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03. adrenergic drugs
- 1. Anatomy of Sympathetic (thoracolumber)Nervous System Nerves arise from spinal cord Pre-ganglionic nerve fibers arise from thoraco- lumber region of sp.cord (T1-L2;containing cell bodies) terminate in sym. ganglia near spinal column (either sides) Post-ganglionic fibers arise form ganglia & reach to organs
- 2. Chemical Mediators (neurotransmitters) Preganglionicsympathetic nerve fibers secrete Acetylcholine Postganglionic sympathetic nerve fibers (except sweat glands) secrete Noradrenaline
- 3. AUTONOMIC & SOMATICMOTOR NERVES
- 4. Classification of Adrenoceptors ADRENOCEPTORS -adrenoceptors-adrenoceptors 1 2 1 2 3 1A 2A 1B 2B 1D 2C 1L Cont.
- 5. All subtypesof & belong to G-protein coupled receptor family 1- receptor activate PLC--IP3 & DAG as 2nd messenger 2-receptors inhibit adenylate cyclase CAMP formation All types of -receptors stimulate adenylate cyclase
- 6. Effects of Adrenoceptors a)1-receptor activation Vasoconstriction, relaxation of GI smooth muscle, salivary secretion stimulation & hepatic glycogenolysis b) 2-receptors activation Inhibition of transmitter release (including NA & ACh release for autonomic nerves), platelet aggregation, contraction of vascular smooth muscle, inhibition of insulin release
- 7. c) 1-receptors Increasedcardiac rate & force d) 2-receptors Bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis & muscle tremors e) 3 receptors lipolysis
- 8. Major effects mediatedby & adrenoceptors
- 9. Neurotransmission at adrenergic neurons Sixstages Synthesis Storage Release Binding to receptors Termination of action of norepinephrine Recycling of precursor
- 10. 1. Synthesis ofNorepinephrine Tyrosine (precursor) Transported (Na-linked carrier) into axoplasm of adrenergic neuron hydroxylation to DOPA dopamine
- 11. 2) Storage ofnorepinephrine in vesicles Dopamine transported & stored in vesicles to synaptic vesicle NE Ad medulla= NE (methylated to epinephrine) stored in chromaffin cells Ad medulla = release NE (20%) + EP (80%)
- 12. 3) Release ofNoradrnaline Arrival of action potential at nerve junction triggers opening of Ca2+ channels passage of Ca2+ from extracellular fluid to cytoplasm of neurons fusion of vesicles with cell memb. rupture of vesicles release of NE
- 13. 4) Binding to receptors NE release from synaptic vesicles Diffuse across synaptic space Binds to either post synaptic receptors on effector organ or to presynaptic receptors on nerve ending
- 14. 5) Removal ofnorepinephrine NE 1) diffuse out of synaptic space & enter general circulation --- OR 2) metabolized by COMT to O-methylated derivatives in synaptic space------OR 3) recaptured by uptake system that pumps back NE into neurons
- 15. 6) Potential fateof recaptured norepinephrine Once NE reenters cytoplasm of neurons May taken up into vesicles & be sequestered for release by another action potential It may persist in a pool It may be oxidized by MAO enzyme Inactive NE metabolites = excreted in urine as vanillylmandelic acid, metanephrine & normetanephrine
- 16. Synthesis & releaseof norepinephrine from adrenergic neuron
- 17. Classification of Adrenoceptor agonists 1)According to their chemical structure 2) By types of adrenoceptor stimulation 3) By direct or indirect action
- 18. 1.Based on chemicalstructure Two groups Catecholamines Noncatecholamines
- 19. A- Catecholamines Drugscontain catechol nucleus in their chemical structure Catechol nucleus= OH group at position 3 & 4 on benzene ring e.g., adrenaline (Ad), noradrenaline (NE), isoprenaline (ISOP) , dopamine (DA) , dobutamine (Dob)
- 20. Properties of Catecholamines 1.High potency Highest potency in activating α or β receptors 2. Rapid inactivation These catecholamines metabolized by COMT (postsynaptically) + MAO (intraneuronally) Also metabolized in liver, gut wall by MAO+COMT Given parenterally ; ineffective when given orally Cont.
- 21. 3. Poor penetrationinto CNS Catecholamines are polar = not readily penetrate into CNS Most have clinical effects attributable to CNS effects= anxiety, tremor & headache
- 22. B) Noncatecholamines Sympathomimeticsdo not contain catechol nucleus in their chemical structure e.g., amphetamine, ephedrine, phenylepohrine (Phe), methoxamine, salbutamol (Salb), terbutaline, fenoterol Poor substrates for MAO Prolonged duration of action Lipid solubility permits greater access to CNS
- 23. 2) Based oneffects of drugs on receptor types A. Both alpha & beta agonists e.g., Ad, NE, ephedrrine, amphetamine B. Mainly alpha agonists i) Mainly α1 agonists e.g., Phe, methoxamine ii) Mainly α2 agonists e.g., clonidine, methyldopa, guanabenz, guanfacine Cont.
- 24. c) Mainly Betaagonists i) Mainly β1 & β2 agonists e.g., ISOP ii) Mainly β1 agonists e.g., Dob, prenalterol iii) Mainly β2 agonists e.g., Salb, terbutaline, ritoderine, fenoterol iv) Dopamine agonists e.g., DA, bromocriptine, fenoldopam, ibopamine
- 25. 3. Based onmechanism of action of adrenergic agonists A. Direct acting agonists Act directly on α or β receptors producing effects similar to those that occur following stimulation of sympathetic nerves e.g., Ad, NE, ISOP, Phe, Salb
- 26. B. Indirect actingagonists Agents act indirectly Their actions dependent on release of endogenous catecholamine They have either of two d/f mechanisms: a) displacement of stored catecholamines from adrenergic nerve ending e.g. amphetamine & tyramine Cont.
- 27. b) Inhibition ofreuptake of catecholamines already released e.g., cocaine, & tricyclic antidepressants
- 28. C. Mixed actionagonists They have capacity to stimulate adrenoceptors directly + release NE from adrenergic neurons e.g., Ephedrine & pseudoephedrine
- 29. Site of actionof direct, indirect & mixed- acting adrenergic agonists
- 30. PHARMACOLOGICAL ACTIONS Adrenaline isthe prototype (α1, α2, β1, β2). CNS:- in clinically used dose→ no effects CVS:- a) Heart:- (β1) ↑HR + ↑force of contraction →↑CO +↑ O2 consumption Conduction velocity ↑ in conducting tissue b) B.V.:- (α1 in periphery) → vasoconstriction (β2 in deep) → vasodilation (Dale’s reversal)
- 31. PHARMACOLOGICAL ACTIONS (contd.) Resp. Sys:-(β2) Bronchodilation (α1) Decongestion of mucosa /submuc. G.I.T:- (α1+β2) << important clinically- Relaxn Eye:- (α1 on radial muscles) → Mydriasis. Skeletal Musc:- (β2) ↑Release of ACh→ Twitching & Tremors.
- 32. PHARMACOLOGICAL ACTIONS (contd.) Metabolic:- (β2) Glycogenolysis (α2)↓Release of Insulin→ Hyperglycemia Uterus :- (β2) Relaxation Spleen:- (α1) Contraction (not significant in humans) Urinary Bladder :- (β) Detrusor –Relaxation, (α) Trigone - Constrict
- 33. Effect on CNS Action of sympathomimetics on CNS vary dramatically depending on ability to cross BBB Catecholamines ---CNS effects at high doses (nervousness, tachycardia, tremor) Noncatecholamines with indirect actions (amphetamine) mild alerting with improved attention to boring tasks, elevation of mood, insomnia, euphoria, anorexia, fully blown psychotic behavior
- 34. THERAPEUTIC USES A) VascularUses i) Hypotensive states:- Anaphylaxis- Ad. Septic/ cardiogenic shock- DA, Dobutamine ii) With LA:- Small dose; vasoconstriction iii) In local bleeding:- Epistaxis Gastric bleeding (ulcer)– NA in cold saline iv) Nasal Decongestant- Pseudoephedrine v) Peripheral vascular disease- Isoxsuprine vi) Hypertension- Clonidine, α-Methyl Dopa.
- 35. THERAPEUTIC USES (contd.) B)Cardiac Uses i) AV Block- Adrenaline ii) Cardiac Arrest- Adrenaline C) Central Uses i) Hypno-Sedative Poisoning- Amphetamines ii) Narcolepsy (Sleep during fits)- Amphetamines iii) Obesity- Fenfluramine, Sibutramine iv) De-addiction- Clonidine (alcohol / opioids)
- 36. THERAPEUTIC USES (contd.) D)Respiratory- β2 agonists- Asthma E) Ophthalmic- Mydriatic- Phenylephrine Glaucoma- Apraclonidine/ Brimonidine F) Uterine- Isoxsuprine, Ritodrine Abortions – Threatened & Habitual