Flashcards in Cardiovascular Pharmacology Deck (118):
What are the principal categories of drugs that are used in hypertension?
2. Sympathoplegics (blockers of sympathetic NS)
4. Angiotensin antagonists
5. Single renin inhibitor (aliskiren)
What are the diuretics most important in treating hypertension?
1. Thiazides : hydrochlorothiazide - mild hypertension.
2. Loop diuretics : furosemide - moderate to severe hypertension.
What are the CNS active agents (sympathoplegics) used in hypertension?
1. α2 agonists (clonidine, methyldopa) : given orally, decrease in SNS outflow via activation in the CNS - major compensatory response is salt retention.
2. Sudden discontinuation of clonidine causes rebound hypertension - α blocker phentolamine is given.
What are the postganglionic sympathetic nerve terminal blockers used in hypertension?
2. Guanethidine, guanadrel
3. MAO inhibitors were used.
What are the adrenoceptor blockers that are used in hypertension?
1. α1 blockers (prazoxin, doxazosin, terazosin) - moderately effective - adverse effect is orthostatic hypotension.
2. β blockers (propranolol, atenolol, metoprolol, carvedilol, nebivolol (new)) - heavily used in hypertension.
What are the four mechanisms by which vasodilators act?
1. Release of NO
2. Opening of potassium channels
3. Blockade of calcium channels
4. Activation of D1 receptors
What are the main features of hydralazine and minoxidil (vasodilators in hypertension)?
1. More effect on arterioles than on veins.
2. Orally active and suitable for chronic therapy.
What is the mechanism of action of hydralazine ?
Release of NO from endothelial cells.
What are the features of minoxidil?
1. Extremely efficacious - for severe hypertension.
2. Is a prodrug - its metabolite is a K channel opener.
3. Compensatory responses require concomitant use of diuretics and β blockers.
4. It can cause hirsutism - use for baldness.
What are the principal calcium channel blockers ?
Same as nifedipine :
Mention 3 drugs (vasodilators) that are used in hypertensive emergencies.
1. Nitroprusside : short acting, release of NO from the drug molecule.
2. Diazoxide : thiazide derivative, K channel opener + reduces insulin (treat hypoglycemia also).
3. Fenoldopam (dopamine D1 receptor activation) - marked arteriolar dilation, intravenously, short acting (10min).
What are the two primary groups of angiotensin antagonists?
1. ACE inhibitors
2. Angiotensin II receptor blockers (ARBs)
What is the main ACE inhibitor ?
What is the situation in which ACE inhibitors are contraindicated?
Mention the principal ARBs used in hypertension?
What are the steps in polypharmacy of hypertension?
1. Lifestyle measures such as salt restriction and weight reduction.
2. Diuretics (a thiazide)
3. Sympathoplegics (β blocker)
4. ACE inhibitors
5. Vasodilators (first a Ca channel blocker)
What are the two main strategies in angina pectoris treatment?
1. Reduction of oxygen demand
2. Increase of oxygen delivery to the myocardium
What are the three main categories of drugs used in angina treatment?
2. Cardiac depressants
3. Other drugs
What is the new strategy in angina treatment?
Increase the efficiency of oxygen utilization by shifting energy substrate preference of the heart from fatty acids to glucose - pFOX inhibitors :
What is the first pass effect for nitroglycerin?
Mention other nitrates that are used besides nitroglycerin.
1. Isosorbide dinitrate
2. Isosorbide mononitrate (oral)
How do nitrates release NO within the smooth muscle cells?
Through the action of the mitochondrial enzyme aldehyde dehydrogenase-2 (ALD2).
In what formations is nitroglycerin available?
1. Sublingual (tablet or spray) : 10-20 min
2. Oral : 4-6h
3. Transdermal : tolerance after 10h
What are the potential toxic effects of nitroglycerin?
The responses evoked by vasodilation :
1. Tachycardia (baroreceptor)
2. Orthostatic hypotension
3. Throbbing headache from meningeal artery vasodilation
What can nitrites cause at high concentrations?
How can cyanide poisoning be treated?
3 step procedure :
1. Immediate exposure to amyl nitrite
2. Intravenous administration of sodium nitrite - rapidly increases the methemoglobin level in order to remove significant amount of cyanide from cytochrome oxidase.
3. Intravenous sodium thiosulfate - converts cyanomethemoglobin resulting from step 2 to thiocyanate and methemoglobin.
Mention some principal Ca channel blocking drugs used in the treatment of angina.
All orally active - half lives of 3-6h
What is the mechanism of action of Ca Chanel blocking drugs used in angina?
Block voltage gated L-type calcium channels.
What is the toxicity of calcium channel blocking drugs used in angina?
2. Pretibial edema
6. Heart failure
7. AV blockade
8. Sinus node depression
What is the clinical use of β blockers in angina treatment?
Only for prophylactic therapy.
What are the three major group of the drugs used in cardiac failure?
1. Positive inotropic drugs
3. Miscellaneous drugs for chronic failure
What are the pharmacologic therapies for heart failure?
1. Removal of retained salt and water with diuretics.
2. Reduction of afterload and salt and water retention by means of angiotensin-converting enzyme (ACE inhibitors).
3. Reduction of excessive sympathetic stimulation by means of β blockers.
4. Reduction of preload or afterload with vasodilators.
5. In systolic failure : direct augmentation of depressed cardiac contractility with positive inotropic drugs such as digitalis glycosides.
What is the prototype cardiac glycoside used in heart failure?
What is the half-life of digoxin?
What is the mechanism of action for digoxin?
Inhibition of Na/K ATPase.
A small increase in intracellular Na - less Ca is removed from the cell - increased contractile force.
What are the mechanical effects of digitalis in the heart function?
1. Increase in contractility
2. Increased ventricular ejection
3. Decreased end-systolic and end-diastolic size
4. Increased CO
5. Increased renal perfusion
What are the electrical effect of digitalis?
Early responses :
1. Increased PR interval, caused by the decrease in AV conduction velocity
2. Flattening of T wave.
3. Effects on the AV node - largely parasympathetic.
Toxic responses :
1. Increase automaticity caused by Ca overload.
2. Premature ventricular beats.
What are the clinical uses of digitalis?
1. Congestive heart failure : traditional positive inotropic agent.
2. Atrial flutter and fibrillation : reduces conduction velocity + increases refractory period of the AV node.
Mention some basic interactions of digoxin.
1. With quinidine - increase in serum level of digoxin.
2. Hypocalcemia, hypokalemia and hypomagnesia increase the arrhythmogenesis of digoxin.
3. Loop diuretics and thiazides may significantly reduce serum K so...
What are the major signs of digitalis toxicity?
What are the steps for the treatment of digitalis toxicity?
1. Correction of K and Mg deficiency.
2. Antiarrhythmic drugs.
3. Digoxin antibodies.
Besides digitalis, what other categories of drugs are used for heart failure?
2. Angiotensin antagonists
3. β1-adrenoceptor agonists
4. β-adrenoceptor antagonists
5. Phosphodiesterase inhibitors
What diuretics are used in HF?
What angiotensin antagonists are used in HF?
1. Losartan (ARB)
2. Captopril (ACE inhibitor)
What β1-adrenoceptor agonists are used in HF?
What β-adrenoceptor antagonists are used in HF?
What phosphodiesterase inhibitors are used in HF ?
3. Theophylline (aminophylline)
What vasodilators are used in HF?
5. Isosorbide dinitrate
What are the five general categories in which the drugs for arrhythmia fall into?
1. Group 1 : Na channel blockers
2. Group 2 : β blockers
3. Group 3 : K channel blockers
4. Group 4 : Ca channel blockers
5. Group 5 : Miscellaneous group
Mention some of the clinical important arrhythmias.
1. Atrial flutter
2. Atrial fibrillation
3. Atrioventricular nodal reentry
4. Premature ventricular beats
5. Ventricular fibrillation
6. Torsades de pointes
What is torsades de pointes?
1. Ventricular arrhythmia of great pharmacologic importance because it is often induced by anti-arrhythmic and other drugs that change the shape of the action potential and prolong the QT interval.
2. Polymorphic ventricular tachycardia - waxing and waning QRS amplitude.
3. Associated with long QT syndrome.
What are the three categories of group 1 antiarrhythmics (local anesthetics) ?
Group 1A agents (procainamide) : prolong the AP
Group 1B drugs (lidocaine) : shorten the AP
Group 1C drugs (flecainide) : no effect on AP duration
What is the main action of all group 1 drugs?
1. Slow conduction in ischemic and depolarized cells.
2. Slow or abolish abnormal pacemakers wherever these processes depend on Na channels.
Mention 4 drugs with group 1A action.
What is the mechanism of action of group 1A drugs?
1. Affect both atrial and ventricular arrhythmias.
2. Block I(Na) - slow conduction velocity in the atria, purkinje fibers, ventricular cells.
What is the action of Amiodarone ?
1. I(Na) block .
2. The greatest prolonging effect (I(K) block).
Mention some important drugs with group 1B action.
1. Lidocaine (IV or IM routes)
2. Mexiletine (orally active)
What is the mechanism of action of group 1B drugs?
Lidocaine and Mexiteline
1. selectively affect ischemic or depolarized Purkinje and ventricular tissue, and have little effect on atrial tissue.
2. Reduce AP duration in some cells - they slow recovery of Na channels from inactivation + not shorten the effective refractory period.
3. No effect on ECG.
Phenytoin : used to reverse digitalis induced arrhythmias + resembles lidocaine in lacking significant effects on the normal ECG.
What is the prototype drug with group 1C actions?
What is the action of group 1C drugs?
1. No effect on ventricular AP duration or the QT interval.
2. Powerful depressants of Na current - markedly slow conduction velocity in atrial and ventricular cells.
3. Increase QRS duration.
What is the clinical use of group 1A drugs ?
1. Procainamide : used in all types or arrhythmia - atrial and ventricular arrhythmias most responsive + also in acute phase myocardial infarction.
2. Quinidine and dysopyramide similar effects, but used less frequently.
What are the major potential adverse effects of group 1A drugs?
1. Procainamide : hypotension + reversible syndrome similar to lupus.
2. Quinidine : cinchonism (headache, vertigo, tinnitus) + cardiac depression + GI upset + autoimmune reactions + reduces the clearance of digoxin.
3. Dysopyramide : marked antimuscarinic effects - heart failure.
4. All group 1A drugs may precipitate new arrhythmias.
What usually exacerbates the toxicity of group 1A drugs ?
What is the clinical use of lidocaine?
In acute ischemic ventricular arrhythmias, for example, after myocardial infarction.
What is the clinical use of Mexiletine?
Similar to lidocaine, but is given orally for chronic arrhythmias and for certain types of neuropathic pain.
How is lidocaine usually administered ?
Intravenously, but intramuscular administration is possible. Never orally because of high first pass effect - potentially cardiotoxic.
What are the adverse effects of lidocaine and Mexiletine ?
1. Occasionally cause typical anesthetic toxicity : CNS stimulation.
2. Usually minor cardiovascular depression.
3. Allergy - usually rashes but it may extend to anaphylaxis.
4. May precipitate arrhythmias, but much less commonly than with group 1A drugs.
What is the clinical use of flecainide ?
Atrial and ventricular arrhythmias, but it is approved only for refractory ventricular tachycardias + certain intractable supraventricular arrhythmias.
What is the toxicity of flecainide?
1. Exacerbate or precipitate arrhythmias (proarrhythmic effect).
2. Also cause local anesthetic-like CNS toxicity.
3. Hyperkalemia increases the toxicity of these agents.
What are the principal β-blockers used as antiarrhythmics?
What is the mechanism of action of propranolol and esmolol?
1. Cardiac adrenoceptor blockade + reduction in cAMP.
2. Reduction of both Na and Ca currents.
3. Suppression of abnormal pacemakers.
4. AV node particularly sensitive.
5. Prolonged PR interval.
What drugs are generally classified as group 3 drugs, but have group 2 β-blocking effects?
Sotalol and Amiodarone.
What is the clinical use of esmolol as antiarrhythmic drug?
Exclusively in acute arrhythmias - short acting and given intravenously.
What is the clinical use of propranolol, metoprolol and timolol as antiarrhythmics?
Prophylactic drugs in patients who had a myocardial infarction.
What are the major group 3 antiarrhythmics (K current channel blockers)?
3. Sotalol (2 isomers)
What is the hallmark of group 3 drugs?
Prolongation of the AP duration.
What is the most efficacious of all antiarrhythmic drugs?
Amiodarone : useful in most types of arrhythmias.
What is the mechanism of action of Amiodarone?
1. Blocks Na, K, Ca, channels.
2. Blocks adrenoceptors.
What are the adverse effects of Amiodarone?
1. Microcrystalline deposits in the cornea and skin.
2. Thyroid dysfunction (hyper- or hypothyroidism).
5. Pulmonary fibrosis
What is the clinical use of dronedarone?
Atrial fibrillation and flutter.
What are the principal group 4 antiarrhythmics (Ca L-type channel blockers)?
What is the mechanism of action of verapamil and diltiazem?
1. Cause a state- and use-dependent selective depression of Ca current.
2. AV conduction velocity is decreased.
3. Effective refractory period + PR interval are increased by these drugs.
In what arrhythmias are verapamil and diltiazem effective?
Arrhythmias that must traverse Ca-dependent cardiac tissue, such as the AV node.
What is the most important toxicity of verapamil and diltiazem?
Excessive depression of :
1. Cardiac contractility
2. AV conduction
3. Blood Pressure
Should be avoided in ventricular tachycardias.
Mention some important features of adenosine as antiarrhythmic.
1. Markedly slows or completely blocks conduction in the AV node (when given in high doses 6-12mg).
2. Hyperpolarization of AV node tissue through increased K current + reduces Ca current.
3. The drug of choice in abolishing AV nodal arrhythmia.
4. Extremely short acting (15sec).
What are the adverse effects of adenosine ?
3. Transient dyspnea and chest pain may also occur.
What is the prototype CA inhibitor?
What is the mechanism of action of acetazolamide?
Inhibition of CA in the brush border of the cytoplasm (renal tubules) - generally inhibits CA in all tissues.
What are the principal effects of acetazolamide?
1. Bicarbonate diuresis (results in metabolic acidosis).
2. Significant K wasting.
3. Reduced secretion of bicarbonate into aqueous humor and CSF.
4. Reduction in intraocular pressure can be achieved.
5. CNS : acidosis of CSF results in hyperventilation - protect against high-altitude sickness.
What is the clinical use of acetazolamide?
1. Parenterally in the treatment of severe acute glaucoma.
2. Also orally, but topical analogs are available for topical use in the eye (dorzolamide, brinzolamide).
3. Used also to prevent acute mountain (high-altitude sickness).
4. Used as diuretic only if edema is accompanied by significant metabolic alkalosis.
What are the adverse effects of acetazolamide?
1. Drowsiness and paresthesia after oral therapy.
2. Cross-allergenicity with other sulfonamide derivatives may occur.
3. Alkalinization of the urine by these drugs may cause precipitation of Ca salts - formation of renal stones.
4. K wasting may be marked.
5. Patients with hepatic impairment : hepatic encephalopathy - increased ammonia reabsorption.
Mention some important loop diuretics.
4. Ethacrynic acid
What is the mechanism of action of loop diuretics?
Inhibit the cotransport of Na, K, and Cl (NKCC2) - short acting - diuresis occurs over a period of 4h following a dose.
What are the effects of loop diuretics?
1. Massive NaCl diuresis - blood volume may be significantly reduced.
2. If tissue perfusion is adequate, edema fluid is rapidly excreted.
3. The diluting ability of the nephron is reduced.
4. Loss of lumen-positive potential - reduced reabsorption of cations - increased Ca excretion.
5. Hypokalemic alkalosis may occur.
6. Also reduced pulmonary vascular pressure (unknown mechanism).
What is the clinical use of loop diuretics?
1. Edematous states (heart failure, ascites, acute pulmonary edema).
2. Sometimes in hypertension, if thiazides are inadequate.
3. Severe hypercalcemia.
What are the adverse effects of loop diuretics?
1. Hemoconcentration - if diuresis without volume replacement.
2. Hypokalemic metabolic alkalosis.
3. Severe K wasting due to large amount of Na presented to collecting tubules.
5. CVS complications.
What is the target of the thiazide diuretics?
The NCC Na-Cl cotransporter in the distal convoluted tubule.
What is the prototype thiazide diuretic?
How are thiazides administered?
What is the duration of action of thiazides?
6-12h - considerably longer than loop diuretics.
What are the effects of thiazide diuretics?
1. In full doses : moderate but sustained Na and Cl diuresis.
2. Hypokalemic metabolic alkalosis may occur.
3. Urine Ca content is decreased - opposite effect of loop diuretics.
4. Dilutional hyponatremia.
5. Also reduce blood pressure.
What is the clinical use of thiazides?
1. Hypertension (major application).
2. Chronic therapy of edematous conditions - mild heart failure.
3. Chronic renal Ca stone formation can sometimes be controlled with thiazides.
What are the adverse effects of thiazides?
1. Massive Na diuresis - hyponatremia - uncommon, but dangerous early toxicity of thiazides.
2. Chronic therapy is often associated with K wasting.
3. Significant hyperglycemia in diabetic patients.
4. Serum uric acid and lipid levels are also increased in some persons.
5. Potential sulfonamide allergenicity.
Mention 4 important K-sparing diuretics.
What is the mechanism of action of spironolactone and epleronone?
Pharmacologic antagonists of aldosterone in the collecting tubules.
Combine and block the intracellular aldosterone receptor, they reduce the expression of genes that code for the epithelial Na channel (ENaC and Na/K ATPase).
What is the clinical use of K-sparing diuretics?
1. K wasting caused by chronic therapy with loop or thiazide diuretics.
2. Aldosteronism (cirrhosis, heart failure)
3. Hyperkalemia (most important toxic effect).
4. Endocrine abnormalities : gynecomastia + antiandrogenic effects (spironolactone).
What are the principal osmotic diuretics?
1. Mannitol (prototype) - IV given.
What is the mechanism of action of osmotic diuretics?
1. They are freely filtered but poorly reabsorbed - they remain in the lumen and "hold" water by virtue of their osmotic effect.
2. Major site : proximal convoluted tubule.
3. Reduced reabsorption of water in the DLH and collecting tubule.
What are the effects of osmotic diuretics?
1. Volume of urine increased.
2. Most filtered salutes are excreted in large amounts unless they are actively reabsorbed.
3. Rate of urine flow greatly increased.
4. Mannitol : reduces brain volume + intracranial pressure - similar effect in the eye.
What is the clinical use of osmotic diuretics?
1. To maintain high urine flow (when renal blood flow is reduced).
2. In acute glaucoma : reducing intraocular pressure.
3. In neurologic conditions : reducing intracranial pressure.
What are the adverse effects of osmotic diuretics?
2. Pulmonary edema
Mention 2 prototypical ADH agonists.
Mention 4 important ADH antagonists.
3. Demeclocycline (previously used)
4. Lithium (but never used)
What is the mechanism of action of ADH ?
Facilitates water reabsorption from the collecting tubule by the activation of V2 receptors (Gs).
What are the effects and clinical use of ADH agonists?
1. Reduce urine volume
2. Useful in pituitary diabetes insipidus
What are the effects and clinical use of ADH antagonists?
1. Oppose the actions of ADH on the same V2 receptors.
2. Used in the syndrome of inappropriate ADH secretion.
What are the adverse effects of ADH agonists?
1. Dangerous hyponatremia
2. Hypertension in some individuals