I.

DRUG THERAPY OF THE MUSCULAR SYSTEM:

A. CENTRALLY ACTING SKELETAL MUSCLE RELAXANT: Actions: exact mechanism of action is still unknown, except that they act by CNS depression. All of these muscle relaxants produce some degree of sedation & most physicians believe that the benefits from these agents come from the sedative effect rather from the actual muscle relaxing effect Uses: for relief from muscle spasm (spinal cord injuries, rheumatic d/o) Side Effects: sedation, weakness, GIT upset Adverse effects: liver damage, blood dyscracias Drug interactions: Alcohol, narcotics, barbiturates, anticonvulsants, sedative hypnotics, tranquilizers and anti depressants can ENHANCE its depressive effect Agents: carisoprodol, chlorzoxazone, metaxalone, methocarbamol, tizanidine B. DIRECT ACTING SKELETAL MUSCLE RELAXANT; DANTROLENE Actions: this agent acts directly on skeletal muscles producing generalized mild weakness of skeletal muscles & decreases the force of reflex muscle contraction, hyperrelfexia, clonus, muscle stiffness, involuntary muscle movements & spasticity Uses: Cerebral palsy, multiple sclerosis, stroke syndrome, Malignant hyperthermia Side effects: weakness, diarrhea, drowsiness, dizziness Adverse effects: photosensitivity. Liver damage Drug interactions: CNS DPRESSANT: alcohol, analgesics, tranquilizers, potentiates the sedative effect of dantrolene C. NEUROMUSCULAR BLOCKING AGENTS: Actions: Acts by interrupting transmission of impulses from motor nerves of muscles at the NMJ. Neuromuscular blocking agents have no effect on consciousness, memory or pain threshold Uses: used during induction of anesthesia, intubation and electroshock therapy Side effects: salivation, discomfort Adverse effects: signs of respiratory distress, diminished cough reflex, & inability to swallow Drug interactions: Drugs that enhance Therapeutic & toxic effect: anesthetics, the aminoglycosides, beta blockers, quinidine, diuretics. Agents: atracurium, cisatracurium, doxacurium, mivacurium, succinylcholine, tubocurarine Cl.

II.

DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM

A. DRUGS USED TO TREAT HYPERLIPIDEMIAS: 1. BILE ACID-BINDING RESIN: Actions: cholestyramine & colestipol are resins that bind bile acids in the intestines. After oral administration, the resin forms a non-absorbable complex with bile acids, preventing enterohepatic recirculation of the bile acid. Because of the removal of the bile acid, liver cells compensate by increasing metabolism of cholesterol to p[roduce more bile acids , resulting in the net reduction in total cholesterol levels Uses: used in conjunction with dietary therapy to decrease elevated cholesterol concentration, in type II hyperlipidemia. Also for treating pruritus in biliary stasis, diarrhea Side effects: constipation, bloating, fullness, nausea Adverse effects: Flatulence Drug interactions: digitoxin, warfarin, thyroxine, diuretics, Phenobarbital, NSAIDS, tetracyclines & beta blockers: reduces absorption. Bile acid binding agents reduces absorption of fat soluble vitamins 2. NIACIN: Actions: this is also called nicotinic acid. A water soluble vitamin B. the exact mechanism of action is unknown, but it appears to inhibit the formation of VLDL which in turn lowers the LDL levels Uses: used in conjunction with dietary therapy to reduce cholesterolin type II, III, IV, & V hyperlipidemias Side effects: flushing, pruritus, headache, nausea, abdominal discomfort, dizziness, fatigue Adverse effect: myopathy, anorexia Drug interactions: Lovastatin if combined w/ niacin enhances the myopathic effect 3. HMGCoA REDUCTASE INHIBITORS; Actions: also called statins. They competitively inhibit the enzyme responsible for converting HMG-CoA to mevalonatein the biosynthetic pathway to cholesterol in the liver. The reduction in liver cholesterol increases the removal of LDL from the circulating blood. These agents are more effective if administered at night because peak of production of cholesterol during this period. Uses: For hypelipidemia/cholesterolemia Side effects: head ache, nausea, abdominal discomfort. Adverse effects: Myopathy, liver dysfunction Drug interactions: Cyclosporine, itra/keto/fluco nazoles, niacin, verapamil, eryhthromycin increases the incidence of myopathy. Ranitidine, omeprazole & cimetidine, increases statin levels

 Agents: atorvastatin, fluvastatin, simvastatin, lovastatin 4. FIBRIC ACID: Actions: exact action is unknown Uses: for hypertriglyceridemia. Fibric acids are not recommended in combination with statins due to the risk of rhabdomyolysis Side effects: nausea, diarrhea, abdominal discomfort, fatigue Adverse effects: myopathy, jaundice Drug interactions: enhanced Warfarin effect, enhanced insulin effect. Probenecid increases its toxic effect B. DRUGS USED TO TREAT HYPERTENSION 1. DIURETICS: Actions: causes volume depletion, sodium excretion, & vasodilatation of peripheral arterioles. It has 4 classes: (a.) carbonic anhydrase inhibitors, (b.) Thiazide & thiazide like agents, (c.) loop diuretics, (d.) potassium sparing diuretics. These are the most commonly prescribed antihypertensive agents because it is proven to lower cardiovascular morbidity & mortality associated with hypertension Uses: antihypertensive. 2. BETA BLOCKERS: SEE MIDTERM NOTES 3. ANGIOTENSIN CONVERTING ENZYMES INHIBITORS (ACEI) Actions: these act by inhibiting angiotensin I converting enzyme (dipeptidyl dipeptidase), the substance responsible for conversion of angiotensin I to angiotensin II Use: antihypertensive Side effects: nausea, dizziness, diarrhea Adverse effects: Orthostatic hypotension, facial edema, neutropenialiver damage, hyperkalemia, chronic cough, teratogenesis Drug interactions: lithium, digoxin, capsaicin reduces therapeutic effects Agents: captopril, enalapril, quinipril, ramipril 4. ANGIOTENSIN II RECEPTOR ANTAGONISTS: (AT1receptor antagonist) Actions: binds to angiotensin II receptor sites, blocking the very potent vasoconstrictor. Uses: antihypertension Side effects: head ache, dyspepsia, diarrhea Adverse effects: orthostatic hypotension, may be a teratogenic agent, hyperkalemia Drug interactions: Enhanced effect with: diuretics, alcohol, beta blockers

 Agents: candesartan, irbesartan, losartan, valsartan 5. CALCIUM ION ANTAGONIST: Actions: inhibits the movement of calcium ions across a cell membrane, this results in fewer arrhythmias a slower rate of cardiac contraction & relaxation of smooth muscles of blood vessels, resulting in vasodilatation & reduced BP Uses: antihypertensive Side effects: syncope, hypotension Adverse effect: edema Drug interactions: enhanced effect with- alcohol, phenothiazines, beta blockers, histamine antagonists Agents: amlodipine, nifedipine, nicardipine, verapamil 6. ALPHA 1 BLOCKING AGENTS: Actions: blocks post-sympathetic alpha1 adrenergic receptors to produce arteriolar & venous dilatation, reducing peripheral vascular resistance w/o reducing cardiac output or inducing a reflex tachycardia. These agents do not increase catecholamines therefore there is no increase in heart rate or myocardial oxygen consumption. Because of the presence of alpha 1 receptors in the prostate gland & bladder, TERAZOSIN & DOXAZIN are also able to reduce urinary outflow resistance in men with BPH. Uses: hypertension, BPH Side effects: headache drowsiness, tachycardia, fainting Adverse affects: lethargy Drug interactions: Enhanced effect with- diuretics, tranquilizers alcohol, barbiturates, antihistamines Agents: Doxazin, terazosin 7. CENTRALLY ACTING ALPHA 2 ANTAGONISTS Actions: stimulates the alpha adrenergic receptors in the brain stem , resulting in a reduced sympathetic outflow from the CNS with a decreased HR, & PVR, resulting in BP drop Uses: Antohypertensive Side effects: drowsiness, mouth dryness, dizziness Adverse effects: DEPRESSION Drug interaction: enhanced effect with- digitalis, guanethidine, barbiturates, tranquilizers, beta blockers Agents: Clonidine, methyldopa 8. PERIPHERALLY ACTING ADRENERGIC ANTAGONISTS: Actions: causes release & subsequent depletion of NE from adrenergic nerve endings. This causes a relaxation of vascular smooth muscle which decreases TPR & venous return. A hypotensive effect results that is greater in the standing than

in the supine position. Heart rate is decreased & fluid retention occurs. Sedation occurs due to depletion of NE in the brain Uses: Hypertension Side effects: sedation Adverse effects: orthostatic hypotension, edema Drug interactions: Enhanced effect with- barbiturates, diuretics, tranquilizers, antihistamines, alcohol Agents: guanethedine, reserpine, guanadrel

9. DIRECT VASODILATORS Actions: causes direct arteriolar smooth muscle relaxation resulting in a decreased PVR. The reduction in peripheral resistance causes a reflex increase in HR, CO, & renin release with sodium & water retention. Uses: for stage 2 & 3 hypertension, baldness Side effects: nausea, dizziness, tachycardia, fever, chills Adverse effects: myalgia, arthralgia, orthostatic hypotension Drug interactions: enhanced effect with- diuretics, alcohol, beta blockers Agents: minoxidil, hydralazine, nitroprusside sodium

C. DRUGS USED FOR THE TREATMENT OF HEART FAILURE: 1. DIGITALIS GLYCOSIDES: DIGOXIN Actions: derived from the foxglove plant, this agent increases the force of contraction & slows down the heart rate, reducing the conduction velocity & prolonging the refractory period at the AV node. The excat mechanism of action is unknown. Uses: heart failure Side effects: bradycardia, tachycardia, n/v Adverse effects: HypoK, HypoMg, HypoCa Drug interactions: Enhanced effect with- nifedipine, verapamil, antibiotics, betablockers Agents: digitoxin, digoxin 2. PHOSPHODIESTERASE INHIBITORS: Actions: increases the force & velocity of myocardial contractions by inhibiting CAMP phosphodiesterase activity & increases cellular level of CAMP in heart muscles. It is also a vascular smooth muscle relaxantthat causes vasodilatation, reducing preload & after load Uses: for short term treatment of heart failure

Side effects: N/V, abdominal discomfort Adverse effects: arrhythmias, hypotension, thrombocytopenia, liver damage Drug interactions: digitalis & furosemide. Agents: amrinone, milrinone

3. ANGIOTENSIN CONVERTING ENZYME INHIBITORS Actions: Reduces afterload & help reduce circulating blood volume by inhibiting the secretion of aldosterone Uses: reduces BP & increases renal blood flow

D. DRUGS USED TO TREAT ARRHYTHMIAS 1. ADENOSINE: Actions: it has a variety of roles including energy transfer, promotion of prostaglandin release, inhibition of platelet aggregation, antiadrenergic effects coronary artery dilatation & suppression of heart rate Uses: strong depressant of SA & AV node. Used in paroxysmal supraventricular tachycardia Side effects: flushing, dyspnea, chest pressure, nausea, head ache Adverse effects: Are short lived because the half life of adenosine is only 10 seconds Drug interactions: Enhanced effect with- dipyridamole & carbamazipines 2. AMIODARONE: Actions: action is unknown. This is a class III agent that acts by prolonging the action potential of atrial and ventricular tissues and by increasing the refractory period w/o altering the RMP, thus delaying repolarization Uses: SVT, atrial fibrillation & flutter, bradycardia-tachycardia syndrome, & hypertrophic cardiomyopathies Side effects: chest pain, fatigue, syncope, palpitations, edema Adverse effects: narrowing of pulse pressure, dyspnea, ataxia, confusion, bluured vision, yellow brown pigments in the cornea, photosensitivity & liver damage 3. BETA ADRENERGIC BLOCKING AGENTS: Actions: Class II agents. They block the cardiac response to sympathetic nerve stimulation by blocking the beta receptors, as a result, the HR, BP & CO reduces Uses: sinus tachycardia, paroxysmal atrial tachycardia, PVC 4. BRETYLIUM Actions: inhibits the release of norepinephrine. This is a class III agent Uses: ventricular arrhythmias Side effects: dizziness, n/v

 Adverse effects: hyper/hypotension Drug interactions: digitalis glycosides 5. DISOPYRAMIDE: Actions: class Ia antiarrhythmic agent Uses: for atrial fibrillation, Wolf-Parkinson-White syndrome, ventricular tachycardias Side effects: dryness of mouth & throat Adverse effect: bradycardia/heart failure, urinary hesitancy, constipation 6. FLECAINIDE: Actions: Class Ic antiarrhythmic agent. This agent has a negative inotropic effect that can lead to worsening of heart failure. Uses: ventricular tachycardias, PVCs. Side effects: dizziness, syncope, blurred vision, headache, n/v Adverse effects: edema, increasing dyspnea, arrhythmias Drug interactions: agents that enhance its effect: amiodarone, cimetidine, disopyramide 7. LIDOCAINE: Actions: Class Ib agent Uses: most commonly used drug for ventricular arrhythmias & the drug of choice for ventricular arrhythmias secondary to AMI Side effects: muscle twitching, light-headedness Adverse reactions: respiratory depression Drug interactions: Enhanced effect with- phenytoin, procainamide, tocainide, beta blockers 8. MEXILETINE: Actions: Class Ib anti-arrhythmic agent similar to lidocaine Uses: PVCs, ventricular tachycardias Side effects: n/v, dyspepsia Adverse effects: neurotoxic, arrhythmia Drug interaction: reduced effect with phenytoin

9. MORICIZINE: Actions: inhibits the influx of sodium ions into the myocardial cells, making it a class I agent Uses: ventricular arrhythmias Side effects: dizziness, hypotension, nausea Adverse effects: arrhythmias, euphoria Drug interactions: enhanced effect with digoxin, cimetidine, & propranolol 10. PHENYTOIN:

Actions: Class Ib drug Uses: paroxysmal atrial tachycardia, ventricular arrhythmias Side effects: n/v, sedation, drowsiness, blurred vsion Adverse effect: Confusion, dermatologic manifestations Drug interactions: enhanced effect with- warfarin, disulfiram, INH, carbamazipine, chloramphenicol, amiodarone, sulfonamides

11. PROCAINAMIDE: Actions: Class Ia drug that has many cardiac effects similar to quinidine Uses: ventricular & supraventricular arrhythmias Side effects: drowsiness sedation, dizziness Adverse effects: myalgia, arthralgias, skin eruptions Drug interactions: Enhanced effect with- histamine receptor blockers, quinidine, trimethoprim & beta blockers 12. PROFAPENONE: Actions: Class Ic agent, that has a weak beta blocking & calcium channel blocking effect Uses: Paroxysmal atrial fibrillation, & ventricular tachycardia Side effects: n/v, dizziness, constipation Adverse effects: arrhythmias Drug interactions: Enhanced effect with quinidine & cimetidine 13. QUINIDINE: Actions: derived from the cinchona bark. It is a class Ia agent. It slows down the heart rate & changes a rapid, irregular pulse to a slow regular pulse Uses: atrial fibrillation, atrial flutter, PSVT, PVC Side effects: diarrhea, dizziness Adverse effects: Cinchonism- fever, chills, tinnitus Drug interactions: enhanced effect with- cimetidine, procainamide, digitalis, phenothiazines, verapamil, beta blockers 14. TOCAINIDE: Actions: Class Ib agent. This is the first available derivative of lidocaine Uses: ventricular tachycardia Side effects: n/v, dizziness, cofusion, numbness Adverse effects: dyspnea, wheezing, thrombocytopenia Drug interactions: enhanced effect with- procainamide, disopyramide, quinidine

E. DRUGS USED FOR ANGINA PECTORIS 1. NITRATES:

 Actions: oldest effective therapy for angina pectoris. They relieve angina by inducing relaxation of peripheral vascular smooth muscles, resulting in dilatation of arteries & veins, this reduces venous blood return to the heart leading to a decreased oxygen demand in the heart. Nitrates also increase myocardial oxygen supply by dilating large coronary arteries & redistributing blood flow, enhancing oxygen supply to ischemic areas Uses: Ntroglycerine- DOC for angina pectoris Side effects: headache, tolerance Adverse effects: excessive hypotension Drug interactions: alcohol, calcium ion antagonist, beta blockers Agents: amyl nitarite, ISDN, ISMN, nitroglycerine 2. BETA BLOCKERS: Actions: reduces myocardial oxygen demand by blocking the beta receptors of the heart. Uses: for angina 3. CALCIUM ION ANTAGONISTS Actions: inhibits the movement of calcium ions across cellular membranes Agents: amlodipine, nifedipine, verapamil

F. DRUGS USED FOR PERIPHERAL VASCULAR DISEASES 1. PENTOXIFYLLINE Actions: hemorrheologic agent. It increases RBC flexibility, decreases the concentration of fibrinogen in blood & prevent aggregation of RBc & platelets Uses: for intermittent claudication Side effects: n/v, dyspepsia, dizziness, HA Adverse effects: chest pain arrhythmias, dyspnea Drug interactions: Antihypertensive agents, theophylline 2. CYCLANDELATE: Actions: Vasodilator. Directly relaxes smooth muscles in blood vessels Uses: intermittent claudication, thromboangitis obliterans, leg cramps, Reynauds disease Side effects: flushing, tingling, n/v Adverse effects: diaphoresis Drug interactions: no known drug interactions 3. ISOXSUPRINE HCL Actions: vasodilator. Uses: Buergers disease, Reynauds disease, arterial occlusive disease Side effects: same as (2)

 Drug interactions; Antihypertensive agents 4. 5. 6. PAPAVERINE HCL Actions: vasodilator Uses: cerebral & peripheral ischemia Side effects: same as 2 & 3 Drug interactions: antihypertensive agents PHENOXYBENZAMINE HCL: Action: vasodilator Uses: Reynauds disease, leg ulceration, frostbite Side effects: nasal stiffiness, tachycardia Adverse effects: hypotension Drug interactions: antihypertensives TOLAZALINE: Actions: vasodilator Uses: Reynauds disease, chronic leg ulcers, frost bite gangrene Side effects: flushing, tingling, sweating, n/v Adverse effects: arrhythmias, tachycardias, anginal pain, hallucination Drug interactions: antihypertensives

7. CILOSTAZOL Actions: Platelet aggregation inhibitor. Inhibits CAMP phosphodiesterase III resulting in vasodilatation, & inhibited platelet aggregation Uses: Intermittent claudication Side effects: dyspepsia, diarrhea, dizziness Adverse effects: chest pain, palpitations, arrhythmias Drug interactions: dilatiazem, erythromycin, omeprazole, fluconazole, sertraline, ketoconazole, grapefruit juice G. DRUGS USED FOR DIURESIS 1. CARBONIC ANHYDRASE INHIBITORS: ACETAZOLAMIDE Actions: a weak diuretic that acts by inhibiting the enzyme, carbonic anhydrase w/in the kidneys, brain and eyes. It promotes the excretion of potassium water & bicarbonates Uses: for glaucoma patients. Not commonly used 2. METHYLXANTHINES: AMINOPHYLLINE: Actions: acts by improving blood flow to the kidneys Uses: rarely used as a diuretic

3. LOOP DIURETICS: a. BUMETAMIDE: Actions: a potent diuretic that acts by inhibiting sodium & chloride reabsortion from the ascending loop of Henle in the glomeruli of the kidneys. It also acts by increasing renal blood flow into the glomeruli & inhibits electrolyte absorption in the proximal tubule, enhancing Na, chloride, PO3, HCO3 excretion in the urine. Diuretic activity starts 30-60 minutes after administration Uses: CHF, renal & liver disease, including nephritic syndrome Side effects: gastric irritation, hives Adverse effects: hypokalemia, changes in mental status Drug interactions: alcohol, barbiturates, digitalis, aminoglycosides, cisplastin, NSAIDS, steroids b. ETHACRYNIC ACID: Actions: acts on the ascending limb of the loop of Henle to prevent sodium and chloride reabsorption. Its effect starts 30min, peaks after 2 hours and lasts for 6-8 hours. Uses: renal & liver diseases, CHF Side effects: orthostatic hypotension Adverse effects: Hypokalemia, change in mental status, deafness, GIT bleeding, hyperglycemia Drug interactions: aminoglycosides, cisplastin, NSAIDS, difitalis, steroids c. FUROSEMIDE: Actions: acts on the ascending loop of Henle but also affects the proximal & distal tubules to prevent sodium & chloride reabsorption. Effect starts 5-10 minutes after IV administration peaks after 30 minutes and lasts for 2 hours Uses: liver & renal diseases, CHF, HTN Side effects: oral irritation, hypotension Adverse effects: Electrolyte imbalance, dehydration, hyperuricemia, hyperglycemia Drug interactions: Digitalis, propranolol, aminoglycosides, cisplastin, NSAIDS, salicylates, phenytoin d. TORSEMIDE Actions: sulfonamide type loop diuretic

4. THIAZIDES: Actions: Benzothiadiazides acts primarily on the distal tubules of the kidneys to block the reabsorption of sodium & chloride ions. Uses: CHF, renal & liver disease, obesity, premenstrual syndrome Side effects: hypotension, n/v, constipation, gastric irritation

 Adverse effects: Electrolyte imbalance, hyperuricemia, hyperglycemia Drug interactions: digitalis, steroids, lithium, NSAIDS, oral hypoglycemic agents

5. POTASSIUM SPARING DIURETICS: a. AMILORIDE: Actions: exact mechanism of action is unknown, but it acts on the distal renal tubule to retain K & excrete Na resulting in a mild diuresis Uses: combined with other diuretics. For CHF Side effects: n/v, anorexia, headache, flatulence Adverse effects: electrolyte imbalance (HyperK) Drug interactions: Lithium, K supplements b. SPIRONOLACTONE: Actions: blocks the sodium retaining & potassium & magnesium excreting properties of aldosterone, resulting in loss of water with increased sodium excretion Uses: used in relieving edema & ascites. It also shows reduction in morbidity & mortality in a CHF patient Side effects: diarrhea, headache Adverse effects: mental confusion, electrolyte imbalance, gynecomastia, reduced libido, breast tenderness Drug interactions: K supplements, salt substitute c. TRIAMTERENE: Actions: blocks the exchange of potassium for sodium in the distal tubule of the kidneys, resulting in K retention & Na excretion Uses; Combined with thiazides Side effects: leg cramps, nausea, Adverse effects: electrolyte imbalance, dehydration Drug interactions: DO NOT ADMINISTER WITH POTASSIUM SUPPLEMENTS= HYPERKALEMIA 6. COMBINATION DIURETIC PRODUCTS: Spironolactone + HCTZ Triamterene + HCTZ AMILORIDE + HCTZ

H. DRUGS USED TO TREAT THROMBOEMBOLIC DISORDERS 1. PLATELET INHIBITORS a. ASPIRIN

 Actions: Inhibits thromboxane A2 Uses: TIA Side effects: see midterm lecture notes b. CLOPIDOGREL: Actions: chemically related to ticlodipine. The metabolite of this drug acts to inhibit platelet aggregation. Antiplatelet activity is seen after 3- 7 days Uses: TIA, Post MI, Angina pectoris, peripheral arterial disease, stroke Adverse effects: Neutropenia, agranulocytosis, GIT blleding Drug interactions: phenytoin, tamoxifen, warfarin, torsemide, fluvastatin, NSAIDS c. DIPYRIDAMOLE Actions: inhibits Thromboxane A2, increases CAMP in platelets, potentiating prostacyclin-mediated inhibition Uses: TIA, thromboembolism Side effects: dizziness, GIT distress Adverse effects: postural hypotension 2. ANTICOAGULANTS: a. ARDEPARIN Actions: this is a LMWH that enhances antithrombin activity against factor Xa and thrombin which prevents completion of the coagulation cascade. (Ardeparin). DO NOT INJECT IM Uses: DVT Adverse effects: Bleeding b. DALTEPARIN: Action: same as ardeparin Use: DVT Adverse effect: bleeding d. ENOXAPARIN: Actions: same as a and b Uses: DVT, unstable angina Adverse effect: bleeding

e. HEPARIN: Actions: acts as catalyst to accelerate the rate of action of a naturally occurring inhibitor of thrombin, antithrombin III (heparin cofactor). Uses: cerebral embolism, DVT, PE Side effects: BLEEDING Antidote is protamine

f.

WARFARIN: Actions: inhibits activity of vitamin K ( Factors II, VII, IX ,X) Uses: DVT, atrial fibrillation with embolism, PE Adverse effect: Bleeding Antidote: Vit K

3. FIBRINOLYTIC AGENTS: Actions: activates the conversion of plasminogen to plasmin/ fibrinolysin, w/c digests fibrin, dissolving the clot Uses: Stroke, MI Agents: streptokinase, urokinase, Anistreplase/APSAC, alteplase, reteplase