Antiarrhythmic Agents riness in Purkinje and ventricular muscle fibers Amiodarone is slowly and poorly absorbed after oral administration It is metabolised slowly in liver to active metabolite Adverse effects include hypotension due to vasodilatation and depression of myocardial performance is frequent with the IV route Heart block, bradycardia, corneal microdeposits, photosensitivity, hepatitis, gastrointestinal upset may occur 193 echolamines and has direct antiarrhythmic property Bretylium may reverse the shortening of action potential duration caused by ischemia It acts due to K+ channel blockade It is used in the treatment of ventricular tachycardia and ventricular fibrillation CALCIUM CHANNEL BLOCKERS The detailed pharmacology is discussed in chapter ‘Antihypertensive agents’ BRETYLIUM These drugs inhibit Ca2+ mediated slow channel inward current, thus inhibiting Ca2+ mediated depolarization Phase depolarization in SA node and Purkinje fibres is reduced They also prolong AV nodal effective refractory period thus AV conduction is slowed There is also negative inotropic action It has direct action on myocardium and interferes with the neuronal release of cat- It is indicated in PSVT, to control ventricular rate in atrial flutter or atrial fibrillation It is indicated in tachyarrhythmias associated with WPW syndrome, atrial flutter and fibrillation, paroxysmal tachyarrhythmias not responding to other agents Ventricular tachycardia and ventricular arrhythmia refractory to other treatment This page intentionally left blank etrer t p p a h CCh 4.5 1.4 Antihyperlipidemic Pharmacodynamics (ModeAgents of Action of Drugs) These drugs are used for treatment of hyperlipidemia They lower the levels of lipoproteins and lipids in blood The plasma lipids are present in lipoproteins after combining with apoproteins They are high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL) Atherosclerosis is main cause of cardiovascular deaths It is characterized by a localised plaque in the intima and is composed of cholesterol esters, deposition of fibrous proteins and calcification These plaques may narrow the arterial lumen and can cause distalischemia The coronary and cerebral circulation are main sites of atherosclerosis Raised levels of VLDL, LDL Table 4.5.1: Classification for antihyperlipidemic agents I HMG CoA reductase inhibitors Lovastatin (LOVASTROL) 10-40 mg/day Simvastatin (SIMCARD) 5-20 mg/day Atorvastatin (ATOCOR) 10-80 mg/day Pravastatin (PRASTATIN) 40 mg/day II Fibric acid derivatives Clofibrate (ATROMID) 0.5-1 g BD Gemfibrozil (GEMPAR) 600 mg before meals III Agents inhibiting production of VLDL and lipolysis in adipose tissue Nicotinic acid 100 mg TDS, increased to 2-6 g/day IV Interferes with intestinal absorption of cholesterol Cholestyramine g TDS Colestipol 5-10 g TDS V Inhibit synthesis of LDL Probucol 500 mg BD after meals VI Miscellaneous Gugulipid (GUGLIP) 25 mg TDS 196 Section 4/ Drugs Acting on Cardiovascular & Urinary System and IDL are atherogenic, while HDL is protective because it facilitates removal of cholesterol from tissues SIMVASTATIN The drugs used in the treatment of hyperlipidemia are classified as in table 4.5.1 Simvastatin has been shown to reduce both normal and elevated low-density lipoprotein (LDL) cholesterol concentrations Apolipoprotein B, VLDL cholesterol and plasma triglycerides also reduce and can produce increase in HDL cholesterol HMG CoA REDUCTASE INHIBITORS Also known as statins HMG CoA reductase (Hydroxymethyl-Glutaryl Coenzyme A Reductase) inhibitors block the synthesis of cholesterol in liver by competitively inhibiting HMG CoA reductase activity, also cause depletion of critical intracellular pools of sterols and increased transcription of LDL receptors leading to enhanced removal from plasma of LDL cholesterol and LDL precursors They also reduce hepatic synthesis of VLDL, increase plasma HDL Reduction of LDL occurs over 4-6 weeks LOVASTATIN It is a potent HMG CoA reductase inhibitor This enzyme catalyzes the conversion of HMG CoA to mevalonate in liver which is an important early and rate limiting step in the cholesterol synthesis It causes marked reduction in LDL cholesterol and also raise HDL level and may lower the triglyceride level After oral administration it is extensively metabolised in liver and metabolites are excreted in bile Adverse reactions include arthralgia, myopathy, vertigo, tremor, memory loss, alteration of taste, peripheral neuropathy, anxiety, insomnia, depression, hepatitis cholestatic jaundice, abdominal pain, alopecia, blurred vision etc It is indicated in primary hypercholesterolemia and hyperglyceridemia Simvastatin, is twice as potent as lovastatin Simvastatin reduces total cholesterol, LDL cholesterol and triglycerides by 25%, 35%, and 10% respectively The increase in HDL is upto 12% Adverse effects are flatulence, diarrhoea, constipation, nausea, abdominal pain, cramps, heart burn and dysgeusia Rarely myopathy, rhabdomyolysis with acute renal failure may also occur Other adverse effects include headache, dizziness, rashes/pruritus, impotence insomnia, blurring of vision and lens opacities Simvastatin is indicated in patients with coronary heart disease and hypercholesteremia, for the reduction of elevated total and LDL cholesterol in patients with primary hypercholesterolemia (type IIa and IIb hyperlipoproteinemia), combined hypercholesterolemia and hypertriglyceridemia Simvastatin is also used in combination with nicotinic acid It is found to be the most useful drug combination for the treatment of dyslipidemias associated with coronary artery disease It is particularly effective in normalizing the lipid profiles of patients with familial combined dyslipidemia ATORVASTATIN Atorvastatin reduces total cholesterol, LDL-cholesterol and apolipoprotein B Antihyperlipidemic Agents hypercholesterolemia and mixed dyslipidemias Atorvastatin also reduces VLDL-cholesterol and TG and produces variable increases in HDL-cholesterol and apolipoprotein A1 Atorvastatin reduces LDL-cholesterol in patients with familial hyper-cholesterolemia (FH) Atorvastatin is generally well tolerated Adverse effects include constipation, flatulence, dyspepsia, abdominal pain, headache, nausea, myalgia, diarrhoea, asthenia and insomnia Dose related and reversible elevated serum ALT levels have also been reported Elevated serum CPK levels have been reported in some patients but only rarely patients have concurrent muscle pain, tenderness or weakness It is indicated as an adjunct to diet to reduce elevated total cholesterol, LDLcholesterol and TG levels in patients with primary hypercholesterolemia, diabetic dyslipidaemia or mixed hyperlipidemia, hypertriglyceridemia, dysbetalipoproteinemia and familial hypercholesterolemia PRAVASTATIN Pravastatin sodium besides increasing LDL cholesterol catabolism, also inhibits LDL-cholesterol production by inhibiting hepatic synthesis of VLDL-cholesterol, the LDL-cholesterol precursor These effects result in a reduction of total cholesterol, LDL-cholesterol, VLDL-cholesterol, apolipoprotein B and trigly-cerides, whilst increasing (HDL-cholesterol) and apolipoprotein A It has little effect on cholesterol synthesis in other tissues Pravastatin is administered orally in the active form and is rapidly absorbed, with 197 peak plasma levels occurring to 1.5 hours after dosing Pravastatin undergoes extensive first-pass extraction in the liver, which is its primary site of action It is 50% bound to plasma proteins Adverse effects include rash, myalgia, headache, non-cardiac chest pain; rarely nausea/vomiting, diarrhoea and fatigue may occur Pravastatin is indicated as an adjunct to diet in patients with primary hypercholesterolemia, mixed dyslipidemia, elevated serum triglyceride levels and primary dysbetalipoproteinemia who not respond adequately to diet FIBRIC ACID DERIVATIVES These activate lipoprotein lipase which is a key enzyme in degradation of VLDL resulting in lower circulating triglycerides These drugs lower triglyceride levels by 2050% with 10-15% decrease in LDL cholesterol and a 10-15% increase in HDL cholesterol CLOFIBRATE It has a specific action on type III hyperlipo-proteinemia and also reduces VLDL and LDL but because of its association with a small increase in risk of gastrointestinal and hepatobiliary neoplasia, it is seldom used GEMFIBROZIL Gemfibrozil reduces plasma triglycerides by 40 to 55% by decreasing the concentration of VLDL Its effectiveness is less in lowering LDL It also decrease hepatic synthesis and secretion of VLDL The lowering of ... 4.5 1.4 Antihyperlipidemic Pharmacodynamics (ModeAgents of Action of Drugs) These drugs are used for treatment of hyperlipidemia They lower the levels of lipoproteins and lipids in blood The plasma... circulation are main sites of atherosclerosis Raised levels of VLDL, LDL Table 4.5.1: Classification for antihyperlipidemic agents I HMG CoA reductase inhibitors Lovastatin (LOVASTROL) 10-40 mg/day... mg/day II Fibric acid derivatives Clofibrate (ATROMID) 0.5-1 g BD Gemfibrozil (GEMPAR) 600 mg before meals III Agents inhibiting production of VLDL and lipolysis in adipose tissue Nicotinic acid