Hypolipidemic drugs

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Hypolipidaemic drugs & plasma

expandersDr. K. R. Prabhakar M.D

Assistant Professor

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Introduction • Cardiovascular & cerebrovascular ischemic diseases

are leading cause of morbidity & mortality.

• Dyslipidaemia is the major cause of ischemia.

• Hypolipidaemic drugs lower the levels of lipids & lipoproteins in blood.

• Lipids are transported in plasma in lipoproteins, which are associated with several proteins called as apoproteins.

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• Lipoproteins are divided based on their particle size & density .

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Metabolism of lipoproteins

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Lipoprotein disorders• LDL transport CH for peripheral utilization .• Excess CH gets deposited in arterial wall as atheroma

& in skin as xanthoma.

• Hyperlipoproteinaemias can be classified as1. Primary:

Familial/genetic due to single gene defect Multifactorial/polygenic

2. Secondary: associated with diseases & drugs.

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Pharmacotherapy of hyperlipidaemiasClassification:1. HMG-CoA Reductase inhibitors: (Statins)– Lovastatin, Simvastatin,, Pravastatin,

Atorvastatin, Rosuvastatin, Pitavastatin

2. Bile acid binding resins: – Cholestyramine, Colestipol, colesevelam.

3. Sterol absorption inhibitor: Ezetimibe, Gugulipid .

4. Newer drugs (CEPT inhibitors): Torcetrapib, Anacetrapib.

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5. Activators of LPL: (PPAR activators Fibrates)– Clofibrate, Gemfibrozil, Bezafibrate ,Fenofibrate

6. Inhibitors of lipolysis & TG synthesis – Nicotinic acid (Niacin)

7. Miscellaneous agents– Gugulipid & fish oil derivatives.

• These are 2nd line lipid lowering agents.• More effective in lowering TGL & VLDL.

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HMG-CoA Reductase inhibitors: (Statins)MOA: • ↓se cholesterol synthesis by competitively inhibiting

rate limiting HMG CoA reductase.HMG CoA

statins - HMG CoA reductaseMevalonic acid

↓se cholesterol synthesis

Compensatory ↑se in LDL receptor expression in liver

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• Statins differ in their potency & max efficacy in reducing LDL cholesterol.

• Statins shows the ceiling effect due to compensatory induction of HMG CoA reductase.

• Dose - dependent lowering of LDL – CH is seen.• TG ↓se by 10-30 % due to fall in VLDL.• Statins use also causes rise in HDL (5-15%).• HMG – CoA reductase activity is maximum at

midnight, all statins are administered at Bed time.• Except rosuvastatin all are metabolized by CYP3A4.

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Lovastatin: It is lipophilic & given in precursor form (lactone)

absorption is incomplete & 1st pass metabolism is extensive.

Dose: 10-40 mg/day (max 80 mg).

Simvastatin: More efficacious & twice potent than lovastatin. It is

also lipophilic & given in lactone precursor form. Dose: 5-20 mg/day (max 80 mg).

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Pravastatin: It is hydrophilic & given in active form. It also causes

decrease in plasma fibrinogen level. Dose: 10-20 mg.

Atorvastatin: Newer statin, good LDL – CH lower effect. It has

much longer t ½ (18-24hrs). It has additional anti-oxidant property.

Dose: 10-40 mg/day (max 80 mg)

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Rosuvastatin: Latest & most potent statin. t ½ - 18 – 24 hrs. It

raises maximum HDL level compare to other statin. Dose: 5-20 mg/day max 40 mg/day.

Pitavastatin: Latest & most potent statin. Combination with gemfibrozil is avoided , ↓se

clearance. Dose: 1-4 mg/day.

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Adverse effects:• Headache,• Sleep disturbance,• Raise serum transaminase,• Muscle tenderness & rise in CPK levels.• Myopathy (<1/1000) is the only serious A/E, it is

more when given along with nicotinic acid / gemfibrozil/ CYP3A4 inhibitors e.g ketoconazole.

• Fenofibrate is safe for combining with statins.• Statins should be avoided in pregnant women.

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Uses: 1st choice in primary (↑LDL, TCH-IIa, IIb, V) &

secondary hyper lipidaemias. It decreases CVS mortality by decreasing raised LDL

level. Improved coronary compliance and atheromatous

plague stabilization. Improvement in endothelial function & increased

NO production. They are the 1st choice drugs for dyslipidaemia in

diabetics.

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Bile acid binding resins• Bile acids (BA) are synthesized in the liver from CH.• Secreted in the duodenum aids dietary fat

absorption. Undergoes EHC.MOA:• Non-absorbable anion exchange resins that complex

with negatively charged bile acids in SI.• Resin+ BA complex gets excreted through feces.• Biosynthesis of BA from CH increases, leads to partial

depletion of hepatic CH pool. • Unsutable as monotherapy for long term use.

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• Cholestyramine, colestipol & colesevelam • Drugs of choice for- type IIa, type IIb- with niacin.• Pruritis in pt with cholestasis, • Digitalis toxicity Dose:• Cholestyramine, colestipol (16g daily)- granules.• Mixed with water or juice taken with meals.• Colesevelam- 625mg tablet, 6 tablets/dayAE• Constipation , exc of hemorrhoids, GIT distress.• Absorption of fat sol vit & folic acid impaired.

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Lipoprotein lipase activators (Fibrates)• Activate lipoprotein lipase (which degrades VLDL)

thus lowering circulating TGs level.• Effect is exerted through peroxisome proliferator

activated receptor (PPAR ). It’s activation enhances lipoprotein lipase activity & synthesis.

• PPAR also enhances LDL receptor expression. • This class primarily lower TGs (20 – 50%). • 10 –15% decrease in LDL & 10 –15 % increase in HDL

is also seen.

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Gemfibrozil: • Apart from main action it causes suppression of

hepatic synthesis of TGs. Additional actions include decreasing level of clotting factor VII phospholipid complex and promotion of fibrinolysis (antiatherosclerotic effect)

A/E : GI distress, eosinophilia, impotence and blurred vision. Myopathy is uncommon. C/I in pregnancy.

Uses: 600mg BD before meals is used to treat increased TGs & acute prancreatitis in hypertriglyceridaemia (III, IV & V).

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Bezafibrate :

2nd generation fibric acid derivative & alterative to gemfibrozil in (type III, IV & V).

• Has greater LDL lowering action than gemfibrozil.

• A/E are less (G.I upset, rashes etc). Action of anticoagulant is increased.

• Combination with statin not found to increase risk of rhabdomyolysis.

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Fenofibrate:

2nd generation prodrug of fibric acid derivative. • Apart from decreasing TGs. It also cause moderate

decrease in LDL & increase in HDL levels.

• Longer t ½ (20hrs) hence given OD. Cholelithiasis & rhabdomyolysis is rare (won’t potentiate statin induced myopathy).

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Lipolysis & TG synthesis inhibitorsNicotinic acid (Niacin-vit B3)• ↓se VLDL, LDL & LP(a), ↑se HDL-CH & inexpensive.MOA:

Strongly inhibits lipolysis in adipose tissue↓

Reduced levels of circulating FFAs↓

↓se TG synthesis↓

↓se VLDL & LDL

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• ↓se catabolism of Apo-I, hence ↑se HDL levels.• Boosts secretion of tissue plasminogen activator &

lowers plasma fibrinogenUses • Type IIb & IV.• Pts with ↑se risk of CHD.AE• Cutaneous flush & pruritis. In first 14 days. Reduced

by premedication with low dose aspirin.• Cholestasis, hyperuricaemia & hepatic dysfunction.

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Sterol absorption inhibitor (Ezetimibe)

1. Inhibit cholesterol absorption by interfering with specific CH transport protein (NPC1L1) in intestinal mucosa.

2. Both dietary & biliary CH level decreases.3. Compensatory increased in CH synthesis take place

(blocked by statin & hence good combination).4. Weak hypolipidaemic drug (LDL ↓by 15 -20 %)

when given alone.5. Hepatic dysfunction & myositis are rare S/Es.

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CEPT Inhibitors• Cholesteryl ester transfer protein (CEPT) facilitates

transfer of CE from HDL TO LDL & VLDL.

• In 2004 two CEPT inhibitors are developed.

• Torcetrapib & anacetrapib.

• Anacetrapib ↑ HDL by 129% with statin like ↓ in LDL

• CEPT inhibition potential target for ↑ HDL.

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Gugulipid• Developed at Central Drug Research Institute, Lucknow.

• Contains Z & E gugulsterones isolated from guggul gum.

• Inhibits CH biosynthesis & enhances its excretion.

• Dose: 25mg tablet TDS

• ↓ TCH, LDL, ↑HDL & modest lowering of TG.

• Well tolerated, loose stools are only side effect.

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Fish oil derivatives (Omega-3 fatty acids)• Contains poly unsaturated fatty acids (PUFA).

• Eicosa-pentanoic & docosa-hexanoic acids.

• Used for prophylaxis in high risk pt of CAD with hyperlipidaemia.

• Membrane stabilizing & antioxidant action.

• Usually formulated with Vit-E.

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Guidelines on the use of hypolipidemic drugs

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Plasma lipid levels (mg/dl)

Total CH LDL CH HDL CH TGs

Optimal <200 <100<70 CAD

>40(M)>50 (W)

<150

Borderline high

200-239 130-159 - 150-199

High ≥240 160-189 >60 200-499

V.high - ≥190 - ≥500

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LDL- CH lowering treatment guidelines

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Management of shock• Shock is also called circulatory failure.• O2 perfusion fails to meet the metabolic demands.• Results in regional hypoxia & lactic acidosis• Eventually leads to end organ damage & failure.

Classification• Hypovolaemic shock• Cardiogenic shock• Septic shock• Anaphylactic shock

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Hypovolaemic shock• Results from major reduction in blood volume.• Loss of plasma due to burns.• Loss of fluid & electrolytes– vomiting & diarrhea.

Cardiogenic shock• Results due to severe pump failure.• E.g MI, cardiomyopathy, • Arrhythmias • Valvular dysfunction

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Septic shock• Occurs secondary to Gram negative bacteraemia.• Risk factors are extremes of age, DM,

immunosuppression, invasive procedure.• Vasodilatation occurs secondary to endotoxins.• Also called warm shock.

Anaphylactic shock• Severe immediate hypersensitivity reaction.• Excessive vasodilatation, ↑capillary permeability,

exudation, angioneurotic edema, bronchoconstriction.

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Neurogenic shock• Caused by traumatic spinal cord injury ,• Spinal/epidural anesthesia adverse effect.• Results in loss of sympathetic tone →• Reflex vagal parasympathetic stimulation →• Vasodilatation, hypotension, bradycardia & syncope.

• CVP is typically reduced in hypovolemic & anaphylactic shock.

• CVP elevated in cardiogenic shock, unpredictable in neurogenic / septic shock.

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Management of shockHypovolaemic shock• Treated with immediate infusion of blood substitutes• In severe dehydration volume replacement with- raid

infusion of isotonic saline/RL.• Plasma expanders (colloids) not useful.• Dopamine to maintain adequate ventricular

performance.• Phenoxybenzamine- counteract vasoconstriction,

shifts blood from pulmonary to systemic circuit & extravascular to vascular compartment, ↑CO

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• Dopamine infusion (2-3mcg/kg/min)- stimlates D1 R in kidney & β1 R in heart.

• ↑ HR, contractility, & GFR.• Phenylephrine is alt for pt at risk of arrhythmias.• O2 should be supplemented

Cardiogenic shock• Requires small amounts of fluid replacement.• Dobutamine: 2.5μg/kg/min I.V infusion.• ↑contractility, ↓afterload• Dopamine 2-3μg/kg/min I.V infusion.

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• Norepinephrine: reserved for patients with refractory hypotension 2-4μg/kg/min I.V infusion.

Septic shock• Treat the infection-

meropenem(I.V)/ticarcillin+clavulanic acid.• Requires large volumes of fluid replacement due to

capillary leak.• Drotrecogin alpha: 24μg/kg/hr for 96hrs improves

mortality in severe septic shock with organ failure.• Vasopressin: causes peripheral vasoconstriction (V1).• Reduces NO synthesis ,↑the effect of catecholamines

on vasculature. Stimulate cortisol production

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• ↑BP even if there is resistance to adrenaline.• Corticosteroids: hydrocortisone (50mg QID) with

fludrocortisone (50mcg OD) X7 days.• Supress formation of NO & PG.• Shortens duration of use of vaspressors, ↓mortality.• Prevents adrenal insufficiency.• Positive ionotropes useful in some patients.• Other measures by maintaining Pulmonary capillary wedge pressure: 12-16mmHg,

CVP: 8-12cm H2O Proper urine output: furosemide may be used. Blood glucose levels.

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Anaphylactic shock• Adrenaline 0.5 mg (0.5 ml of 1 in 1000 solution) i.m.;

repeat every 5-10 min in case patient does not improve or improvement is transient.

• Causes bronchodilatation &↑BP.• H1 antagonists & glucocorticoids are used as adjuvants

Neurogenic shock• Rx similar to hypovolemic shock.• Norepinephrine/phenylephrine to maintain BP.

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Plasma expanders• Ideally human plasma/whole blood or reconstituted human

albumin are preferred to correct hypovolemia due to hemorrhage.

• These are high molecular weight substances which exert colloidal osmotic pressure.

• When given I.V, they retain fluid in the vascular compartment.

• They are used to correct hypovolemia due to loss of plasma/ blood.

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Desirable properties of plasma expander

• Should exert oncotic pressure comparable to plasma.• Should remain in circulation and not leak out in

tissues or be too rapidly disposed.• Should be PD inert.• Should not be pyrogenic or antigenic.• Should not interfere with grouping & cross matching

of blood. • Should be stable, easily sterilizable & cheap.

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Dextran • Polysaccharide, available as dextran-70.

• 6% sol in dextrose/ NS. mol wt 70000.

• Dextran 70 is the most commonly used preparation.

• Acts for 24 hrs, may interfere with blood grouping & cross matching.

• Can interfere with coagulation & platelet function.

• Allergic reactions occur occasionally.

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• Dextran 40 (mol wt 40000) 10% sol in dextrose/ NS.

• Acts more rapidly, reduces blood viscosity.

• Shorter duration of action– rapid glomerular filtration.

• Causes tubular obstruction- conc in tubule in oliguria.

• Dextrans can be stored for several years & cheap.

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Degraded gelatin polymer (Polygeline)

• Polypeptide with mol.wt around 30,000.

• Not antigenic, hypersensitivity reactions are rare.

• Doesn't interfere with grouping & cross matching.

• Acts for 12hrs, excreted slowly by kidneys.

• Has a shelf life of 3 years & expensive than dextran.

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Hydroxyethyl starch (Hetastarch)

• Not commonly used due to side effects.

• Acts for more than 24hrs.

• Contains ethoxylated amylopectin of different

molecular sizes.

• Smaller molecules (40%) are excreted by kidneyswith

in 24hrs.

• Larger molecules are excreted very slowly (2weeks).

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• 6% sol has colloidal properties similar to human

albumin.

SE:

• Swelling of salivary glands,

• Periorbital edema,

• Bronchospasm

• Vomiting

• Chills, rigor, flu like symptoms & urticaria.

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Human albumin

• It is obtained from pooled human plasma.

• It can be used without regard to patient's blood

group and does not interfere with coagulation.

• It is free of risk of transmitting serum hepatitis or

AIDS.• No risk of sensitization with repeated infusion.

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• 100ml of 20% human albumin solution is equivalent-

• 400ml of fresh frozen plasma or

• 800ml of whole blood

• Expensive

• Crystalloid solutions should also be infused

concurrently.

• Can also be used in hypoproteinaemia.