This document discusses hypolipidaemic drugs and plasma expanders. It begins by introducing cardiovascular diseases and dyslipidemia as major causes of morbidity and mortality. It then describes the classification, metabolism, and disorders of lipoproteins. The main sections discuss the pharmacotherapy of hyperlipidemias including statins, fibrates, nicotinic acid, ezetimibe, and other agents. Adverse effects and guidelines for use are provided. Management of shock includes types of shock and treatment approaches for hypovolaemic, cardiogenic, septic, anaphylactic, and neurogenic shock. Ideal properties and examples of plasma expanders like dextran are also summarized.

1. Hypolipidaemic drugs
& plasma expanders
Dr. K. R. Prabhakar M.D
Assistant Professor
1

2. 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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3. • Lipoproteins are divided based on their particle size
& density .
3

4. Metabolism of lipoproteins
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5. 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 as
1. Primary:
 Familial/genetic due to single gene defect
 Multifactorial/polygenic
2. Secondary: associated with diseases & drugs.
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6. 6

7. 7

8. Pharmacotherapy of hyperlipidaemias
Classification:
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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9. 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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10. HMG-CoA Reductase inhibitors: (Statins)
MOA:
• ↓se cholesterol synthesis by competitively inhibiting
rate limiting HMG CoA reductase.
HMG CoA
statins - HMG CoA reductase
Mevalonic acid
↓se cholesterol synthesis
Compensatory ↑se in LDL receptor expression in liver
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11. • 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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12. 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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13. 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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14. 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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15. 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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16. 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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17. 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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18. • 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/day
AE
• Constipation , exc of hemorrhoids, GIT distress.
• Absorption of fat sol vit & folic acid impaired.
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19. 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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20. 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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21. 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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22. 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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23. Lipolysis & TG synthesis inhibitors
Nicotinic 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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24. • ↓se catabolism of Apo-I, hence ↑se HDL levels.
• Boosts secretion of tissue plasminogen activator &
lowers plasma fibrinogen
Uses
• 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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25. 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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26. 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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27. 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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28. 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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29. Guidelines on the use of hypolipidemic drugs
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30. 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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31. LDL- CH lowering treatment guidelines
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32. 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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33. 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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34. 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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35. 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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36. Management of shock
Hypovolaemic 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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37. • 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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38. • 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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39. • ↑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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40. 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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41. 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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42. 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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43. 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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44. • 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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45. 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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46. 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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47. • 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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48. 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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49. • 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.
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