Pharm Unit 2 Anti-hypertensives 1. Anti- arrhythmics 1. Physiology a. Arrythmia- disturbance in normal sinus rhythm i.

Caused by scarring/ischemia in cardiac tissue conduction system ii. Symptoms range- benign palpations to severe low CO- death. iii. Analogy- highway, arrhythmia is like a pot hole, road block, etc. iv. Clinical classification of arrhythmias take into consideration the origin and change in the rate and rhythm of the arrhythmia v. Goal is to prevent atrial arrythm from becoming ventricle arrythm. vi. Normal sinus rhythm- SA node is pacemaker 1. AV delay- built in to allow time for atria to empty before ventricular contraction vii. QRS wave- ventricular depolarization 1. Distance b/w P and R interval- tells how long AP takes to go from atria to ventricle. Conduction blocks- very long PR interval 2. QT interval- change in QT interval means it is taking forever for AP to go through interval 3. Any drug that prolongs QT interval will cause problems. viii. Action potentials 1. Phase 0 is opening of Na voltage gated channels>depolarization 2. Phase 2- Ca is entering cell. 3. Phase 3- K efflux (cell depolarizes again, returning to -90 mV potential. 4. SA and AV nodes- phase 0 is Ca influx

5. ix. Significance of AV delay? 1. Slowing phase 4 or 0 , or prolonging phase 3 can prolong AV delay. 2. Semantics: making AV node refractory = prolonging AV delay. x. Refractory periods (RPs) of the ventricular myocyte xi. K channel blockers will increase refractory period

1. 2. Basic Pathology a. Ectopic/aberrant/errant impulse generation i. Signals that arise in tissues other than the SA node, which can then set pace in heart, replacing SA node. ii. Unidirectional block and reentry phenomena- has three requirements 1. A closed conduction loop 2. A region of unidirectional block (can be transient) 3. Sufficiently slow conduction of impulse around the loop 4. Unidirectional block- in damaged tissue, impulse travels in one direction, but cant return back b/c of refractory block 5. Re-entry excitation may be responsible for atrial and ventricular tachycardias iii. Strategies to interrupt reentrant arrhythmias 1. Na+ channel block- causes returning impulse to die out 2. Prolonging refractory period causes the returning impulses to find tissue unexcitable (K+ channel blockade) 3. Sympathetic overactivity can increase the pacemaker activity of ischemic tissue and reentry especially in ventricles: Beta blockers are good for all arryhtmias 4. If reentry involves AV node, make AV node refractory b. Atrial Flutter i. Occurs in patient with pre-existing heart disease, conditions, etc. ii. 180-350 BPM. Many of these impulses reach AV during refractory, so are not transmitted, but ventricular will be about 120 BPM. iii. Treatment 1. Quickest- electrical cardioversion (shock- AED) 2. Drug therapy is used in patients without an immediate need a. Drugs that slow conduction through AV node (Beta blockers, calcium channel blockers, digoxin) b. Once rate is slowed, drugs aimed at slowing conduction or prolong the refractory period of the atrial myocardium c. Atrial Fibrillation i. 350-600 BPM, ventricle appx. 140-160 BPM ii. Treatment is same for atrial flutter + need to add anti-coagulants to prevent thrombo-embolism d. AV nodal reentrant tachycardia (AVNRT) i. Reentrants circuits involve the AV node ii. Rapid treatment with IV adenosine which impairs the AV nodal conduction iii. Intravenous Ca channel blockers or beta blockers e. AVRT/Wolff- Parkinson White Syndrome

i. Conduction of AP goes through AV node and bi-pass tract ii. Ca channel blocker will block AV node, but not bi-pass tract f. Certain Anti- arryhtmic drugs can cause deadly arrhythmias: Torsades de Pointes (twisting of points) i. Cause- prolongation of QT (indicates lengthened ventricular AP) due to: 1. Anti-arrhythmic agents that block K+ channels a. Class I and III drugs 3. Arrythmia treatment goals: a. Restore cardiac rhythm to normal, reduce risk of disease progression, prevent recurrence, reduce hemodynamic consequences (low CO and clot formation) 4. Anti-arrythmias: Drug Classes a. Vaughn- Williams based on electrophysiologic mechanisms of actions i. Class I: Na channel blockers (divided into A, B, C) 1. IA- intermediate (prolongs AP duration). IA is not only Na blocker, but also K+ channel blocker, which is why it prolongs repolarization 2. IB: Fast (shorten AP duration) 3. 1C: slow (no effect on AP duration)

4. 5. Class IA Drugs a. Quinidine- derived from cinchona bark i. What does it do? Na blocker ii. Used in conjunction with Digoxin, must be aware of Digoxin dose iii. Metabolized in liver iv. Reduces clearance of Digoxin, lower dose of Digoxin when Quinidine is added v. Side effects 1. Nausea, Diarrhea, Cinchonism (deafness, tinnitus, blurred vision , flushing and tremor) 2. Quinidine Syncope (dizziness and fainting) b/c ventricular arythms associate with prolonged QT interval 3. Thrombocytopenia purpura 4. Contraindicated in long QT syndrome

b. Procainamide i. Derivative of local anesthetic procaine ii. MOA- similar to quinidine, but does not prolong AP duration (or QT interval, so does not precipitate torsades). Less HTN compared to quinidine iii. Only IV and IM available in US iv. 50% exreted onchanged in urine, ret acetylated in liver to active form, NAPA, which is also eliminated renally (reduce dosage in PT with renal failure) c. Disopyramide (Norpace) i. Reserved for arythms that are refractory to quin and procain ii. Adverse Effects: pronounced anti-muscarinic effects 1. Dry mouth, blurred vision, constipation, urine retention, glaucoma 2. Can worsen heart block and adversely effect sinus node activity iii. Prolongs QT interval iv. Contraindicated in long QT syndrome d. Class IA: Treatment of overdose i. Give sodium lactate IV 1. MOA- increases sodium current by increasing the ionic gradient 2. Reduces drug receptor binding by alkalinizing the tissue ii. Hyperkalemia can exacerbate cardiac effects of class IA drugs 6. Class IB Antiarythms a. Lidocaine, Tocainidine (seldom used), Mexilitine b. IB MOA: block Na+ channel in slightly depolarized or ischemic tissue i. Shortens phase 3 repolarization, and hence AP duration ii. Quickly dissociate from Na channel, and so are less likely to interfere with conduction of normal impulses. c. Lidocaine i. Used in hospital ii. Drug of choice to terminate digitalis induced arythms; and in ER after Amiodarone iii. IV only, thus only used in emergency settings iv. Must reduce infusion rate in conditions of reduced hepatic flow (heart failure or older patients) d. Mexilitine i. Similar to Lidocain, but can be given orally ii. Treats chronic arythms associated with MI iii. Combine with beta blocker most effective

iv. 90% metabolized in liver, lower dose for liver patient v. CNS side effects 7. Class IC Drugs a. Flecaindine, Encaindine, Propafenone, Moricizine b. Reserved for arythms that progress to VF c. MOA: potent Na+ blocker i. Slows phase 0 marekdly and conduction velocity in atria, ventricles and purkinjes ii. Slows phase 4 in AV node currents and makes it refractory iii. Can block conduction through by pass tract (eg in WPW) iv. Very proarrythmic- increases rate of mortality. Basically only use in patients with normal hearts d. Side effects i. Proarrythmic ii. CNS effects iii. Negative ionotropic effect and can aggravate CHF ii. Class II: beta blockers 1. Esmolol, Propranolol, Acebutalol, Metoprolol 2. MOA: blocks sympathetic effects a. phase 4 slope > rate of firing >automaticity

b. 3. Clinical Use a. Suppress tachyarrythmias induced by excessive sympathetic activation b. First line treatment in patients who have had a previous MI. protective effects for 2 yrs + after MI 4. Class II Side Effects a. Bradycardia, bronchospasms, fatigue b. Use with caution in patients asthma, diabetes c. Dont use with Ca channel blockers 5. Esmolol a. Very short acting (9 mins t1/2) b. Given IV c. Used exlusively in acute arythmias

i. Control ventricular response to atrial fibrillation or flutter during or after surgery iii. Class III: K+ channel blockers (most important of the antiarrythmias, she said) 1. Amiodarone, Sotolol, Ibutilide, Dofetilide, Bretylium 2. MOA: prolongs repolarization

a. 3. Amiodarone a. Major effect: prolongs AP duration and refractoriness of all cardiac fibers b. Secondary effect as weak class I, II and IV c. Used for a wide spectrum of ventricular and supraventricular arrhythmias d. First line agent for emergency treatment of ventricular arrhythmias during cardiac resuscitation, more effective than Lidocaine e. Pharmacodynamics i. Very slow hepatic metabolism, long half life, very lipophilic, accumulates in tissues f. Side effects i. Contains Iodine, so hypo or hyper thyroid hormone ii. SMURFISM skin iii. Pulmonary fibrosis iv. Corneal microdeposits v. GI side effects 4. Sotalol a. In addition to K+, als is non-selective beta blocker, this effect residing in the L isomer b. Can prolong QT interal and cause Torsades, but lacks extensive side effects of Amiodarone c. Adjust dosage in case of renal disease iv. Class IV: Ca channel blockers 1. Verapamil, Diltiazem

a. Slows conduction in AV node (most potent in tissues in which AP depends on Ca currents) b. Clinical effects include i. Slowing of heart rate ii. Slows transmission of rapid atrial impulses to ventricles: used in atrial fibrillation and flutter iii. Terminates AV nodal reentrant arrhythmias c. Electrophysiological effects in pacemaker cells i. Blocks L-type Ca channels ii. AV nodal conduction is slowed (prolongs phase 0) iii. Slows phase 4 depolarization and reduces spontaneous depolarization iv. PR interval is increased v. Decreases contractility vi. DO NOT give to CHF patient vii. DO NOT combine with beta blocker v. Misc.- drugs that dont fall into any category above 1. Adenosine, Digoxin a. Adenosine i. Drug of choice to terminate acute supraventricular (nodal) tachycardia, especially AVNRT ii. Lower toxicity than class IV iii. Advantages: 1. Not orally active > IV bolus 2. Ultra short acting (10 secs) can be administered several times if needed without side effects iv. MOA- agonist at -1 receptors in the SA node, AV node 1. Opens K+ channels > hyperpolarization > automatcicity, also decreases If Ca currents > automaticity and conduction through AV node v. Side effects 1. Flushing, HTN, chest pain, dyspnea 2. Digoxin (Digitalis) a. MOA: inhibits Na/K ATPase > intracellular Na levels > Ca extrusion by Na/Ca exchanger > more Ca in SR > more Ca released at next AP = force of contraction b. Increase vagal tone, decrease HR, but increase force of contraction Anti-Anginals 1. Sign of ischemic heart disease a. Not usually in women, they have neck or jaw pain 2. Ischemic heart disease a. Most often caused by atherosclerotic disease of the coronary arteries

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b. Can result in death of tissue (infarction) Determinants of O2 supply and demand a. Later stages of CHF, have increase in supply for 02, due to increase ventricle wall (heart needing to work hearter Angina a. Result of: myocardial O2 supply, and O2 demand b. Underying pathology i. Atherosclerosis ii. Transient platelet aggregation thrombus iii. Coronary vasoconstriction due to accumulation of potent vasoconstrictors at sites of endothelial injury iv. Excess sympathetic activity increased 02 demand ischemia, angina Stable Angina a. Triggered by exercise/physical activity b. Relieved by resting c. EKG shows temporary depression of ST segment d. Cause: fixed narrowing of coronary arteries Variant Angina a. Occurs at rest, during same time of day b. Cause- coronary spasm rather than block c. EKG shows transient shift in ST segments Unstable Angina (Crescendo) a. Pattern of increased frequency and duration with minimal physical activity b. Highly likely to produce MI c. Cause: reduced coronary perfusion due to thrombus or plaque obstructing coronary blood flow. Stable Angina Treatment strategies a. Goal: prevent recurrence of angina with drugs that improve O2 supply and reduce myocardial oxygen deman i. Long acting nitrates ii. Beta blockers (non-selective and B1 selective) iii. Ca channel blockers b. Treat underlyin atherosclerosis (eg Statins) c. Prophylaxis against thrombosis (aspirin) Drug Classes for Stable Angina

a. b. Oragnic Nitrates i. Amyl Nitrite ii. Glyceryl Nitrate (Nitroglycerine- most widely used

iii. Iosorbide nitrates (di, mono) iv. Clinical uses 1. Termination of acute angina attack 2. Prophylaxis of stress induced attacks 3. Long term prophylaxis against recurrent attacks 4. Patients with frequent symptoms 5. Patients who are not responsive to or intolerant of B blockers (asthma, diabetes) or Ca channel blockers 6. Treatment of cyanide poisoning v. Therapeutic actions 1. Reduce myocardial oxygen consumption by reducing work load a. Peripheral venodilation (reduces preload) b. Dilate arteries and arterioles, reducing BP and hence reducing afterload 2. Increases O2 supply to the ischemic area a. Nitrates dilate coronary arteries vi. Nitrates vs. Dipryridamole 1. Dipyridamole can decrease blood flow to ischemic area- NOT GOOD! vii. Nitrates- Signal Transduction 1. Administered Nitrates > Nitrites > nitric oxide > cGMP > dephosphorylation of myosin light chain viii. Nitrates- Adverse Affects 1. Flushing, nausea, throbbing headache, orthostatic Hypo, refelex tachycardia, large IV doses can cause methemoglobinemia ix. Tolerance of side effects 1. After a few days of therapy, develop tolerance, Monday Morning Sickness 2. Tolerance more likely from longer half-life or transdermal patches of nitroglycerine 3. Also develop tolerance to therapeutic effects, this can be overcome with a daily nitrate free interval in the night x. Contraindications 1. Do not prescribe Phosphodiesterase (PDE) inhibitors (Sildenafil, Tadelafil) to patients taking Nitrates a. PDE prevents breakdown of cGMP and prolong the effects of nitrates. Can lead to hypotensive shock when combined with Nitrates. 2. Concurrent use of nitrates with migraine meds (methysergide, bromocriptine) may increase blood pressure and decrease effects of nitrates xi. Formulation Nitrates 1. Nitroglycerine a. Sublingual tablet i. 2 min onset ii. 25 min duration

iii. Used for acute angina attacks, most widely used, under tongue b. Oral- sustained release i. 35 min onset ii. 4-8 hr duration c. Transdermal i. 30 min ii. 8-14 hrs xii. Formulations- Important considerations 1. Must schedule 10-12 hr nitrate free interval to maintain therapeutic effectiveness 2. Sublingual tablets- dark bottles- light and air sensitive (Lose potency) a. Expire in 6 mos after container open c. Beta Blockers i. Therapeutic Effects in Stable Angina 1. Can minimize reflex tachycardia, used with Nitrates to take care of side effects 2. Reduces myocardial workload and O2 demand ii. B blocker side effects 1. Bradycardia, bronchospasm, fatigue, depression, rebound HTN, use with caution in Asthma and Diabetes d. L-type Ca blockers i. Dyhydropyridines (preferentially block vascular L-type channels) 1. Nifedipine 2. Bepiridil ii. Phenylalkylamines (prefer block cardiac L type channels 1. Verapamil iii. Bezothiazepines (block both cardiac and vascular) 1. Diltiazem iv. Therapeutic effects in Stable Angina 1. Can combine with nitrates 2. Do not combine with B blockers 3. Block calcium influx, reduce cardiac contractility and heart rate by reducing myocardial workload 4. Cause arterio and vasodilation by blocking vascular Ca influx 5. Increase O2 supply by dilating coronary arteries to increase coronary perfusion and reverse coronary vasospasm v. Other therapeutic effects 1. PSVT 2. Migraine (Verapamil, amilodipine) 3. Reynauds disease 4. Stroke (Nimodipine, amilodipine) vi. Dihydropyridines 1. Nifedepine in Angina a. Reduces preload by causing venodilation

b. Reduces TPR and hence afterload c. Very effective in relieving coronary vasospasm, especially in variant angina d. Adverse effects i. Headache, flushing, ankle edema, excessive hypotension, can make the ischemia worse, reflex tachycardia (less than nitrates), constipation (effects on GI smooth muscle), gingival hyperplasia 2. Bepiridil a. Blocks both Na and Ca channels b. Used in chronic and stable angina c. Older drug, you dont want to use it d. Side effects i. Heart failure when combined with B blocker ii. Torsades and other arrhythmias iii. Agranulocytosis vii. Phenylalkylamines 1. Verapamil in Angina a. Stable angina, variant angina b. Therapeutic action i. Decrease cardiac workload and oxygen demand 1. Slows heart rate 2. Slows conduction velocity through AV node 3. Decrease contractility c. Side effects i. Constipation (mainly Verapamil) and gingival hyperplasia ii. Sinus bradycardia iii. High doses can cause 1. Myocardial depression 2. Heart failure 3. Vascular effects (edema, headache, hypotension and reflex tachycardia) 4. Do not combine with B blockers: can cause AV block.

10. 11. Variant Angina Treatment Strategies a. Goal- relieve chest pain and minimize myocardial damage i. Nitrates, Ca blockers (N, V, D), B blockers b. Treatment tapered off after 6-12 mos c. B blockers have minimal effect on coronary vasospasm and are not useful in variant angina d. Treatment of angina in patients with concomitant disease

e. Clinical recognition of Unstable Angina i. Prolonged resting angina (>20 min), increasing in severity, severe new onset within 2 mos of presentation, decreased response to rest or nitroglycerin (BIG SIGN) ii. Higher risk of MI, requires prompt action f. Treatment of unstable angina in the context of acute coronary syndrome (ACS) i. Can occur in patients with coronary artery disease at any time

ii. Is a continuum from unstable angina to full blown MI with necrosis of heart muscle

g. Management of ACS i. GOAL: to relieve chest pain and prevent MI ii. Manage unstable angina by reducing myocardial demand and improving coronary perfusion 1. B blockers, nitrates iii. Opioids to reduce angina pain and prevent excessive SNS activation (CNS effect) iv. Anticoagulants and antiplatelet drugs to interfere with formation or progression of the thrombus v. Evaluate the type of myocardial infarct (NSTEMI or STEMI) vi. Evaluate for surgical intervention 1. More potent anti-platelet agents 2. Thrombolytics to open blocked arteries h. Therapeutic Management of post ACS i. Short term 1. Anti-platelet agents 2. Antiarrythmic agents ii. Long term 1. Manage reversible risk factors with life style modification

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2. ACE inhibitors, beta blockers 3. Anti-platelet agents (to prevent reocclusion) 4. Statins B blockers in unstable Angina and post ACS i. Unstable angina 1. Acutely, slows progression of the MI and reduces mortality a. With first appearance of chest pain, IV B1 blockers followed by long term oral use in high risk patients b. Chronic use to reduce recurrence of angina, arrhythmia Anti-Hyperlipidemics

1. Atherosclerosis a. Underlying pathology of the most common cardiovascular diseases b. Lipid accumulation and chronic inflammatory condition involving lipids, thrombosis, vascular wall elements and immune cells c. Pathological Hallmarks i. Focal lesions in inner linings of arteries ii. Fatty streaks progress to plaques iii. Accumulate over decades, angina one of first signs d. Modifiable Risk Factors i. Reduce LDL, increase HDL ii. Raised C reactive protein, coagulation factors (VII, fibrinogen) e. Prevention i. Treat HTN, Diabetes, drugs that reduce LDL ii. Diet (lower LDL) and exercise (increases HDL-C) iii. Drugs that improve endothelial function 1. ACE inhibiotors 2. Drugs that increase NO iv. Anti-nflammatory measures 1. Antioxidants a. Vit C and E, folic acid, estrogen 2. Anti-thrombitics a. Aspirin 2. Cholesterol Transport and Synthesis a. 5 major classes of lipoproteins i. Chylomicrons ii. VLDL, IDL, LDL, HDL b. Know the role of the apoproteins (Train ticket puncher) c. Exogenous Pathway i. Dietary fats absorbed by small intestine > repackaged as chylos w/Apo B-48 > enter circulation vi lymphatics > HDL transfers ApoE and C subtypes from HDL to chylos in blood stream ii. Apo CII promotes interaction of chylos w/ LPL on the luminal surface of adipose, skeletal and cardiac muscle capillary endothelium. TGs in Chylos are hydrolyzed to FFAs > taken up by adipose for storage or muscle for energy.

iii. ApoE then mediates uptake of chylos to liver iv. Some cholesterol in liver is incorporated into the bile acids, which are exported to the intestine, completing the exogenous pathway. d. Endogenous (Hepatic Pathway) i. Liver packages cholesterol into VLDL particles w/ Apo B-100 and phospholipids (VLDL has high triglyceride content) ii. VLDL interact with HDL in blood, acquiring Apo C and E, and cholesteryl ester via CETP. VLDL is then catabolized by LPL, similar to chylos. iii. 50% of VLDL remnants (IDL) are then cleared by the liver by the hepatic receptors that recognize ApoE iv. Remaining IDL is further catabolized by LPL and heaptic lipases (HL) which remove additional triglycerides, ApoE and ApoC forming LDL particles. The LDL particles retain Apo B-100. Plasma clearance of LDL occurs primarily via LDL receptor endocytosis in the liver (and also peripheral cells) directed by Apo B100. The expression of LDL receptors is tightly coupled to the amount of intracellular cholesterol e. Reverse Cholesterol Transport i. In cholesterol excess, peripheral cells synthesize transporters that can initiate efflux of cholesterol from the cell to lipid poor ApoA1 in the circulation leading to the formation of immature HDL particles > this free cholesterol is then esterified to CE by the enzyme LCAT, this CE is then exchanged with any Apo Bcontaining lipoprotein particles (VLDL, IDL, LDL) that deliver cholesterol back to the liver. HDL also transports cholesterol to the liver and hormone producing tissues via scavenger receptor SR-B1 f. LDL is Proatherogenic i. LDL may supply cholesterol to the atherosclerotic lesions g. HDL is anti-atherogenic i. HDL can acquire cholesterol from peripheral tissues, macrophages, and atherosclerotic lesions, and deliver it back to the liver. ii. The chance of LDL being cleared form the blood depends on cholesterol stores in the liver. h. NCEP Guidelines for Managing Patients with Dysplipidemia i. CHD+ multiple risk factors <60 ii. Known CHD <100 iii. >2 risk factors <130 iv. 0-1 risk factors <160 3. Lipid Lowering Drugs

a. b. STATINS- HMG CoA Reductase Inhibitors (3-hydroxy-3 methylglutaryl-coenzyme A (HMG CoA) i. Specific, competitive inhibitors 1. Lo, Sim, Flu, Pra, Pita, -vastatin ii. Long lasting inhibiotrs 1. Ator, Rosu, -vastatin. These two reduce plasma LDL by 50% iii. STATINS inhibit endogenous cholesterol synthesis in the liver (inhibit HMG-CoA to Mevalonic acid by inhibiting HMG CoA reductase). STATINS compoete with HMG CoA to occupy and inhibit reductase enzyme. iv. Main Effect on lipid profile 1. Reduce plasma LDL 2. Smaller reduction in plasma triglyceride 3. Increase in HDL v. Pharmokinetics 1. Well absorbed orally 2. Extensive first pass effect leads to variable bioavailability (5-30% of administered dose) 3. Most have active metabolites 4. Sim and Lo are inactive pro-drugs, activated in liver to active form, hydroxy fat vi. Other considerations 1. In the plasma, more than 90% of the statins and their metabolites are protein bound 2. Short acting statins should be taken in the evening, since peak cholesterol synthesis occurs between midnight and 2 AM. vii. Potential Cardioprotective effects of Statins 1. Improve endothelial function by increasing NO synthesis 2. Stabilize plaque 3. Anti-inflammatory a. Reduce C-reactive protein (CRP) b. Reduce LDL oxidation c. Reduce platelet aggregation viii. Adverse Effects 1. Well tolerated

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2. Mild unwanted effects a. Raised concentrations of liver enzymes in plasma b. Myalgia (sore muscles), GI disturbances, insomnia, rash Rare but Serious Side Effects 1. Hepatoxicity a. Liver damage is a classic effect of statins b. Must monitor liver enzyme levels 2. Myopathy a. Classic effect of statins b. Dose related c. Risk is more in combination therapies d. Can cause kidney failure e. CK/CPK levels must be monitored!! 3. Contraindicated in pregnancy Recommendation for Liver Function tests 1. ALT and AST a. Monitor within 2-4 weeks of initiating therapy b. After 12 weeks, and annually thereafter Recommendation for evaluating Myopathy 1. Evaluate muscle symptoms and check CK a. Before starting therapy b. In 6-12 seeks after starting therapy c. Then at each follow up visit 2. Patients presenting with muscle soreness should have a CK test on presentation to minimize the dev of myopathies 3. Incidence is lower with Lo and Sim 4. Pra and others can increase CK levels 5. Concurrent therapy with drugs Eg: cyclosporine, macrolide, antibiotics, azole antifungals, niacin, fibrates and nefazodone can increase the risk. STATINS in combination with other lipid lowering drugs

1. c. Fibrates

i. Fenofibrate, Gemfibrozil ii. MOA 1. Stimulate LPL (increase LPL levels = breakup chylos and VLDLs = lower cholesterol in blood) 2. Decrease release of VLDL by liver 3. Promote LDL uptake into the liver 4. Increase Apo AI and AII and to increase plasma HDL levels iii. Effect on Lipid Profile 1. Reduce circulating VLDL and hence trigylcerides 2. Moderate reduction in LDL-C 3. Moderate increae in HDL-C iv. Pharmacokinetics 1. Well absorbged orally 2. Half life 1-20 hrs 3. 60-90% of the oral drug undergoes Glucuronidation and excreted renally a. Use with caution in renal impairment b. Serum creatinine levels should be monitored v. Side Effects 1. Same as STATINS but worse a. GI, rash, itch vi. Rare but Severe Side Effects 1. Myositis (inflammation of the muscles) can lead to a. Myoglobinuria / Rhabdomyolosis (rapid breakdown of skeletal muscle) 2. Acute renal failure 3. Lithiasis a. Increased biliary excretion of cholesterol predisposes to the formation of gall stones. b. Significant with clofibrate vii. Contraindications 1. Renal impairment patients- use caution, dosage adjustment 2. Contraindicated in severe renal patients 3. Clofibrate- use only if persons gall bladder has been removed 4. Gemfibrozil crosses placenta- contraindicated in pregnancy. 4. Drugs that Inhibit Cholesterol Absorption/ Reabsorption in the GI tract a. Bile Acid Sequestrants i. Colestyramine, Colestipol, Colesevelam b. Cholesterol Transport Blocker i. (Zeita) 5. Bile Acid Sequestrants a. 1st gen drugs, insoluble anion-exchange resins that are ingested in the form of a slurry of as gel formulation b. Reduce cholesterol reabsorption nand lower plasma cholesterol levels

c. Bulky and unappetizing. Used as adjuncts in the treatment of patients with severe dyslipidemia d. Treatment with these drugs translates to reduced risk of CHD and MI e. MOA i. Forms insoluble complex with bile acids and salts in small intestine, preventing their reabsorption from the intestine. ii. absorption of dietary cholesterol and increased excretion of bile acids and salts in feces iii. synthesis and secretion of bile acids, decreasing hepatic cholesterol content iv. LDL receptor expression v. clearance of LDL from plasma vi. HDL-C concentration is unchanged vii. Transient in TG f. Works best when used in conjunction with STATINS g. Adverse Effects i. Low systemic toxicity b/c they are not absorbed ii. GI disturbances 1. Bloating, dyspepsia iii. Decreased absorption of fat soluble vitamins (eg Vit K) 1. Reduces coagulation and causes bleeding gums. h. Pharmacokinetics i. Interfere with absorption of fat soluble drugs 1. Eg. Chlorthiazide, Digoxin, Warfarin, and STATINS 2. These should be taken at least an hour before or 4-6 hours after taking the bile acid resins 6. Cholesterol Transport Blockers a. Ezitemibe i. Inhibits absorption of cholesterol form the duodenum by blocking cholesterol transporter NPCILI in the intestine ii. Used as and adjunct to diet and statins 1. Statins result in increased intestinal cholesterol absorption, so this drug inhibits that iii. Only used as monotherapy in patients who cannot tolerate statins iv. Pharmakokinetics 1. Taken orally, absorbed in intestine by brush border 2. Long half life of 22 hrs a. Extensively metabolized as glucuronide complex which remains active b. Total concentration peaks 1-2 hours after administration c. Slow elimination v. Adverse Affects 1. Generally well tolerated a. GI, diarrhea, rash, abdominal pain, headache, angioedema b. Enters milk (resins dont), contraindicated in breast feeding women

b. Vytorin i. Combo of Ezetimibe and Simvastatin 1. Avg 60% reduction in LDL-C 2. More expensive c. Niacin i. General Features 1. Oldest drug 2. Water soluble B complex vitamin 3. In high doses can lower 4. Nicotinamide a. Has to be converted to niacin for anti-lipid effects ii. MOA 1. Poorly understood 2. Inhibits hormone sensitive lipase to reduce formation and transport of FFA into the liver and decreases hepatic TG synthesis iii. Effects on Lipids 1. Inhibits hepatic TG production and VLDL secretion, which reduces plasma TG (30%) and LDL-C (25%) 2. Best agent available for increasing HDL 3. Clinical trials show reduction in MI related mortality iv. Adverse effects 1. Limited use because of side effects a. Flushing, pruritus b. Palpitations c. GI disturbances i. Dyspepsia (impaired digestion) d. High doses cause hepatotoxicity e. Impaired glucose tolerance (contraindicated for diabetics) f. Precipitates gout by increasing urate concentrations g. Contraindicated in pregnant women; causes birth defects 7. Summary of Antilipidemics

a. 8. Omega 3 acid ethyl esters a. Lovaza i. First FDA approved omega-3 FA indicated for patients with >500 mg/ml cholesterol. ii. MOA 1. Increased hepatic beta-oxidation 2. Reduction in hepatic synthesis of TGs 3. Increase in plasma lipoprotein lipase activity iii. Side Effects 1. Upset stomach, burping, sense of taste, back pain, rash, infection, flu like symptoms