Drugs acting on Autonomic Nervous System / Sympathomimetic drugs (Adrenergic Agonist) / Sympatholytic drugs (Adrenergic Antagonist)
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Drugs acting on Autonomic Nervous System, Sympathomimetic drugs (Adrenergic Agonist) Sympatholytic drugs (Adrenergic Antagonist) Alpha Blockers Beta Blockers B. PHARM SEMESTER IV (2nd Year 2nd Sem.)
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Drugs acting on Autonomic Nervous System / Sympathomimetic drugs (Adrenergic Agonist) / Sympatholytic drugs (Adrenergic Antagonist)
- 1. Drugs acting on Autonomic Nervous System copy right @ www.pharmawisdom.co.in Sympathomimetic drugs (Adrenergic Agonist) Sympatholytic drugs (Adrenergic Antagonist) Alpha Blockers Beta Blockers B. PHARM SEMESTER IV (2nd Year 2nd Sem.) S.SEETARAM SWAMY, M.Pharm., Assoc. professor, Dept. of Pharmaceutical Chemistry, E-mail: seetaram.443@gmail.com
- 2. The nervous system is a complex network of nerves and cells that carry messages to and from the brain and spinal cord to various parts of the body. The Central nervous system is made up of the brain and spinal cord and The Peripheral nervous system is made up of the Somatic and the Autonomic nervous systems. copy right @ www.pharmawisdom.co.in
- 3. Adrenergic Neurotransmitters: Naturally occur in our body Both Agents that activate adrenergic receptors are called Sympathomimetics The agents that block the activation of adrenergic receptors are called Sympatholytics Adrenergic Neurotransmitters are 3 types Collectively called catecholamines 1. Noradrenaline (NA) - at postganglionic sympathetic sites(except sweat glands, hair follicles) & in certain areas of brain. 2. Adrenaline(Adr) - secreted by adrenal medulla 3. Dopamine(DA)- transmitter in basal ganglia, limbic system, CTZ, anterior pituitary. copy right @ www.pharmawisdom.co.in
- 4. Steps in the synthesis of Catecholamines (CAs) - Synthesis of CAs - Storage of CAs - Release of CAs - Uptake of CAs - Metabolism of CAs copy right @ www.pharmawisdom.co.in
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- 6. Biosynthesis of Catecholamine copy right @ www.pharmawisdom.co.in
- 7. Metabolism of neurotransmitter: • Endogenous & exogenous catecholamines are metabolised mainly by two enzymes, monoamine oxidase & catechol-O-methyl transferase (COMT). • MAO occurs within cells bound to surface membrane of mitochondria, abundant in noradrenergic nerve terminals. • COMT a widespread enzyme that occurs in both neuronal and nonneuronal tissues, acts on both catecholamines & its deaminated products, produced by action of MAO. • Main final metabolite of adrenaline & noradrenaline is 3-methoxy- 4-hydroxymandelic acid (VMA). copy right @ www.pharmawisdom.co.in
- 8. Catabolism of Catecholamine copy right @ www.pharmawisdom.co.in
- 9. All belong to super family of G-protein-coupled receptors. Adrenergic receptors are classified into two types copy right @ www.pharmawisdom.co.in
- 10. Adrenergic drugs are medications that stimulate certain nerves in your body. They do this either by mimicking the action of the chemical messengers epinephrine and norepinephrine or by stimulating their release. These drugs are used in many life-threatening conditions, including cardiac arrest, shock, asthma attack, or allergic reaction. Sympathomimetic agents that partially or completely mimic the actions of norepinephrine (NE) or Epinephrine (Epi). They are also called as Sympathomimetic drugs / Adrenomimetic Drugs / Adrenergic Agonist / Adrenoreceptor Agonists Sympathomimetic drugs / Adrenergic Agonist copy right @ www.pharmawisdom.co.in
- 11. Classification of Sympathomimetic Drugs They could be classified on two different basis 1) Chemical Classification 2) Based on the mechanism of Action 1. Chemical Classification: They are chemically classified into two main categories A) Catecholamines B) Non-catecholamines A) Catecholamines: They contain catechol (3, 4-dihydroxy benzene ring) nucleus. Exp: Nor-epinephrine, Epinephrine, Dopamine, Dobutamine, Isoproterenol copy right @ www.pharmawisdom.co.in
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- 13. B) Non-catecholamines: They do not contain catechol nucleus and have prolonged duration of action, because they are not inactivated by COMT. Exp: Ephedrine, Phenylephrine, Terbutaline, Oxymetazoline, Pseudoephedrine, Clonidine, Amphetamine copy right @ www.pharmawisdom.co.in
- 14. 2. Based on the mechanism of Action Sympathomimetic Drugs Direct acting: Nor-epinephrine Epinephrine Phenylephrine Dopamine Methyldopa Clonidine Naphazoline Oxymetazoline Xylometazoline Dobutamine Isoproterenol Terbutaline Salbutamol Bitolterol Indirect acting agents: Hydroxyamphetamine Pseudoephedrine Propylhexedrine Mixed Agents: Ephedrine Metaraminol Direct Acting agents: Directly act as agonist on α & β or both. Indirect acting agents: Acts on adrenergic neuron to release N.A Mixed Agents: They act directly or indirectly. copy right @ www.pharmawisdom.co.in
- 15. SAR of Adrenergic Agonists / β-phenylethylamines / Sympathomimetic Agents/ Arylethanolamines 1. Structure required for Activity a) Phenyl Ethylamine as parent compound b) Catechol or Aromatic Ring c) β-carbon hydroxy & amino terminal copy right @ www.pharmawisdom.co.in
- 16. SAR of Sympathomimetic agents was studied by 3 different substituents 1. Phenyl Ring Substitution 2. Substitution at carbon in side chain 3. Substitution at nitrogen 1. Phenyl ring substitution 3-hydroxy substitution is required for α - activity 4-hydroxy substitution is required for β – activity 3, 4 –dihydroxy substitution is required for both α & β - activity Replacement of catechol by resorcinol increases β2 selectivity and also decreases metabolism by COMT and produce longer duration of action. Exp:- Terbutaline copy right @ www.pharmawisdom.co.in
- 17. Replacement of meta hydroxyl of catechol increases β2 selectivity and decreases metabolism by COMT. Exp:- Salbutamol Removal of para hydroxyl group from epinephrine produce selective α1 agonist. Exp: - Phenylephrine copy right @ www.pharmawisdom.co.in
- 18. 2. Substitution at carbon in side chain Small alkyl group (methyl or ethyl) present at α carbon decreases the metabolism by MAO (Mono amine oxidase ) Ethyl group present at α carbon decreases the activity. OH (hydroxyl) group substitution on the β carbon is essential for activity. copy right @ www.pharmawisdom.co.in
- 19. 3. Substitution at nitrogen The nature of amino substituent determines α / β receptor selectivity. As the size of alkyl group on nitrogen increases, activity at α-receptor decreases and activity at β -receptor increases. Exp:- Isoproterenol Primary & secondary amines have good adrenergic activity copy right @ www.pharmawisdom.co.in
- 20. SAR of Non-catecholamines: 1. Bridging Unit (X) : Usually a single methylene group / amino group is essential for agonist activity Exp: - X = CH2 (α1 agonist) – Clonidine = NH (α2 agonist ) – Oxymetazoline 2. Imidazoline rings are highly active α- agonist activity 3. Aromatic ring: Agonist activity is enhanced when the aromatic ring is substituted with halogen or small alkyl groups (methyl). copy right @ www.pharmawisdom.co.in
- 21. Synthesis of Phenylephrine - Selective α1-Agonist - Phenylephrine increases BP by the vasoconstrictor Action - Locally it is used as Nasal Decongestant copy right @ www.pharmawisdom.co.in
- 22. Synthesis of Salbutamol - Selective β2-agonist - It is used as a bronchodilator and is the drug of choice in the treatment of Bronchial Asthma copy right @ www.pharmawisdom.co.in
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- 24. Therapeutic Uses of Sympathomimetic Agents A – Anaphylactic Shock – Exp: Epinephrine B – Bronchial Asthma – Exp: Salbutamol, Terbutaline, Isoprenaline, Epinephrine C – Cardiogenic shock – Exp: Dobutamine / Cardiac Arrest - Exp: Epinephrine D – Delay of Parturition – Exp: Terbutaline, Ritodrine / Delay absorption of Local Anesthetics – Exp: Adrenaline H – Hypertension – Exp: Clonidine M – Migraine – Exp: Clonidine N – Used as CNS stimulant in Narcolepsy – Exp: Amphetamine N – Nasal Decongestion – Exp: Ephedrine, Phenylephrine, Methoxamine P – Premature labor – Exp: Salbutamol copy right @ www.pharmawisdom.co.in
- 25. Sympatholytic drugs / Adrenergic Antagonist Alpha & Beta Antagonists are prevent the interaction of endogenous neurotransmitter NE or Sympathomimetics with corresponding adrenergic receptors. Bind specifically to alpha receptors and interfere with catecholamine and Sympathomimetic action. Role of Alpha-1 & Alpha-2 Antagonists Alpha-1: -Vasoconstriction - Increased peripheral resistance - Increased blood pressure Alpha-2: -Inhibition of Norepinephrine release - Inhibition of insulin release Alpha adrenergic blockers / Alpha Antagonists The agents which antagonise the action of Sympathomimetic agents or sympathetic stimulations are called Sympatholytic agents. copy right @ www.pharmawisdom.co.in
- 26. Alpha Blockers Non-Selective Irreversible Phenoxybenzamine Reversible Phentolamine Tolazoline Selective Alpha 1 Blocker Prazosin Terazosin Doxazosin Alfuzosin Alpha 2 Blocker Yohimbine Miscellaneous Miscellaneous Ergot Alkaloids Dihydroergotamine Methysergide copy right @ www.pharmawisdom.co.in
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- 28. It is a imidazoline Derivative Non-selective α-adrenergic blocker It is used in the treatment of Reynaud's Disease, Cerebral Vascular Accidents. Synthesis of Tolazoline copy right @ www.pharmawisdom.co.in
- 29. • Hypertension - alpha-1 selective • Pheochromocytoma (Conditions associated with increased sympathetic activity) • Hemodynamic shock • Peripheral vascular disease – Raynaud’s • Congestive heart failure (CHF) • Benign prostatic hyperplasia (BPH) • Pulmonary hypertension – tolazoline Therapeutic Uses of Alpha-Adrenergic Blockers copy right @ www.pharmawisdom.co.in
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- 31. Bind selectively to beta receptors Interfere with ability of catecholamines or Sympathomimetics to provoke beta receptors (heart, smooth muscle of airway and blood vessel). Propranolol is standard beta antagonist drug to which all beta antagonists are compared. Role of Beta-1 & Beta-2 Antagonists Beta-1: -Tachycardia - Increased lipolysis - Increased myocardial contractility Beta-2: - Vasodilation - Bronchodilation - Increased release of glucagon Beta adrenergic blockers / Beta Antagonists copy right @ www.pharmawisdom.co.in
- 32. Classification of Beta Blockers copy right @ www.pharmawisdom.co.in
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- 34. Synthesis of Propranolol - Non-selective β-blocker - It is used in hypertension, Arrhythmiasis, Angina Pectoris, Coronary artery disease & open angle glucoma. copy right @ www.pharmawisdom.co.in
- 35. SAR of Beta Blockers / Adrenergic Antagonists / Sympatholytic Agents/ Aryloxy Propanolamines 1. - OCH2 group is placed between the aromatic ring and ethanolamino side chain, which is essential for the activity. 2. The hydroxyl bearing carbon of the aryloxy prpanolamine side chain play critical role in the interaction of β-antagonist drugs with β-receptor. copy right @ www.pharmawisdom.co.in
- 36. 3. Alkyl Amino group is must be a secondary amine for optimal activity. 4. Isopropyl and t-butyl groups present on the amino group provides nucleophilicity to the amino group. E.g: Atenolol 5. The two carbon chains are essential for activity. 6. N, N-disubstitution decreases the beta blocking activity. 7. The aromatic ring and it substituent is the primary determinant of β1 antagonist activity. 8. Alkenyl groups present in the ortho position on aryl ring gives good beta antagonist activity. E.g: Oxprenolol, Alprenolol 9. Most of the derivatives have different aryl group like Phenyl, Naphthalene & Indole. E.g: Atenolol, Propranolol & Pindolol copy right @ www.pharmawisdom.co.in
- 37. copy right @ www.pharmawisdom.co.in Therapeutic Uses of Beta-Adrenergic Blockers
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