Arrhythmia and Lipid Disorders - PPT II - Final Exam

What do antiarrhythmic drugs do?

-reduce ectopic pacemaker activity through blocking Na or Ca channels

-modify conduction in reentrant circuits by slowing conduction in reentrant arrhythmias

What tissues are affected more by therapeutic uses of antiarrhythmics?

abnormal tissues like reduce impluse generation more in ectopic pacemakers rather than SA node

What is the function of class I antiarrhythmic?

Na+ channel blockade

What is class I divided into?

IA, IB, IC

What is the MOA of class IA antiarrhythmics?

-slow conduction velocity and pacemaker rate

-prolong and increase AP duration

-produce direct depressant effects on SA and AV nodes

-moderate Na channels blockade

-increase effective refractory period in ventricular action potential

-increase QT interval

What are the class IA antiarrhythmic agents?

-quinidine

-procainamide

-disopyramide

What is the MOA of class IB antiarrhythmics?

-produce small increase in APD and ERP

-weak Na+ channel

-preferentially affect ischemic or depolarized Purkinjee and ventricular tissue

-weaker effects on heart than IA or IC

What are the class IB antiarrhythmic agents?

-lidocaine

-mexiletine

What is the MOA of class IC antiarrhythmics?

-cause strong NA+ blockade

-significantly prolongs ERP in AV nodes

-minimal effect on AP duration

-large increase in QRS duration

What is the relatively newer-good class IC?

propafenone

What are the class IC antiarrhythmic agents?

-flecainide

-propafenone

What are the class II antiarrhythmics?

beta blockers

What is the MOA of class II antiarrhythmics?

-decrease in heart rate and contractility

-decrease SA and AV nodal activity by decreasing cAMP

-decrease Ca2+ current

-suppress abnormal pacemaker

-increase PR interval

What class II antiarrhythmic is used for acute arrhythmias during surgery?

esmolol

What are the class II antiarrhythmic agents?

-acebutolol

-propanolol

-esmolol

What is the MOA of the class III antiarrhythmics?

-block K+ channels

-delay in repolarization in phase III to prolong action potential duration, ADP and effective refactory period

-decrease calcium current

-non-competitive adrenergic blockade

What are the class III antiarrhythmic agents?

-amiodarone

-sotalol

-dofetilide

-ibutilide

What are the class IV antiarrhythmics?

calcium channel blocker likes

What is the MOA of class IV antiarrhythmics?

-slow SA node automaticity and AV node conduction velocity

-decrease cardiac contractility

-reduce BP

What are the class IV antiarrhythmic agents?

-verapamil

-diltiazem

What are the other agent antiarrhythmics?

-adenosine

-digoxin

-ranolazine

-ivabradine

What are the characteristics of amiodarone?

-anti-anginal agent

-coronary vasodilator to improve coronary circulation

-peripheral dilation to decrease PVR

-slow onset and long duration

What are the therapeutic uses of class IA antiarrhythmics?

atrial and ventricular antiarrhythmias, especially re-entrant and ectopic SVT and VT

What are the adverse effects of class IA antiarrhythmic, quinidine?

-diarrhea

-fever

-rash

-cinchonism (headache with tinnitus)

-antimuscarinic effects

What are the adverse effects of class IA antiarrhythmic, procainamide?

reversible SLE-like syndrome

Wat are the adverse effects of class IA antiarrhythmic, disopyramide?

heart failure

What is the general adverse effect of all class IA antiarrhythmics?

thrombocytopenia

What are the therapeutic uses of class IB antiarrhythmics?

-ventricular arrhythmias following heart attack

-digoxin-induced arrhythmias

What are the adverse effects of class IB antiarrhythmics?

-neurological symptoms

-convulsions

-hearing disturbances

-tremor

-lightheadedness

-large doses=hypotension

What are the therapeutic uses of class IC antiarrhythmics?

-supra ventricular arrhythmias

-do not use in ischemic conditions

What are the adverse effects of flecainide?

-bronchospasm

-leukopenia

-thrombocytopenia

What are the adverse effects of propafenone?

-hematological abnormalities

-agranulocytosis

-anemia

-thrombocytopenia

What are the contraindications of class IC antiarrhythmics?

-proarrhythmic, especially post MI contraindicated

-structural and ischemic heart disease

What are the therapeutic uses of class II antiarrhythmics?

-ventricular arrhythmias

-atrial antiarrhythmias (atrial flutter and fibrillation)

What are the therapeutic uses of class III antiarrhythmics?

atrial and ventricular arrhythmias

What are the adverse effects of class III antiarrhythmics?

-proarrhthmias

-hepatitis

-decrease in cardiac contraction

-HF symptoms

-hypotension

What are adverse effects of amiodarone?

-pulmonary fibrosis

-hepatotoxicity

-neurologic effects

-constipation

Why is nifedipine not used as an antiarrhythmic?

likely to cause reflex tachycardia due to pronounced vasodilation

What are the therapeutic uses of class IV antiarrhythmics?

-supraventricular tachycardia

-atrial fibrillation

What are the adverse effects of class IV antiarrhythmics?

-constipation

-flushing

-edema

-cardiovascular effects (AV block, SA node depression)

-severe bradycardia and hypotension

-danger if combined with beta blockers

What is adenosine used for?

terminate acute paroxysmal supraventricular tachycardia

What is digoxin used for?

slow ventricular rate in pt. with atrial fibrillation though beta blockers and calcium channel blockers are usually preferred

What are ranoalazine and ivabradine used for?

angina and certain arrhythmias

What are the major contraindications of other agent antiarrhythmics?

-heart failure

-history of myocardial infarction

-cardiac transplant

What are the contraindications of disopyramide?

prostatism as it causes urinary retention due to marked anticholinergic activity

What are the contraindications of procainamide?

chronic arthritis causes lupus like syndrome

What are the contraindications of amiodarone?

advanced lung disease causes pulmonary fibrosis

What are the classes of drugs for dyslipidemia?

-HMG-CoA reductase inhibitors

-fibric acid derivatives

-niacin

-bile acid-binding resins

-intestinal sterol absorption inhibitor

What drugs are in HMGCo-A reductace inhibitors?

-atrovastatin

-simvastatin

-lovastatin

-pravastatin

-fluvastatin

What are the fibric acid derivatives?

-fenofibrate

-gemfibrozil

What are the bile acid-binding resins?

-colestipol

-cholestyramine

-colesevelam

What is the intestinal sterol absorption inhibitor?

ezetimibe

What are the other dyslipidemia agents?

-lomitapide

-mipomersen

-PCSK9 inhibitors

What are the characteristics of HMG-CoA reductase inhibitors?

structural analogs of HMG-CoA reductase which is the intermediate, formed during mevalonate, a cholesterol precursor synthesis

What is the MOA of HMG-CoA reductase inhibitors?

What are the additional molecular MOAS of HMG-CoA reductase inhibitors?

-statins completely inhibit HMG CoA reductase to reduce cholesterol synthesis

-decreased cholesterol in hepatocytes cause cleavage of sterol regulatory element binding protein

-SREBP diffuses into the nucleus to bind to sterol response elements and causes upregulation of LDL-receptor

-increased LDL-R expression results in plasma LDL clearance and reduced circulating LDL level

What are the therapeutic uses of HMG-CoA reductase inhibitors?

-dyslipidemia

-prevention of cardiovascular disease

-useful for lowering plasma LDL given alone or in combination with niacin or ezetimibe

-significantly reduce mortality from myocardial infarction and in CVD patients at high risk

What are the common adverse effects of HMG-CoA reductase inhibitors?

-well tolerated typically

-GIT problems

-abdominal cramps

-constipation

-diarrhea

-heartburn

What are the less frequent and rare adverse effects of HMG-CoA reductase inhibitors?

-hepatitis

-elevate serum level of hepatic enzymes

-rhabdomyolysis

-myopathy where very few progress to rhabdomyolysis

What are the potential drug drug interactions of HMG-CoA reductase inhibitors?

-atrovastatin, simvastatin, and lovastatin are metabolized by CYP3A4 (erythromycin and itrazonazole inhibit CYP)

-fluvastatin is metabolized by CYP2C9 (NSAIDs inhibit CYP)

What is the MOA fo fibric acid derivatives?

-act as ligands for nuclear transcription factor PPAR-alpha in hepatocytes

-act as agnoists for nuclear transcription factor PPAR-alpha causing down regulation of Apo-CIII resulting in VLDL metabolism

-decrease VLDL levels

-plasma TG are reduced

-modest increase in HDL in some hypertriglyceridemic patients

What are the therapeutic uses of fibric acid derivatives?

-hypertriglyceridemia

-hypercholesterolemia

-mixed dyslipidemia

What are the adverse effects of fenofibrate?

-GIT side effects (more common than others)

-blood cell deficiencies

-headache

-myopathy/rhabdomylosis

-increased heptaic enzymes

-cholestatic hepatitis

What are the adverse effects of gemfibrozil?

-GIT side effects

-fatigue

-skin rash

-myopathy/rhabdomyolysis

What is the MOA of niacin?

-inhibits lipolysis in adipose tissue and the release of free fatty acids from adipose tissue

-inhibits the formation and secretion of hepatic VLDL

-reduces total cholesterol, apolipoprotein B, TG, VLDL, LDL, Lp(a)

What are the therapeutic uses of niacin?

dyslipidemia as mono or adjunctive therapy

What are the adverse effects of niacin?

-flushing with the skin (can be reduced with aspirin or NSAIDs and tolerance)

-increase blood glucose

-cause hyperuricemia adn gout

-rashes

-pruritus

What are the GIT side effects of niacin?

-nausea

-abdominal discomfort

-diarrhea

What are the hepatic side effects of niacin?

-increased serum transaminase

-hepatitis

What are the CNS side effects of niacin?

-dizziness

-insomnia

-headache

What are the skeletal side effects of niacin?

-myalgia

-myopathies

What is the MOA of bile acid-binding resins?

-bind to bile acids in intestinal lumen

-prevents reabsorption of bile acids from the intestine and causes the liver to synthesize replacement of bile acids from cholesterol

-increased bile acid synthesis and reduces amount of hepatic cholesterol

-reduction in hepatic cholesterol causes upregulation of LDL receptors

-enhances removal of LDL from circulation

-lowers plasma LDL

-upregulate 7alpha-hydrozylase

What are the therapeutic uses of bile acid binding resins?

-adjunct in the management of primary hypercholesterolemia

-may be used for treating digoxin toxicity

How are bile acids synthesized?

by the liver by oxidation from cholesterol

What are the adverse effects of bile acid binding resins?

-no significant systemic side effects

-heartburn and diarrhea

-bloating and constipation from decreased fat absorption

-hypoprothrombinemia due to vitamine K malabsorption

-steatorrhea in pt with bowel disease

-skin rash

-may impair absorption of digoxin, thiazides, tetracyclines, fluvastatin, thyroxine, aspirin

What is the MOA of intestinal sterol absorption inhibitors?

-inhibits intestinal absorption of cholesterol and phytosteroles via sterol transporter

-decreased delivery of cholesterol to the liver

-reduced total cholesterol, LDL, TG, and minimal increase in HDL

-effective when there is no dietary cholesterol because it inhibits absoprtion of cholesterol excreted in the bile

What are the therapeutic uses of intestinal sterol absorption inhibitors?

-primary hyperlipidemia

-homozygous familial hypercholesterolemia

What are the adverse effects of intestinal sterol absorption inhibitors?

-diarrhea

-myalgia

-fatigue

-headache

What is the MOA of lomitapide?

-microsomal triglyceride transfer protein inhibitor

-reduces preduction and release of VLDL and LDL levels in the plasma

What dies triglyceride transfer protein (MTP) do?

loading of triglyceride onto apolipoprotein B100 which is part of the assembly process of VLDL in liver

What is the therapeutic use of lomitapide?

homozygous familial hypercholesterolemia

What are the adverse effects of lomitapide?

-diarrhea

-nausea

-vomiting

-abdominal pain

-elevation of serum transaminase levels

-hepatotoxicity

What is the MOA of mipomersen?

oligonucleotide that binds to the mRNA for apoB, reventing synthesis of apo B required for VLDL production in liver

What are the therapeutic uses of mipomersen?

homozygous familial hypercholesterolemia

What are the adverse effects of mipomersen?

-nausea

-headache

-flu like symptoms

-injection site reactions

-elevation of serum transaminase levels

-hepatotoxicity

What are the PCSK9 inhibitors?

-alirocumab

-evolocumab

What is the MOA of PCSK9 inhibitors?

inactivate PCSK9 enzyme preventing the degradation of LDL receptors on liver cells and increasing hepatic clearance of LDL resulting in lower plasma LDL-C levels

What are the therapeutic uses of PCSK9 inhibitors?

homozygous familial hypercholesterolemia

What are the adverse effects of PCSK9 inhibitors?

-symptoms of common cold or flu

-pain at injection site

-redness