Hepatic dysfunction more with sr, Ci in DM, peptic ulcer
& plasma expanders
Dr. K. R. Prabhakar M.D
• 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
• Lipoproteins are divided based on their particle size
& density .
• LDL transport CH for peripheral utilization .
• Excess CH gets deposited in arterial wall as atheroma
& in skin as xanthoma.
• Hyperlipoproteinaemias can be classified as
Familial/genetic due to single gene defect
2. Secondary: associated with diseases & drugs.
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.
HMG-CoA Reductase inhibitors: (Statins)
• ↓se cholesterol synthesis by competitively inhibiting
rate limiting HMG CoA reductase.
statins - HMG CoA reductase
↓se cholesterol synthesis
Compensatory ↑se in LDL receptor expression in liver
• 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.
It is lipophilic & given in precursor form (lactone)
absorption is incomplete & 1st pass metabolism is
Dose: 10-40 mg/day (max 80 mg).
More efficacious & twice potent than lovastatin. It is
also lipophilic & given in lactone precursor form.
Dose: 5-20 mg/day (max 80 mg).
It is hydrophilic & given in active form. It also causes
decrease in plasma fibrinogen level.
Dose: 10-20 mg.
Newer statin, good LDL – CH lower effect. It has
much longer t ½ (18-24hrs). It has additional anti-
Dose: 10-40 mg/day (max 80 mg)
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.
Latest & most potent statin.
Combination with gemfibrozil is avoided , ↓se
Dose: 1-4 mg/day.
• 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.
1st choice in primary (↑LDL, TCH-IIa, IIb, V) &
secondary hyper lipidaemias.
It decreases CVS mortality by decreasing raised LDL
Improved coronary compliance and atheromatous
Improvement in endothelial function & increased
They are the 1st choice drugs for dyslipidaemia in
Bile acid binding resins
• Bile acids (BA) are synthesized in the liver from CH.
• Secreted in the duodenum aids dietary fat
absorption. Undergoes EHC.
• 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.
• Cholestyramine, colestipol & colesevelam
• Drugs of choice for- type IIa, type IIb- with niacin.
• Pruritis in pt with cholestasis,
• Digitalis toxicity
• Cholestyramine, colestipol (16g daily)- granules.
• Mixed with water or juice taken with meals.
• Colesevelam- 625mg tablet, 6 tablets/day
• Constipation , exc of hemorrhoids, GIT distress.
• Absorption of fat sol vit & folic acid impaired.
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.
• 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
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).
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
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
• ↓se catabolism of Apo-I, hence ↑se HDL levels.
• Boosts secretion of tissue plasminogen activator &
lowers plasma fibrinogen
• Type IIb & IV.
• Pts with ↑se risk of CHD.
• Cutaneous flush & pruritis. In first 14 days. Reduced
by premedication with low dose aspirin.
• Cholestasis, hyperuricaemia & hepatic dysfunction.
Sterol absorption inhibitor (Ezetimibe)
1. Inhibit cholesterol absorption by interfering with
specific CH transport protein (NPC1L1) in intestinal
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
5. Hepatic dysfunction & myositis are rare S/Es.
• 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.
• 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.
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
• Membrane stabilizing & antioxidant action.
• Usually formulated with Vit-E.
Guidelines on the use of hypolipidemic drugs
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.
• Hypovolaemic shock
• Cardiogenic shock
• Septic shock
• Anaphylactic shock
• Results from major reduction in blood volume.
• Loss of plasma due to burns.
• Loss of fluid & electrolytes– vomiting & diarrhea.
• Results due to severe pump failure.
• E.g MI, cardiomyopathy,
• Valvular dysfunction
• 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.
• Severe immediate hypersensitivity reaction.
• Excessive vasodilatation, ↑capillary permeability,
exudation, angioneurotic edema, bronchoconstriction.
• 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 &
• CVP elevated in cardiogenic shock, unpredictable in
neurogenic / septic shock.
Management of 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
• Phenoxybenzamine- counteract vasoconstriction,
shifts blood from pulmonary to systemic circuit &
extravascular to vascular compartment, ↑CO
• 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
• Requires small amounts of fluid replacement.
• Dobutamine: 2.5μg/kg/min I.V infusion.
• ↑contractility, ↓afterload
• Dopamine 2-3μg/kg/min I.V infusion.
• Norepinephrine: reserved for patients with refractory
hypotension 2-4μg/kg/min I.V infusion.
• Treat the infection-
• Requires large volumes of fluid replacement due to
• 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
• ↑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.
• 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
• Rx similar to hypovolemic shock.
• Norepinephrine/phenylephrine to maintain BP.
• Ideally human plasma/whole blood or reconstituted
human albumin are preferred to correct hypovolemia due
• These are high molecular weight substances which exert
colloidal osmotic pressure.
• When given I.V, they retain fluid in the vascular
• They are used to correct hypovolemia due to loss of
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
• Should be stable, easily sterilizable & cheap.
• 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 &
• Can interfere with coagulation & platelet function.
• Allergic reactions occur occasionally.
• 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.
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.
Hydroxyethyl starch (Hetastarch)
• Not commonly used due to side effects.
• Acts for more than 24hrs.
• Contains ethoxylated amylopectin of different
• Smaller molecules (40%) are excreted by kidneyswith
• Larger molecules are excreted very slowly (2weeks).
• 6% sol has colloidal properties similar to human
• Swelling of salivary glands,
• Periorbital edema,
• Chills, rigor, flu like symptoms & urticaria.
• 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
• No risk of sensitization with repeated infusion.
• 100ml of 20% human albumin solution is equivalent-
• 400ml of fresh frozen plasma or
• 800ml of whole blood
• Crystalloid solutions should also be infused
• Can also be used in hypoproteinaemia.
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drugs used in hyperlipidemia and familial cholosterolemias