pharma fouda 2_p110-112.pdf

█ LIPIID LOWER RING DRU UGS Classiification of o drugs Drug theerapy is indica...

█ LIPIID LOWER RING DRU UGS Classiification of o drugs Drug theerapy is indica ated in: Inhiibitors of intestinal cholesterrol absorp ption: – Bile acid binding b res sins: cholesstyramine, colestipol Failure of non- – Ezetimibe drug therapy. Acttivators off plasma liipoproteinn lipase: fib bric acid Primary deriivatives (heredita ary) HMMG-CoA re eductase in nhibitors: statins. hyperlipidemia. Inhiibitors of hepatic lip pid produc ction: nico otinic acid, acip pimox Oth her drugs: d-thyroxin n, neomyciin, and proobucol Chole estyramin ne and colestipo c ol Mecha anism of action a They fo orm comp plexes withh bile acidds in the ne and ↓ en intestin nterohepatic absorptioon of bile nd ↓ absorp salts an ption of cho olesterol. Therappeutic use es  Hyp percholeste erolemia (ttype IIa): B Bile acid seq questrants are effec ctive in rreducing plassma choolesterol (10%–20 0%) in patiients with some s normmal LDL re eceptors.  Diarrrhea due tot bile acid d malabso rption.  Pruritus due to o obstructiive jaundic ce. Adverrse effectss – GITT upset (the most co ommon): n ausea, vom miting and hea (due to ↓ fat d steatorrh abssorption). – ↓ abbsorption of o fat-solub ble vitamin ns. – ↓ abbsorption of o anionic drugs e.g. digitalis and a warfarrin. Ezetim mibe ansism of action Mecha Ezetimibe is a se elective inhibitor of intestinal cholestero ol absorptiion. It is effective e even inn the abssence of dietary ch holesterol because it inhibitss reabsorp ption of cholestterol excre eted in the bile. 205  Therap peutic use es Hyperc cholesterolemia: ezettimibe is ssynergistic with HMG G-CoA red ductase inh hibitors, produc cing decrea ase of 25% % in LDL ch holesterol.. Advers se effects Reversiible hepatic c dysfunctio on: liver fun nction tests s should be e done at reegular interv vals. HMG--CoA red ductase inhibitor i rs (Statin ns) (Lovas statin, Prav vastatin, Mevastatin M n, Atorvas statin) Mecha anism of action a Compeetitive inhibition off hydroxyy-methyl-g glutaryl coenzyyme-A (HM MG-CoA) reductase r e → ↓ cholesterol esis and ↑ hepatic up synthe ptake of LD DL. Therap peutic use es  Hyp percholesteerolemia (ttype II).  With h other dru ugs for com mbined hyyperlipidem mia. Advers se effects H : Heppatic dysffunction lleading to o elevationn of serum m transam minases. The erapy shou uld be stop pped if liv ver enzyme es rise > 33-folds the e upper norm mal value. M : Myoopathy, my yositis andd rhabdom myolysis in n both skeeletal and cardiac g to ↑ of crreatine pho musscle leading osphokinas se (CPK) ennzyme. G T upsets: nausea, : GIT n vo miting, anoorexia (the e most commmon). Co-A : Cattaract (lentticular Opaacity) in miiddle-Agedd individuaals. Reductasse nal dysfunc : Ren ction (espeecially withh lovastatin n). Fibric c acid de erivatives s (Fibrate es) (Clofib brate, Feno ofibrate, Bezafibrate B e, Gemfib brozil) Mecha anism of action a Fibrate es act on n nuclearr recepto ors calledd peroxisoome proliiferator acctivated receptoors-α (PPA ding to ↑ ssynthesis of lipopro AR-α) lead otein lipasse → ↑ pe eripheral cataboolism of VLDL and chhylomicron ns (TGs). Therap peutic use es:  Hyppertriglycerridemia (ty ypes IIb, II I, IV and V). V  Fennofibrate haas antidiuretic actioon in individuals with h mild to m moderate diabetes d insipidus. 206 Adverse effects – GIT upsets: nausea, vomiting (the most common). – Increase formation of cholesterol gallstones. – Hepatic dysfunction and elevation of serum transaminases. – Fibrates increase the risk of myopathy if used in combination with statins. – Skin rash and dermatologic reactions. Nicotinic acid (Niacin; vitamin B3) Mechanism of action  Niacin (but not nicotinamide) inhibits lipolysis in adipose tissue and inhibits fatty acid synthesis by the liver → ↓ hepatic VLDL and LDL synthesis.  This is distinct from the role of niacin as a vitamin, in which it is converted to nicotinamide and is used for the biosynthesis of the cofactors NAD and NADP. Therapeutic uses In combination with other drugs for all types of hyperlipidemia (except type I which is mainly treated by diet control). Adverse effects – Skin flushing and burning sensation (the most common). It is harmless effect mediated by PGs and histamine release and can be diminished by taking aspirin 30 minutes before taking nicotinic acid. – Gastric irritation (the drug should be avoided in peptic ulcer). – Hyperglycemia, hyperuricemia, and reversible increase in serum transaminases. █ Summary Effect on LDL Effect on HDL Effect on TGs Bile acid-binding resins ↓↓↓ ↑ ---- Reductase inhibitors ↓↓↓ ↑ ↓ Fibrates ↓ ↑ ↓↓↓ Niacin ↓ ↑↑↑ ↓↓ █ Treatment with drug combinations Hypercholesterolemia Cholestyramine + Reductase inhibitors Hypertriglyceridemia Niacin + Fibrates Familial combined Cholestyramine + Fibrates. hyperlipidemia Cholestyramine + Niacin. Statins + Fibrates (this combination may ↑ risk of myopathy). 207