CVS Drugs PDF

# Drugs Related to Cardiovascular System Dr. Tuan Nadrah Naim Bt T Ismail ## Lecture Outline * Describe mechanism of action, indication, distribution, excretion, side effects and drug interactions of: * Antihypertensive drugs * Antiangina drugs * Lipid lowering agents * Cardiac gly...

# Drugs Related to Cardiovascular System Dr. Tuan Nadrah Naim Bt T Ismail ## Lecture Outline * Describe mechanism of action, indication, distribution, excretion, side effects and drug interactions of: * Antihypertensive drugs * Antiangina drugs * Lipid lowering agents * Cardiac glycosides and other drugs used in cardiac failure * Antiarrhythmic agents * Drugs used in circulatory shock * Antithrombotics & thrombolytics * Explain the implications of drugs used in cardiovascular system for dentistry. ## Antihypertensive Drugs * A = ACE inhibitor, ARB, α-blocker * B = Beta blocker * C = Calcium channel blocker, centrally acting sympatholytic * D = Diuretics > Hypertension is defined as persistent elevation of systolic BP of 140 mmHg or greater and/or diastolic BP of 90 mmHg or greater. ## Physiologic Control of Blood Pressure and Sites of Drug Action The image shows a diagram of how the body regulates blood pressure. The diagram is organized like a flow chart and shows how different factors are involved in regulating blood pressure. The factors contributing to blood pressure are: * Cardiac Output * Stroke volume * Heart rate * Contractility * Peripheral Vascular Resistance * Sympathetic Nervous System * Renin * Angiotensin I * Angiotensin II * Aldosterone * Blood Volume * Renal Sodium Excretion The diagram shows the various sites of action of antihypertensive drugs. * **Vasodilator** * **Beta blocker** * **Alpha-blocker** * **ARB** * **Sympatholytic** * **ACE Inhibitor** * **Diuretic** ## Antihypertensive Medications: Mechanism of Action | Drug Class | Mechanism of Action | |---|---| | Diuretics | Rid body of excess fluids and sodium, May enhance effect of other BP medications | | ACEIs | Lower levels of angiotensin II, Dilate blood vessels | | ARBs | Block angiotensin II receptors, Dilate blood vessels | | BBs | Decrease heart rate and cardiac output | | CCBs | Interrupt movement of calcium into heart and vessel cells | | Aldosterone Receptor Blockers | Decrease salt and water retention | | Renin Inhibitors | Block action of renin, decreasing formation of angiotensin I | ## Diuretics ### Thiazide * **MOA:** Increase sodium and water excretion, decrease blood volume, decrease cardiac output. * **E.g:** Hydrochlorothiazide * **Indication:** Initial treatment for mild to moderate hypertension, used in combination with another class of antihypertensive * **A/E:** Hypokalemia, Elevate plasma levels of glucose, uric acid, and lipids, Hematologic toxicity and aggravate hepatic disease (less common) * **Interaction:** ACE inhibitor, Hypotension, Carbamazepine, Symptomatic hyponatremia, Corticosteroids- Synergistic effect on potassium levels, resulting in hypokalemia * **Advantages:** Least expensive, Has protection against osteoporosis (decrease the urinary excretion of calcium) ### Loop Diuretics * **MOA:** Similar with thiazide * **E.g:** Frusemide (Lasix) * **Indication:** Loop diuretics are usually reserved for use in hypertensive patients who have poor renal function, Congestive heart failure symptoms * **A/E:** Electrolyte imbalance: hypokalemia, Hyperuricaemia, Hyperglycaemia, hypovolemia ### Potassium-Sparing Diuretics * **E.g:** Triamterene, Amiloride * **MOA:** Interfere sodium-potassium exchange in the distal convoluted tubule in the kidneys * **E.g:** Spironolactone * **MOA:** Act as an aldosterone receptor antagonist (they inhibit the sodium channels associated with the aldosterone-sensitive sodium pump) * **Do not produce hypokalemia (can be used with loop and thiazide diuretics)** * **Indication:** Hypertension that cannot be controlled with combinations of three or more other agents. ### Potassium Sparing Diuretics...... * **Contraindications:** Renal dysfunction - Anuria, Elevated serum creatinine, Elevated serum potassium levels, Potassium supplementation * **A/E:** Hyperkalemia * **Drug interaction:** Synergistic effects on potassium elevation with the use of ACE inhibitors, Concomitant use of NSAIDS - decreased diuretic effectiveness and increased potassium levels secondary to decreased synthesis of renal prostaglandins ## Adrenoceptor Antagonists (Selective α1-blockers) * **E.g:** Doxazosin, prazosin, terazosin * **Indication:** Not recommended for the initial treatment of high BP, Can be added to other drugs when blood pressure is not adequately controlled * **MOA:** Inhibit sympathetic stimulation of arteriolar contraction, leading to vasodilation and decreased vascular resistance * **A/E:** Activate sympathetic nervous system (Increase the heart rate, contractile force, and circulating norepinephrine levels and thereby increase myocardial oxygen requirements), Fluid retention (α1-blockers are often given with a diuretic.), Orthostatic hypotension *(*postural*)* ## ẞ-Adrenoceptor Antagonists (β-blockers) * **MOA:** Block ẞ1- adrenoceptors in the heart and other tissues, Reduce sympathetic outflow from the CNS * **E.g:** Atenolol, Bisoprolol, metoprolol * **Blockade of cardiac ẞ1-receptors:** Reduce HR and contractility, Reduce cardiac output, Reduce BP * **Blockade of ẞ1-receptors in renal:** Inhibits renin secretion, Reduces angiotensin II, Reduce aldosterone, Reduces Na+ & water retention, Reduce cardiac output, Reduce BP ## (β-blockers)...... * **Indication:** Hypertensive persons with other cardiovascular diseases (In IHD: lower the risk of myocardial infarction *(*by reducing HR)*, In heart failure: improve symptoms), Combined with other drugs to achieve greater reductions in BP * **A/E:** Bronchoconstriction, bradycardia, depression, mask hypoglycaemia, Physically active persons may find that ẞ-blockers reduce exercise capacity *(*due to reduction in heart rate)*, impotence * **Contraindication:** Asthma & chronic obstructive pulmonary disease because these drugs may cause bronchospasm ## Centrally Acting Drugs * **E.g:** Methyldopa * **MOA:** Inhibit alpha-adrenergic receptors, Decrease sympathetic stimulation to the blood vessels and the heart, Reduce heart beat & relax the blood vessels, Reduce blood pressure * **Indication:** Hypertension in pregnant women *(*does not harm the fetus)* * **A/E:** Sedation, dry mouth, and impaired mental acuity, Severe rebound hypertension can occur if discontinued abruptly *(*dosage should be tapered gradually)*, Immunologic effects *(*Coombs-positive hemolytic anemia, Autoimmune hepatitis)* * **Drug interaction:** Tricyclic antidepressant drugs block the effects of centrally acting sympatholytic drugs ## Angiotensin-Converting Enzyme Inhibitors * **MOA:** (ACE-I) prevent the conversion of angiotensin I to angiotensin II, Vasodilation * **E.g:** Captopril, Enalapril, Perindopril, Ramipril * **C/I:** Pregnant *(*can cause fetal and neonatal injury)*, Bilateral renal artery stenosis *(*can cause renal failure)* *(*because these persons depend on angiotensin II to maintain renal blood flow and glomerular filtration)* ## ACE inhibitors....... * **A/E:** most common - dry cough *(*probably caused by increased bradykinin levels)*, Less common- angioedema, manifested as painful swelling of the lips, face, and throat, Rash and an abnormal taste sensation * **Drug Interactions:** Diuretics and CCBs - increase antihypertensive effect, potassium-sparing diuretics and potassium supplements - increase serum potassium levels, Lithium- incresae lithium levels and provoke lithium toxicity, NSAIDs - reduce the effects of ACE inhibitors * **Indications:** Mild to severe hypertension in patients with coexisting heart failure, myocardial infarction, chronic kidney disease, or DM, In DM patients who exhibit early signs of renal impairment, ACE inhibitors exert a renoprotective effect ## Angiotensin Receptor Blockers * **MOA:** Selectively block AT1 receptors in various tissues *(*vasocons triction, aldosterone secretion, sodium reabsorption by the proximal tubule, norepinephrine release)* * **Indication:** Combined with a diuretic, CCB when greater blood pressure reduction is needed, High risk patients with diabetic nephropathy * **E.g:** Irbesartan, Losartan, Telmisartan * **A/E:** Rarely cause the dry cough, Do not increase serum glucose, uric acid, or cholesterol levels but may cause hyperkalemia, neutropenia, and elevated serum levels of hepatic aminotransferase enzymes * **C/I:** Pregnancy ## MOA ACE Inhibitors and ARBs The image shows a diagram representing the mechanism of action of ACE inhibitors and ARBs, using a simplified flow chart. The starting point is Angiotensinogen. * Angiotensinogen interacts with Renin to produce Angiotensin I. * Angiotensin I can react with ACE. ACE can also react with * non-ACE pathways. * Bradykinin. * When ACE reacts with Angiotensin I, the product is Angiotensin II. * Angiotensin II binds to * AT1 receptors. * AT2 receptors. * ACE inhibitors inhibit the production of Angiotensin II from Angiotensin I. * ARBs block the effect of Angiotensin II on AT1 receptors. * When Bradykinin interacts with ACE, the product is kinin fragments. ## Calcium Channel Blockers * **MOA:** Block calcium ion channels in the plasma membranes of smooth muscle, relax vascular smooth muscle, Vasodilation * **E.g:** Amlodipine, Felodipine, Nifedipine * **Indication:** Initial treatment of high BP, Combined with diuretics or angiotensin system inhibitors, Hypertensive patients who have asthma * **A/E:** Gum hyperplasia, Leg/ankle edema, Lightheadedness, Slower heart rate, Increased appetite, Gastroesophageal reflux disease (GERD) ## Calcium channel blocker causes gum hyperplasia The document briefly describes a case report of amlodipine-induced massive gingival hyperplasia in a 14 year old boy. The text then discusses the importance of recognizing this condition and the options for managing it. The text also refers to a research abstract on the prevalence and risk factors of gingival enlargement in patients treated with nifedipine. ## Classification of Antianginal Drugs ### Vasodilators * **Organic Nitrites and Nitrates:** Isosorbide dinitrate, Isosorbide mononitrate, Nitroglycerin ### Calcium Channel Blockers * **Amlodipine** * **Nifedipine** * **Diltiazem** * **Verapamil** ### ẞ-Adrenoceptor Antagonists * **Atenolol** * **Metoprolol** * **Propranolol** ### Metabolic Modifiers * **Ranolazine** * **Trimetazidine** ## MOA * Antianginal drugs act by several mechanisms to **reduce myocardial oxygen demand** or **increasing oxygen supply**. * **β-blockers** decrease heart rate and contractility. * **Organic nitrates** act primarily on venous tissue and predominantly affect preload. * **CCBs** act mostly on arteriolar muscle to reduce afterload. ## Preload and Afterload The image shows a diagram of a heart, and highlights the concepts of preload and afterload. * **Preload:** The volume entering the ventricles. * **Afterload:** The resistance the left ventricle must overcome to circulate blood. ## Isosorbide dinitrate * **ROA:** Sublingually, orally * **Indication:** Prevention of angina attacks, treatment of angina attacks * **MOA:** Release nitric oxide, Relaxation of vascular smooth muscle *(*preferentially relax venous)* * **Venous pooling of blood:** Decrease in venous blood return to the heart, Decrease in ventricular volume, pressure, and wall tension, Reduce cardiac work & oxygen demand, Reduce CO, Reduce BP * **If BP falls sufficiently, reflex tachycardia can be invoked.** ## Isosorbide dinitrate.... * **Tolerance:** Due to continuous administration * **To prevent tolerance:** Skin patches should be removed for at least 10 hours each day, Long-acting oral medications should be administered only once or twice a day * **Adverse Effects:** Excessive vasodilation *(*Headache, hypotension, dizziness, and reflex tachycardia)*, Tachycardia increases oxygen demand *(*avoid excessive doses)*, To prevent reflex tachycardia, a β-blocker can be used together. * **Drug interaction:** Sildenafil and other 5-phosphodiesterase *(*use for erectile dysfunction)* inhibitors potentiate hypotensive effect ## Nitroglycerin (GTN) * **ROA:** Sublingual, transdermal, topical, oral, and IV administration * **Indication:** Sublingual administration *(*Treatment of acute angina attacks)*, Patches administration *(*Prevention of angina attacks)*, Ointment administration *(*Hospitalized patients with angina or MI)*, Oral *(*sustained release capsules)* administration *(*Prevent angina attacks)*, Intravenous administration *(*Acute heart failure associated with MI and other condition)* ## Classification of Drugs for Hyperlipidemia ### HMG-CoA Reductase Inhibitors * **Atorvastatin** * **Pravastatin** * **Simvastatin** ### Bile Acid-Binding Resins * **Cholestyramine** * **Colestipol** * **Colesevelam** ### Cholesterol Absorption Inhibitor * **Ezetimibe** ### Fibric Acid Derivatives * **Fenofibrate** * **Gemfibrozil** ### Other Drugs Niacin *(*vitamin B3, nicotinic acid)* ## Statins (HMG-CoA Reductase Inhibitors) * **E.g:** Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Rosuvastatin, Simvastatin * **Synthesis of Cholesterol:** The image shows a diagram representing the synthesis of cholesterol, starting with Acetyl-CoA and ending with cholesterol. The diagram shows the various enzymes and metabolites involved. * **The most effective drugs for lowering blood cholesterol levels.** * **Prevent coronary artery disease and reduce mortality.** ## Statins (HMG-CoA Reductase Inhibitors)...... * **Indications:** Persons with hypercholesterolemia * **Adverse Effects:** Abdominal cramps, Constipation, Diarrhea, Heartburn, Hepatitis *(*less common)*, Rhabdomyolysis *(*rare)* * **0.2% of patients receiving statins develop myopathy, and only a few of these cases progress to rhabdomyolysis.** * **Stage of statin-induced myopathy:** Myalgia *(*muscle ache or weakness without elevated creatine kinase levels)*, Myositis *(*muscle inflammation *(*leakage of muscle creatine kinase into the plasma)*, Rhabdomyolysis *(*releasing myoglobin into the circulation, Myoglobin then accumulates in the kidneys and causes ARF, Myoglobinuria- dark urine)* ## Statins (HMG-CoA Reductase Inhibitors)...... * **Interactions:** Atorvastatin, lovastatin, and simvastatin are metabolized by CYP3A4, and their plasma concentrations are increased by strong inhibitors of this isozyme, such as erythromycin, itraconazole, and ritonavir. * **Fluvastatin is metabolized by CYP2C9, and its plasma levels may be increased by inhibitors of this CYP, including some nonsteroidal antiinflammatory drugs (NSAIDs).** * **Statins inhibit the metabolism of certain other drugs by CYP enzymes. For example, they increase warfarin levels slightly by inhibiting warfarin metabolism.** * **statins and fibric acid derivatives should be avoided *(*both cause myopathies)*** ## Bile Acid-Binding Resins * **Moderately effective** * **Excellent safety record** * **E.g:** Cholestyramine, Colestipol, Colesevelam * **MOA:** Resin bind to bile acids in the intestine, prevent them from being reabsorbed into the blood. Liver produces more bile to replace the bile because cholesterol is needed to make bile. Liver uses up the cholesterol in the blood, which reduces the amount of LDL cholesterol circulating in the blood. ## Bile Acid-Binding Resins * **Adverse Effects:** Constipation, fecal impaction, irritation of the perianal area, skin rash * **Indications:** treatment of hypercholesterolemia in patients who cannot tolerate other drugs, combination with other drugs to produce an additive effect, treat diarrhea and pruritus caused by excessive levels of bile acids * **Drug interaction:** Cholestyramine and colestipol can bind to digoxin, thyroxin, warfarin, and other drugs. It is best to take these resins 2 hours before or after taking other medications. A newer resin, colesevelam, does not affect the oral bioavailability of digoxin, warfarin, or lovastatin (can be coadministered with most drugs). ## Classification of Drugs for Heart Failure | | Positively Inotropic Drugs | Vasodilators | ẞ-Adrenoceptor Blocker | Aldosterone Antagonists | Diuretic | |:---:| :------------------------ | :------------------- | :----------------------- | :------------------------ | :------------- | | | ↑CO | ↓ VenousPressure, oedema | Carvedilol | Spironolactone, Eplerenone | Furosemide | | | Digitalis Glycoside: Digoxin, Digoxin immune Fab | Angiotensin Inhibitors: Enalapril, Valsartan | | | | | | Adrenoceptor Agonist: Dobutamine | Other Vasodilators: Hydralazine, Isosorbide dinitrate | Cardiac remodeling | Cardiac remodeling | ↓oedema | | | Phosphodiesterase Inhibitor: Milrinone | | | | | ## Digitalis Glycoside * **MOA:** Na+/K+-ATPase inhibition, ↓ Ca2+ expulsion, ↑ Ca2+ stored in sarcoplasmic reticulum, ↑ cardiac contractility & cardiac parasympathomimetic effect *(*slowed sinus HR, slowed atrioventricular conduction)* * **E.g.:** Digoxin * **Indication:** Chronic symptomatic heart failure * **A/E:** Nausea, vomiting, diarrhea, cardiac arrhythmias ## Adrenoceptor Agonists * **E.g:** Dobutamine * **MOA:** Dobutamine Beta1-selective agonist, ↑ CAMP synthesis, ↑ cardiac contractility & output * **Indication:** Acute decompensated heart failure, Intermittent therapy in chronic failure reduces symptoms * **A/E:** Arrhythmias * **Interactions:** Additive with other sympathomimetics ## Phosphodiesterase inhibitors * **E.g:** Inamrinone, Milrinone * **MOA:** Phosphodiesterase breakdown, Vasodilate, lower peripheral vascular resistance, increase cardiac contractility * **Indication:** Acute decompensated heart failure * **A/E:** Arrhythmias * **Interactions:** Additive with other arrhythmogenic agents ## Vasodilator * **E.g:** Isosorbide dinitrate * **MOA:** Releases nitric oxide (NO), activates guanylyl cyclase, Venodilation, Reduces preload and ventricular stretch * **Indication:** Acute and chronic heart failure, Angina * **A/E:** Postural hypotension, Tachycardia, Headache * **Interactions:** Additive with other vasodilators and synergistic ## Action potential of cardiac muscles The image shows a diagram of the action potential of a cardiac muscle. The diagram shows different phases along a time-axis, and the membrane potential of the cell along a y-axis. The labeled phases are: * **Phase 4:** The resting membrane potential is stable at -90 mV. * **Phase 0:** Transient K+ channels open and K+ efflux returns TMP to 0mV. Rapid Na+ influx through open fast Na+ channels. * **Phase 1:** Influx of Ca2+ through L-type Ca2+ channels is electrically balanced by K+ efflux through delayed rectifier K+ channels. * **Phase 2:** Ca2+ channels close but delayed rectifier K+ channels remain open and return TMP to -90mV. * **Phase 3:** Na+, Ca2+ channels closed, open K+ rectifier channels keep TMP stable at -90mV ## Classification of Antiarrhythmic Drugs * **Vaughan-Williams divided the antiarrhythmic drugs into four main classes:** * Class I, sodium channel blockers * Class II, ẞ-adrenoceptor antagonists *(*β-blockers)* * Class III, potassium channel blockers * Class IV, calcium channel blockers * **Adenosine**- Do not fit into any of these categories. * **Amiodarone**- Could fit in more than one category. ## X aminy ut in linn The image shows a diagram of the action potential of a cardiac muscle. The diagram shows different phases along a time-axis, and the membrane potential of the cell along a y-axis. The labeled phases are: * **Phase 1:** The beginning of depolarization. This is blocked by **Class IV** drugs, calcium channel blockers. * **Phase 2:** The plateau phase, where the membrane potential is relatively stable. * **Phase 3:** The repolarization phase. **Class III** drugs, potassium channel blockers, slow this phase. * **Phase 4:** The resting membrane potential. This is affected by **Class I** drugs, sodium channel blockers, and **Class II** drugs, beta blockers. ## Classification of Antiarrhythmic Drugs ### Sodium Channel Blockers * **Disopyramide** * **Lidocaine** * **Propafenone** ### ẞ-Adrenoceptor Blockers * **Esmolol** * **Metoprolol** * **Propranolol** ### Potassium Channel Blockers * **Amiodarone (Cordarone)** * **Dronedarone** * **Ibutilide** ### Calcium Channel Blockers * **Diltiazem** * **Verapamil** ### Miscellaneous Drugs * **Adenosine** * **Digoxin** * **Magnesium Sulfate** ## MOA * **Antiarrhythmic drugs act by suppressing abnormal impulse formation or conduction.** * **Drugs that block sodium or calcium channels can reduce abnormal automaticity and slow conduction of the cardiac impulse.** * **Drugs that block potassium channels can prolong repolarization and the action potential duration and thereby increase the refractory period of cardiac tissue.** * **Drugs that block ẞ-adrenoceptors reduce the sympathetic stimulation of cardiac automaticity and conduction velocity and thereby prevent the overstimulation that contributes to some arrhythmias.** ## Class I * **MOA:** SODIUM CHANNEL BLOCKERS * **Bind to sodium channels when the channels are in the open and inactivated states, and they dissociate from the channels during the resting state** * **Reduce abnormal automaticity and slow conduction of the cardiac impulse** * **The drugs in Class I have been subdivided into three:** * IA * IB * IC ## Class IA drugs * **Quinidine** * Slow conduction and prolong refractory periods, thereby increasing the QRS duration and the QT interval. * Because of their proarrhythmic effects, their use has declined in favor of Class III agents. ## Class IB drugs * **Lidocaine** is no longer used routinely for acute ventricular arrhythmias. * **Mexiletine** is an orally effective analogue of lidocaine that has been used for prevention of life-threatening ventricular arrhythmias. ## Class IC * **Flecainide** * **Propafenone** * Have a greater effect than other sodium channel blockers on cardiac conduction but have little effect on the action potential duration. * To treat supraventricular arrhythmias and life-threatening ventricular arrhythmias. ## Class II Drugs * **E.g:** Esmolol, Metoprolol, Propranolol * **MOA:** ẞ-adrenoceptor antagonists *(*β-blockers)* * **Inhibit sympathetic activation of cardiac automaticity and conduction.** * **ẞ-Blockers slow the heart rate, decrease the AV node conduction velocity, and increase the AV node refractory period** * **Indication:** These drugs are used to prevent and treat supraventricular arrhythmias. To reduce ventricular ectopic depolarizations and sudden death in patients with myocardial infarction. ## Class III Drugs * **E.g:** Amiodarone, Dofetilide, Ibutilide, Sotalol * **MOA:** Class III drugs act mostly by blocking potassium rectifier currents that repolarize the heart during phase 3 of the action potential * **Prolong repolarization and the action potential duration and thereby increase the refractory period of cardiac tissue.** * **Except for amiodarone, these drugs do not slow the ventricular conduction velocity or increase the QRS duration significantly** ## Class IV Drugs * **E.g:** Diltiazem, Verapamil * **MOA:** calcium channel blockers that have significant effects on cardiac tissue. * **Decrease the AV node conduction velocity and increase the AV node refractory period, and they have a smaller effect on the SA node and heart rate.** * **ROA:** Intravenously * **Indication:** Acute SVT, atrial fibrillation * **A/E:** Can exacerbate VT *(*arrhythmias must be correctly diagnosed before beginning treatment)* * **Other calcium channel blockers *(*amlodipine)* have less effect on cardiac tissue and no role in the treatment of arrhythmias** ## Thank You