart and myocardial oxygen consumption • The mechanisms of action of these drugs also lead to depressed electrical conduction(dromotropy) within the heart. • Some of these drugs may also impair relaxation (lusitropy).

Therapeutic Uses of Cardioinhibitory Drugs

• Hypertension • Angina • Arrhythmias • Heart failure (β-blockers only)

Three Classes of Cardioinhibitory Drugs

• Beta-blockers • Calcium-channel blockers • Centrally-acting sympatholytics

• General Mechanisms of Action

Beta-blockers

• Beta-blockers bind to beta-adrenoceptors located in • cardiac nodal tissue • the conducting system, and • contracting myocytes.

• The heart has both beta1 (β1) and beta2 (β2) adrenoceptors although the predominant

receptor type in number and function is β1 • Beta-blockers prevent the normal ligand (norepinephrine or epinephrine) from binding to the beta-adrenoceptor by competing for the binding site. • beta-blockers are able to reduce sympathetic influences that normally stimulate chronotropy, inotropy, dromotropy and lusitropy • Beta-blockers have an even greater effect when there is elevated sympathetic activity Beta-Blockers • Cardiac Effects • Decrease contractility- (negative intropy) • Decrease relaxation rate (negative lusitropy) • Decrease heart rate- (negative chronotropy) • Decrease conduction velocity (negative dromotropy) • Vascular Effects • Smooth muscle contraction (mild )

• Beta-blockers that are used clinically are

either non-selective (β1/β2) blockers, or relatively selective β1 blockers. • .Beta-blockers are used for treating – Hypertension – Angina – myocardial infarction and – arrhythmias. • Different Classes of Beta-Blockers and Specific Drugs

1) non-selective blockers - block both β1and β2receptors

2) relatively selective

β1 blockers ("cardioselective" beta-blockers). • Some beta-blockers have additional mechanisms besides beta-blockade that contribute to their unique pharmacologic profile • e.g. membrane stabilizing activity (MSA) • intrinsic sympathomimetic activity (ISA). Clinical Uses Angin Class/Drug HTN Arrhy MI CHF Comments a Non- selective

β1/β2 carteolol X ISA; long acting; also used for glaucoma carvedilol X X α-blocking activity labetalol X X ISA; α-blocking activity nadolol X X X X long acting penbutolol X X ISA pindolol X X ISA; MSA propranolol X X X X MSA; prototypical beta-blocker X several other significant mechanisms timolol X X X X primarily used for glaucoma β1-selective acebutolol X X X ISA X X X X betaxolol X X X MSA bisoprolol X X X esmolol X X ultra short acting; intra or postoperative HTN metoprolol X X X X X MSA

relatively selective in most patients; vasodilating (NO X release) • Side Effects and Contraindications

• Bradycardia • Reduced exercise capacity • Heart failure • Hypotension • AV node conduction block **due excessive blockade of normal sympathetic influences on the heart. • Considerable care needs to be exercised if a beta- blocker is given in conjunction with cardiac selective calcium-channel blockers (e.g., verapamil) because of their additive effects in producing electrical and mechanical depression • only carvedilol and metoprolol have been approved for this indication. Other side effects

• Bronchoconstriction (non-selective beta- blockers in asthmatic pxs • Beta-blockers can also mask the tachycardia that serves as a warning sign for insulin- induced hypoglycemia in diabetic patients; therefore, beta-blockers should be used cautiously in diabetics. Cardiostimulatory Drugs

• Cardiostimulatory drugs = cardiotonic drugs • enhance cardiac function by increasing heart rate (chronotropy) and myocardial contractility (inotropy) which increases cardiac output and arterial pressure • Many of these drugs also increase electrical conduction (dromotropy) within the heart and augment relaxation (lusitropy) • Some of the drugs produce systemic vasodilation, whereas others produce vasoconstriction by mechanisms that are different from their cardiac mechanisms. • Therapeutic Use of Cardiostimulatory Drugs

• Heart failure • Shock - cardiogenic - hypovolemic - septic

Classes of Cardiostimulatory Drugs

• Beta-agonists • Digitalis compounds • Calcium sensitizers • Phosphodiesterase inhibitors