Information on Adrenergic Antagonist.pdf

Information on Adrenergic Antagonist.pdf

• 1.
  By- Dr. Prerana B.Jadhav M. Pharm, Ph.D. Pharmaceutical Chemistry Assistant Professor, Sanjivani College of Pharmaceutical Education and Research, Kopargaon. Adrenergic Antagonist
• 2.
  Adrenergic Antagonists • Alphaadrenergic blockers • Non-selective alpha - adrenergic antagonists • Eg. Tolazoline and Phentolamine
• 3.
  • Mechanism ofaction: • Tolazoline and phentolamine have both alpha 1 and alpha 2 blocking activity and produce tachycardia. • Tolazoline is a nonselective vasodilator that has been used for several decades to treat pulmonary hypertension in neonates.
• 4.
  Phenoxybenzamine • Phenoxybenzamine isthe only haloalkylamine in clinical use at present.
• 5.
  • Mechanism ofaction: • They are irreversible blockers of alpha - adrenergic receptors. • Chemically it is a Beta - haloalkylamine produce a long lasting, irreversible alpha adrenergic blockade. • Initial step involves the formation of an intermediate aziridinium ion which will form reversible complex with the receptor. The positively charge aziridinium ion electrophile then reacts with a nucleophilic group on the receptor resulting in the formation of covalent bond between the drug receptor • Metabolism: • It is metabolized (dealkylated) in the liver and excreted in bile and urine. • Therapeutic Uses: • used in treatment of hypertension. • Adverse Reaction: Side effects include nasal congestion, bronchaconstriction
• 6.
  Selective alpha blockers Prazosin •Prazosin is quinazoline alpha 1 - blocker. • Structurally prazosin consists of three components - the quinazolme ring the piperazine ring and acyl moieity • The 4- amino group on quinazolin ring is very important for a receptor affinity. • The piperazine moiety can be replaced with other heterocyclic moieties (eg piperidine moiety) without loss of affinity.
• 7.
  • Mechanism ofaction: It has potent alpha 1 - adrenoreceptor blocking activity. It is potent and effective antihypertensive agent and maybe usefully combined with the beta- blockers, and thiazide diuretics. • Metabolism: • Prazosin is extensively metabolised by the liver • Therapeutic Uses: Used in treatment of hypertension and heart attack. Also help to improve urination flow rate. • Adverse Reactions: • Side effects of prazosin are nasal congestion, dizziness, tiredness, nausea, drowsiness, blurred vision
• 8.
  Dihydroergotamine • Dihydroergotamine increasesthe alpha blocking potency • Metabolism of dihydroergotamine by a cytochrome P-450 • Dihydroergotamine used to treat migraine. • Adverse reaction: Nausea
• 9.
  Methysergide • Methysergide's mechanismof action (MOA) is to block serotonin's effects in the central nervous system (CNS) and gastrointestinal smooth muscle. This helps to prevent migraines and cluster headaches • Methysergide is metabolized into methylergometrine in
• 10.
  Beta adrenergic blockers:SAR of beta blockers • Most of the B-blockers are in the chemical class of aryloxypropanolamines. • The first B- blocker, dichloroisoproterenol was reported in 1958.
• 11.
  1. Dichloroisoproterenol differsfrom isoproterenol in that the agonist directing 3, 4-di OH groups have been replaced by two chloro groups but Dichloroisoproterenol is not a pure antagonist but partial agonist. 2. Propranolol is the standard against which all other B-blockers compared. It consists of OCH2 group which incorporated between the aromatic ring & the ethylamine side chain. 3. OCH2 group is responsible for the antagonistic property of the molecules. However it is not true because several compounds contain - OCH2 group are potent Beta-agonist.
• 12.
  5. One commonstructural feature of many cardioselective Beta-blocker is the presence of a para substitution of sufficient size on the aromatic ring along the absence of meta substituents e.g. Proctolol 6. For B-blockers, the B-OH substituted carbon must be in the S absolute configuration for maximal B-blocking activity. 7. The branched & bulky N-alkyl functional moieties such as ter-butyl, iso- propyl etc. proved to be extremely vital for B-antagonistic activity. 8. The alcoholic function on side chain is an absolute necessary requirement for its activity. 9. Isosteric replacement of the ethereal linkage (-O-) with moieties such as CH, S or NCH3 found to be more or less detrimental. 10. The amine nitrogen should always be a secondary in character with regards to the optimum activity.
• 13.
  Non Selective blockers Propranolol •It blocks the beta 1 & Beta 2 receptors with equal affinity • Propranolol is the most lipophilic drug among the available B-blockers. • It undergoes extensive first pass metabolism one of the major metabolite of propranolol is mephthoxylactic acid. It is formed by metabolic reactions involving N- dealkylation, deamination & oxidation • Therapeutic uses: • Propranolol approved for use in angina pectoris, past myocardial infarction, hypertension, cardiac, migraine prophylaxis • Adverse reactions: Sleep disturbance like insomnia