Pharmacology Test #2- Dyslipidemia and Antiarrthymics

Special IC agent:

*Amiodorone: Thyroid hormone analog. "Broad-spectrum activity" -Blocks Na+, K+, Ca++ channels and β-adrenergic receptors. Interacts with cell lipid membrane! -Widely used agent!.....but..... -Uses: A-Fib, VT, V-Fib

Bile Acid Sequestrants exception of S/E:

*COLESEVALAM= VERY SPECIFIC TO BILE SALTS NO SIGNIFICANT INTERACTION WITH DRUGS IN THE INTESTINE

Class IB uses:

*For arrhythmia's that arise in ventricles! -Do not use for Afib, its an arrhythmia that originates from atria.

Omega 3 fatty acids:

-"Fish Oils" Eicospenatenoic acid (EPA), Docosahexaenoic acid (DHA) -Omacor - enriched (84%) EPA, DHA -4 g/day - added to drug therapy to lower plasma triglycerides

II. Bile-Acid Sequestrants

-"Ion-exchange" resins -Bind bile salts in the intestine to prevent their recycling by the liver (goes out in the feces and is restored in the gallbladder) How does this lower cholesterol levels?? -Liver takes bile salts when we have a meal (trapping bile salts in the gut), prevents reabsorption back to liver and gets excreted by feces. -8-24% reductions in LDL levels. Synergistic effect with statins are possible. *For treatment of mild dyslipidemia.

Statins side effects:

* Pregnancy category X! -Alteration of liver enzymes with serum amino transferease -Dose dependant -Usually not toxicity but "adaptive change" -Monitor liver enzymes (when liver has blockage from statins we will see a minor change in liver enzymes its ok= adaptive change due to statins *Significant increase in liver enzymes = NOT OK!) -Myopathy: Muscle pain, myositis Check CPK levels? Minor increases are common, particularly with heavy physical activity.... Incidence with Statins alone is low (<0.1%) check for interaction with other meds...

Major Side Effects - IB Agents

-"Local anesthetic toxicity" -Initial sedation, dizziness -Tinnitus -CNS stimulation - tremor convulsions -Minor cardiac depression. -Overall good record of safety and low toxicity. (PARADOXICAL EFFECT = TREMORS [at high doses] -Doesn't have profound effects on CO + HR = minor effect on CO)

5. The patient is started on gemfibrozil. Which of the following is a major mechanism of gemfibrozil's action? (A) Increased excretion of bile acid salts (B) Increased expression of high-affinity LDL receptors (C) Increased secretion of VLDL by the liver (D) Increased triglyceride hydrolysis by lipoprotein lipase (E) Reduced uptake of dietary cholesterol

-A major mechanism recognized for gemfibrozil is increased activity of the lipoprotein lipase associated with capillary endothelial cells. Gemfibrozil and other fibrates decrease VLDL secretion, presumably by stimulating hepatic fatty acid oxidation. The answer is D

6. Which of the following is a major toxicity associated with gemfibrozil therapy? (A) Bloating and constipation (B) Cholelithiasis (C) Hyperuricemia (D) Liver damage (E) Severe cardiac arrhythmia

-A major toxicity of the fibrates is increased risk of gallstone formation, which may be due to enhanced biliary excretion of cholesterol. The answer is B.

Ezetimibe pharmacokinetics:

-Absorbed & metabolized to an active glucuronide conjugate. -Both the parent and metabolite undergo repeated enterohepatic recycling to PROLONG drug action. *(Unlike bile salts, ezetimibe is recycled and takes it back to intestine for another pass! Getting a second round of effect of drug= prolongs action time of drug)

Why can atorvastatin & rosuvastatin be given At any time?

-Atorvastatin & Rosuvastatin can take at any time! Long half life that will carry over to night time!! 14-18 hrs

Bile Acid Sequestrants examples:

-Cholestyramine -Colestipol -Colesevalam -made of Resin= big polymers, not absorbed by the gut -Used sprinkled on food or drunk as a slurry before a meal.

Questions 7-10. A 43-year-old man has heterozygous familial hypercholesterolemia. His serum concentrations of total cholesterol and LDL are markedly elevated. His serum concentration of HDL cholesterol, VLDL cholesterol, and triglycerides are normal or slightly elevated. The patient's mother and older brother died of myocardial infarctions before the age of 50. This patient recently experienced mild chest pain when walking upstairs and has been diagnosed as having angina of effort. The patient is somewhat overweight. He drinks alcohol most evenings and smokes about 1 pack of cigarettes per week. 7. Consumption of alcohol is associated with which of the fol-lowing changes in serum lipid concentrations? (A) Decreased chylomicrons (B) Decreased HDL cholesterol (C) Decreased VLDL cholesterol (D) Increased LDL cholesterol (E) Increased triglyceride

-Chronic ethanol ingestion can increase serum concentrations of VLDL and triglycerides. This is one of the factors that places patients with alcoholism at risk of pancreatitis. Chronic ethanol ingestion also has the possibly beneficial effect of raising, not decreasing, serum HDL concentrations. The answer is E.

Treatment of cardiac arrhythmia:

-Class I Agents - Na+ Channel Blockers -IA, IB and IC -Class II Agents - β Blockers -Class III Agents - K+ Channel Blocker -Class IV Agents - Ca++ Channel Blockers -Miscellaneous Agents

Class I Agents - Na+ Channel Blockers

-Class I Agents: Block myocardial Na+ channels to slow conduction (rate) -Slow or abolish "ectopic" pacemakers if Na+ dependent. [most are Na dependent] (Normal cells are not open a lot. Ectopic= na channels are open a lot; more likely for meds to get into these channels! And block from inside the cell ) -"State-dependent" binding? Bind Na+ channel receptors more readily when channels are in open state.

HMG CoA Reductase Inhibitors mechanism:

-Competitive inhibitors of the HMG CoA Reductase Rate-limiting enzyme in synthesis of cholesterol.

Fibrates

-Decrease plasma triglycerides and Increase plasma HDL

Interactions Effects - Statins

-Drugs metabolized by CYP3A4 - macrolide antibiotics, cyclosporine, protease inhibitors, etc... -CYP2C9 - ketoconazole, amiodarone, cimetidine -Pravastatin - mainly non-CYP metabolism (*Given in liver failure bc it doesn't affect liver metabolism, but it's not that potent of a statin)

Class IC Agents

-Ex. Flecainide -Powerful and long duration depressant of Na+ currents -Markedly reduces conduction in atria & ventricles -Does not alter AP duration at all

Class IB Agents

-Ex. Lidocaine -Mexilitine & Tocainide (oral lidocaine forms) -Selectively block Na+ channels in Purkinje and Ventricular tissue - Little effect on atria. -Reduces AP duration somewhat (Little effect on action potential duration)

Class IA agents

-Ex. Quinidine, disopyramide, procainamide -Block Na+ channels - slow conduction velocity in atria & ventricles. -Block K+ channels - increase AP duration *Class 1A: Slowing repolarization + depolarization

Pharmacokinetics - Statins

-Extensive first-pass metabolism, 5-20% of dose reaches general circulation -Is this a big problem?? = NOPE! -CYP450, 3A4 metabolism - Lovastatin, simvastatin, atorvastatin CYP450, 2C9 - fluvastatin (2C9- genetic differences from pt to pt) -Lovastatin & Simvastatin are given as "pro-drugs" (activated in the G.I.T.) Don't need to be activated by liver as the other drugs do [don't have to worry about liver disease] *Target of action of drug= HEPATOCYTES!! -From gut to liver (first pass)! We don't care that drug doesn't get to circulate in blood!

Major Side Effects - IC Agents

-Flecainide (All IC) More likely than other anti-arrhythmic drugs to exacerbate arrhythmia's Marked depression of cardiac function. -Increased mortality in patients following M.I. than placebo (CAST Trial) -Last line agent when all else fails...

Clinical Uses - IC Agents

-Flecainide: Only approved for refractory V. tachycardia that may progress to V. Fib. -Propafenone: Supraventricular Arrhythmia's -Moricizine: Ventricular Arrhythmia's *Work on atrial and ventricular arrhythmia's. *These can cause other arrhythmias due to long effects on Na+.

Side Effects - Niacin

-Flushing: -Pruritus, skin rashes, flushing (blocked by aspirin.....meaning?) ProstaGlandin-mediated (Resolves in 1-2 weeks) -Niaspan - sustained release formulation decreased flushing & pruritus. -Dyspepsia Less if taken after a meal-AVOID IN PT'S WITH PEPTIC ULCER DISEASE -Hyperuricemia - 20% of patients MAY WORSEN GOUT -Possible Hepatotoxicity! Alteration of liver enzymes-Worse with crystalline and sustained release forms (doses >2 .0 g/day) -OTC Product warn patients of possible hepatotoxcity, especially with sustained-release forms and high doses! Insulin Resistance Not for diabetic patients!!

Class I Agents

-Further subdivided based on their different effects on Repolarization. -What ion determines repolarization? K+ IA IB IC

Bile Acid Sequestrant disadvantages:

-G.I. bloating, constipation, irritation. -May raise serum triglycerides! -May bind other drugs in the intestine!! Ex's? THIAZIDES, FUROSEMIDE, DIGOXIN, COUMADIN How can we prevent this??? TAKE THESE MEDS AT DIFFERENT TIMES

Side Effects - Fibric Acid Derivatives

-G.I. effects - most common complaint Increased liver transaminases - 5% of patients -Occasional: Flu-like myositis - greater incidence with "statins" Rash, fatigue, hair loss -Gallstone formation - especially with older clofibrate (not used).

V. Fibric Acid Derivatives

-Gemfibrozil, Fenofibrate -Lipid-lowering effects reported in 1962. -Most effective in treating Hypertriglyceridemia's

Pharmacokinetics - Niacin

-Good p.o. absorption -T1/2 = only 60 minutes therefore multiple dosing required. -Metabolized by liver & eliminated in urine

-Why is it recommended that some of these agents be take in the p.m.?

-Half lives are generally short, that's when most cholesterol synthesis occurs! (when your rest and digest kicks in and restores take place)

Importance of cholesterol in the body:

-Important component in cell membranes [flexibility] -Hormones [steroid producing cells] -Helps digest bile salts

Questions 3-6. A 35-year-old woman appears to have familial combined hyperlipidemia. Her serum concentrations of total cholesterol, LDL cholesterol, and triglyceride are elevated. Her serum concentration of HDL cholesterol is somewhat reduced. 3. Which of the following drugs is most likely to increase this patient's triglyceride and VLDL cholesterol concentrations when used as monotherapy? (A) Atorvastatin (B) Cholestyramine (C) Ezetimibe (D) Gemfibrozil (E) Niacin

-In some patients with familial combined hyperlipidemia and elevated VLDL, the resins increase VLDL and triglyceride concentrations even though they also lower LDL cholesterol. The answer is B.

HMG CoA Reductase Inhibitors Actions:

-Increased expression of LDL receptors on cells. -Increased LDL uptake -LDL lowering of 25-55% depending upon drug efficacy. -Modest increased in HDL's depending upon agent -10-25% decrease in plasma triglycerides.

1. Increased serum levels of which of the following is associated with a decreased risk of atherosclerosis? (A) Cholesterol (B) LDL (C) HDL (D) Triglyceride (E) VLDL

-Increased serum concentrations of LDL and total cholesterol are associated with increased risk of atherosclerosis. High serum concentration of HDL cholesterol is associated with a decrease in the risk of atherosclerotic disease. The answer is C.

Possible causes for arrhythmia's:

-Ischemia -Hypoxia -Acidosis -Autonomic changes -Electrolyte imbalances -Drugs (can affect the pacemaker activity) -Arryth can be caused by genetics!!! r/t differences in ion channels =affect Na + K + Ca channels -Develop arrhythmia's bc ion channels are not working correctly/normally!

III. Ezetimibe

-Localizes at the brush border of the small intestine. -Decreases delivery of cholesterol to the liver. -Reduced hepatic cholesterol stores = increased clearance of cholesterol from the blood. *(DECREASES cholesterol transport from intestine to the liver=As a result, Liver starts to have decreased amounts of cholesterol) *Packs fats into micelle *EZETIMIBE blocks the NPC transporter that takes cholesterol from gut to blood>causes amount of cholesterol in blood to decrease =forces liver to uptake its cholesterol from the blood to maintain its own stores

Mechanism of statins:

-Major action of drug is in HEPATOCYTES Cells that synthesize cholesterol are affected by statins: 1. DIRECTLY INHIBITS SYNTHESIS OF CHOLESTEROL IN CELLS 2. CELLS ARE FORCED TO INCREASE RECEPTOR SITES OF CHOLESTEROL/LDL—BRINGING IN CHOLESTEROL FROM THE BLOOD!

Clinical Uses - IA Agents

-Most types of atrial & ventricular arrhythmia's -Used orally for chronic, outpatient use.

Bile Acid Sequestrant major advantages:

-Non-systemic= Don't leave the gut -No side effects -Acts only in GIT

Specific Side Effects - IA Agents

-Quinidine: Cinchonism- headache, vertigo, tinnitus. ***Cardiac depression (due to suppressing Na and K channels) G.I. - nausea, vomiting, diarrhea -Procainamide: *Reversible "lupus-like" syndrome -Disopyramide: *Significant Anti-muscarinic effects (anticholinergic effects: dry mouth, eyes, inhibition of secretions) MAJOR S/E: ****Torsade des Pointes - a potentially dangerous arrhythmia that can arise from overly slow conduction. -Greater risk with low serum POTASSIUM

Folic acid derivatives -Pharmacokinetics:

-Rapidly & completely absorbed on an empty stomach. -T1/2 - 1.1 h for gemfibrozil, 20 h for fenofibrate. mainstay tx: *Fenofibrate - completely hydrolyzed in the intestine and eliminated as glucuronide conjugate in urine (has very little interactions, no CYP effect at all)

Ezetimibe uses:

-Reduces LDL levels and increases HDL levels. Single dose/day = 10-16% decrease in LDL's -Minimal increases in HDL's when used alone. (that's why it's combined with a statin but doesn't work as well and it's expensive, statins are better)

Statins interactions:

-Significant risk of myopathy and "rhabdomyolysis" with Gemfibrozil ....mechanism?? -Gemfibrozil inhibits statin metabolism & glucuronidation! *Not reported with FENOFIBRATE -Cervistatin removed from market in 2001 due to incidence of rhabdomyolysis.... *RHABDO= irreversible destruction of myocin fibers in muscle

9. After being counseled about lifestyle and dietary changes, the patient was started on atorvastatin. During his treatment with atorvastatin, it is important to routinely monitor serum concentrations of which of the following? (A) Blood urea nitrogen (B) Alanine and aspartate aminotransferase (C) Platelets (D) Red blood cells (E) Uric acid

-The 2 primary adverse effects of the HMG-CoA reductase inhibitors are hepatotoxicity and myopathy. Patients taking these drugs should have liver function tests performed before starting therapy, and at regular intervals during therapy. Serum concentrations of alanine and aspartate aminotransferase are used as markers of hepatocellular toxicity. The answer is B.

4. If this patient is pregnant, which of the following drugs should be avoided because of a risk of harming the fetus? (A) Cholestyramine (B) Ezetimibe (C) Fenofibrate (D) Niacin (E) Pravastatin

-The HMG-CoA reductase inhibitors are contraindicated in pregnancy because of the risk of teratogenic effects. The answer is E.

10. Six months after beginning atorvastatin, the patient's total and LDL cholesterol concentrations remained above normal, and he continued to have anginal attacks despite good adherence to his antianginal medications. His physician decided to add ezetimibe. Which of the following is the most accurate description of ezetimibe's mechanism of an action? (A) Decreased lipid synthesis in adipose tissue (B) Decreased secretion of VLDL by the liver (C) Decreased gastrointestinal absorption of cholesterol (D) Increased endocytosis of HDL by the liver (E) Increased lipid hydrolysis by lipoprotein lipase

-The major recognized effect of ezetimibe is inhibition of absorption of cholesterol in the intestine. The answer is C.

2. A 58-year-old man with a history of hyperlipidemia was treated with a drug. The chart below shows the results of the patient's fasting lipid panel before treatment and 6 mo after initiating drug therapy. Normal values are also shown. Which of the following drugs is most likely to be the one that this man received? (A) Colestipol (B) Ezetimibe (C) Gemfibrozil (D) Lovastatin (E) Niacin

-This patient presents with striking hypertriglyceridemia, elevated VLDL cholesterol, and depressed HDL cholesterol. Six months after drug treatment was initiated, his triglyceride and VLDL cholesterol have dropped dramatically and his HDL cholesterol level has doubled. The drug that is most likely to have achieved all of these desirable changes, particularly the large increase in HDL cholesterol, is niacin. *Although gemfibrozil lowers triglyceride and VLDL concentrations, it does not cause such large increases in HDL cholesterol and decreases in LDL cholesterol. The answer is E.

IV. Niacin (Nicotinic Acid)

-Water-soluble B-vitamin complex. -Reported to be hypolipidemic back in 1955 -Doses of 2-6g/day required for lipid effect *Lowers LDL and triglycerides But may raise HDL

I. HMG CoA Reductase Inhibitors ("Statins")

-reduce morbidity and mortality associated with CAD and stroke. -#1 for tx dyslipidemia -Lots of good secondary effects of these meds: direct effects on blood vessel walls: helps the body to stabilize atherosclerotic clots. -Increases responsiveness of coronary arteries -HMG CoA is the 1st enzyme in rxn of pathway is HMG CoA statins block HMG coa that starts the pathway! -HMG CoA determines the rate the pathway runs at

Statin Actions:

1. Inhibit cholesterol synthesis 2. Upregulate expression of LDL receptors

Niacin mechanism:

1. works on enzyme in fatty tissue [lipid digesting enzyme] hormone sensitive lipase -decreases release of fatty acids from lipids [fat cells] -If we decrease fatty acids then we decrease levels of triglycerides -Liver absorbs cholesterol + triglycerides =less triglycerides then liver not able to make as many LDL molecules 2. Secondary effect= [Apo protein] ApoA1 = involved in synthesis of HDLs -Increases amount of apoA1 in circulation=helps liver make more HDLs

Cardiac Arrhythmia:

Disturbance of cardiac rate and/or rhythm.

5 phases of cardiac muscle cell:

Five phases: Phase 0 - rapid depolarization Phase 1 - early repolarization Phase 2 - plateau Phase 3 - final repolarization Phase 4 - resting potential *Depolarization=depending upon the movement of sodium channels (contraction) *Repolarization=depending upon the movement of potassium channels (resetting) *Plateau- calcium channels in that muscle OPEN + Calcium flows into muscle cell and interacts with actin + myocin for muscle to contract=Ca+ causes muscle cell to contract again. -Action potential duration= overal time it takes cell to go from resting to depolarizing + contracting + repolarizing!

Fibric Acid Derivatives drug interactions:

Gemfibrozil + Cervistatin use has resulted in a number of cases of severe rhabdomyolysis!

I. HMG CoA Reductase Inhibitors ("Statins") Examples:

High potency: (better absorption from gut + better bio availability to the liver + better half lives + better at blocking CoA Reductase ): -Atorvastatin -Simvastatin -Rosuvastatin Low potency: -Lovastatin -Fluvastatin -Pravastatin *Statins also lower HDL

Treatment of Dyslipidemia

I. HMG CoA Reductase Inhibitors:("Statins") II. Bile-Acid Sequestrants III. Ezetimibe IV. Niacin (Nicotinic Acid) V. Fibric Acid Derivatives

Ezetimibe side effects:

Low incidence: -Abdominal pain, Diarrhea -Back & joint pain -Rare myositis

8. If the patient has a history of gout, which of the following drugs is most likely to exacerbate this condition? (A) Colestipol (B) Ezetimibe (C) Gemfibrozil (D) Niacin (E) Simvastatin

Niacin can exacerbate both hyperuricemia and glucose intolerance. The answer is D.

Anti-Arrhythmic s:

Work on arrhythmia by slowing down contraction time: -Slow depolarization (Na+) -Block K channel by back end = slow repolarization *Drugs that modify cardiac electrophysiology often have a very narrow margin between the doses that suppress arrhythmia and those that cause arrhythmia. (Drugs for arrhythmia can also cause arrhythmia!)

How does Ezetimibe lower cholesterol? a.It inhibits cholesterol incorporation into VLDL by the liver. b.It displaces cholesterol from chylomicrons. c.It displaces cholesterol from micelles and increases its loss in the feces. d. It inhibits cholesterol uptake through a brush border protein on enterocytes.

d. It inhibits cholesterol uptake through a brush border protein on enterocytes.