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Hypolipidaemic drugs
& plasma expanders
Dr. K. R. Prabhakar M.D
Assistant Professor
1
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.
2
• Lipoproteins are divided based on their particle size
& density .
3
Metabolism of lipoproteins
4
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.
5
6
7
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.
8
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.
9
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
10
• 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.
11
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).
12
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)
13
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.
14
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.
15
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.
16
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.
17
• 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.
18
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.
19
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).
20
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.
21
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).
22
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
23
• ↓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.
24
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.
25
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.
26
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.
27
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.
28
Guidelines on the use of hypolipidemic drugs
29
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
30
LDL- CH lowering treatment guidelines
31
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
32
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
33
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.
34
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.
35
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
36
• 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.
37
• 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
38
• ↑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.
39
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.
40
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.
41
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.
42
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.
43
• 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.
44
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.
45
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).
46
• 6% sol has colloidal properties similar to human
albumin.
SE:
• Swelling of salivary glands,
• Periorbital edema,
• Bronchospasm
• Vomiting
• Chills, rigor, flu like symptoms & urticaria.
47
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.
48
• 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.
49

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Hypolipidemic drugs

  • 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. 2
  • 3. • Lipoproteins are divided based on their particle size & density . 3
  • 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. 5
  • 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. 8
  • 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. 9
  • 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 10
  • 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. 11
  • 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). 12
  • 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) 13
  • 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. 14
  • 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. 15
  • 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. 16
  • 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. 17
  • 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. 18
  • 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. 19
  • 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). 20
  • 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. 21
  • 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). 22
  • 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 23
  • 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. 24
  • 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. 25
  • 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. 26
  • 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. 27
  • 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. 28
  • 29. Guidelines on the use of hypolipidemic drugs 29
  • 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 30
  • 31. LDL- CH lowering treatment guidelines 31
  • 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 32
  • 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 33
  • 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. 34
  • 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. 35
  • 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 36
  • 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. 37
  • 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 38
  • 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. 39
  • 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. 40
  • 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. 41
  • 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. 42
  • 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. 43
  • 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. 44
  • 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. 45
  • 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). 46
  • 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. 47
  • 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. 48
  • 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. 49

Editor's Notes

  1. Hepatic dysfunction more with sr, Ci in DM, peptic ulcer