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ADRENERGIC RECEPTORS AND 
MODULATORS 
Dr Imran Zaheer 
JNMCH, AMU 
Aligarh
INTRODUCTION
Sympathetic System 
 Preganglionic fibers originate 
from 
• Thoracic (T1-T12) 
segments of the cord 
• Lumbar (L1-L3) 
s...
NEUROTRANSMITTERS 
• 3 types Collectively called catecholamines 
1. Noradrenaline(NA)at postganglionic sympathetic sites...
occurs in 
adrenergic 
neuronal 
cytoplasm 
occurs inside 
granules 
occurs in 
adrenal 
medulla
STORAGE OF TRANSMITTER 
• Stored in synaptic vesicles or granules within adrenergic nerve 
terminal. 
• Vesicular membrane...
RELEASE OF TRANSMITTER 
• Depolarisation of nerve terminal 
membrane opens calcium 
channels in nerve terminal 
membrane &...
REGULATION OF TRANSMITTER RELEASE 
• Release of cotransmitters can be 
modulated by prejunctional 
autoreceptors and 
hete...
UPTAKE OF NEUROTRANSMITTER 
Transport of 
noradrenaline 
Uptake 1 
(Norepinephrine 
Transporter) 
Uptake 2 
(Extraneuronal...
Metabolism of neurotransmitter 
• Endogenous & exogenous catecholamines are metabolised mainly 
by two enzymes, monoamine ...
DEAMINATION DEAMINATION 
ALDEHYDE 
DEHYROGENASE 
ALDEHYDE 
REDUCTASE 
3,4-DIHYDROXYPHENYL GLYCOL 3,4-DIHYDROXYMANDELIC ACI...
ADRENERGIC RECEPTORS 
• All belong to superfamily of G-protein-coupled receptors
α1 α2 β1 β2 β3 
Second 
messengers 
and effectors 
PLC activation ↓cAMP ↑cAMP ↑cAMP ↑cAMP 
↑ IP3 
↑DAG 
↑Ca2+ 
Selective 
...
Effects of receptor activation 
Tissues and 
effects α1 α2 β1 β2 β3 
Blood vessels Constrict Constrict Dilate 
Bronchi Con...
α1 α2 Β1 Β2 β3 
Bladder 
sphincter 
Contract 
Seminal tract Contract Relax 
Iris (radial 
muscle) 
Contract 
Ciliary 
musc...
α1 α2 β1 β2 β3 
Liver Glycogenolysis Glycogenolysis 
Fat Lipolysis 
Thermogenesis 
Pancreatic 
islets 
Decrease 
insulin 
...
α1 α2 β1 β2 β3 
Nerve 
Terminal: 
Adrenergic Decrease 
release 
Increase 
release 
Cholinergic Decrease 
release 
Salivary...
Receptor Regulation 
• Responses mediated by adrenoceptors are not constantly same. 
• Three processes have considerable c...
DRUGS THAT AFFECT ADRENERGIC RECEPTOR
DRUGS THAT AFFECT ADRENERGIC NEURONS
Therapeutic Classification of Adrenergic Drugs 
• Pressure agents 
Noradrenaline Ephedrin Dopamine Phenylephrine Methoxami...
Clinical uses of adrenoceptor agonists 
• Cardiovascular system 
– cardiac arrest: adrenaline 
– cardiogenic shock: dobuta...
• Miscellaneous indications 
– adrenaline can be used to prolong local anaesthetic action 
– miscellaneous indication for ...
TOXICITY OF ADRENERGIC DRUGS 
• Restlessness, palpitation, anxiety, tremor, may occur after s.c. /i.m. 
injection of Adr. ...
ADRENERGIC ANTAGONISTS 
• These are drugs which antagonize the receptor action of adrenaline 
and related drugs. 
• They a...
α ADRENERGIC BLOCKING DRUGS 
I. Nonequilibrium type 
 B-Haloalkylamines - Phenoxybenzamine. 
ll. Equilibrium type 
A. Non...
Pharmacological properties 
 Cardiovascular effect 
• Blockade of α receptors → vasodilatation → decrease in peripheral 
...
• Nasal stuffiness due to blocked of α receptor in nasal blood vessels. 
• Miosis due to loss of tone of radial muscles of...
β ADRENERGIC BLOCKING DRUGS 
Nonselective (β1 and β2 ) 
a. Without intrinsic sympathomimetic activity 
Propranolol, Sotalo...
Classifying B blockers into 3 generations
Pharmacological properties 
Cardiovascular system 
• ↓ heart rate, ↓ myocardial contractility, ↓ conduction velocity,↓ 
my...
Pulmonary system 
– Least affect on bronchial muscle of normal individuals. 
– In asthmatic or COPD pts→ severe bronchocon...
CNS effects 
– ↓ decrease in central sympathetic outflow 
– Chronic use leads to sedation, lethargy and disturbances in 
s...
Therapeutic uses 
Cardiovascular use 
– Hypertension 
– Congestive heart failure 
– Angina pectoris : C/I in prinzmetals a...
Non cardiovascular use : 
– Migraine prophylaxis 
– Anxiety provoking situations 
– Glaucoma 
– Hyperthyroidism 
– Pheochr...
Adverse effects 
– Bronchoconstriction 
– Bradycardia 
– Cold extremities 
– CNS side effects: fatigue ,sleep disturbance ...
THANK YOU
REGULATION OF TRANSMITTER RELEASE 
• The release of cotransmitters can 
be modulated by prejunctional 
autoreceptors and 
...
DRUGS THAT AFFECT ADRENERGIC NEURONS
Adrenergic receptors and its modulators
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Adrenergic receptors and its modulators

  1. 1. ADRENERGIC RECEPTORS AND MODULATORS Dr Imran Zaheer JNMCH, AMU Aligarh
  2. 2. INTRODUCTION
  3. 3. Sympathetic System  Preganglionic fibers originate from • Thoracic (T1-T12) segments of the cord • Lumbar (L1-L3) segments of the cord  Most of the ganglia are located in paravertebral chains that lie along the spinal cord  Few (prevertebral) on the anterior aspect of the aorta  Preganglionic fibers are short and the postganglionic fibers are long
  4. 4. NEUROTRANSMITTERS • 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.
  5. 5. occurs in adrenergic neuronal cytoplasm occurs inside granules occurs in adrenal medulla
  6. 6. STORAGE OF TRANSMITTER • Stored in synaptic vesicles or granules within adrenergic nerve terminal. • Vesicular membrane actively takes DA from cytoplasm & synthesize NA inside vesicle with help of DA β-hydroxylase. • NA stored in a complex with ATP(4:1) adsorbed on protein chromogranin A. • In adrenal medulla, NA thus formed is diffuses into cytoplasm where it is methylated to Adr. • Adr so formed is stored in separate granule  Chromaffin granule.
  7. 7. RELEASE OF TRANSMITTER • Depolarisation of nerve terminal membrane opens calcium channels in nerve terminal membrane & resulting entry of Ca2+ promoting fusion and discharge of synaptic vesicles
  8. 8. REGULATION OF TRANSMITTER RELEASE • Release of cotransmitters can be modulated by prejunctional autoreceptors and heteroreceptors. • Following their release from sympathetic terminals, all three cotransmitter norepinephrine, neuropeptide Y (NPY), and ATP can feedback on prejunctional receptors to inhibit the release of each other. • Enhancement of sympathetic neurotransmitter release can be produced by activation of b2 adrenergic receptors
  9. 9. UPTAKE OF NEUROTRANSMITTER Transport of noradrenaline Uptake 1 (Norepinephrine Transporter) Uptake 2 (Extraneuronal amine Transporter) Vasicular Transporter (VMAT- 2) Specificity NA > A A > NA NA = A Location Neuronal membrane Non-neuronal cell membrane (smooth muscle, cardiac muscle, endothelium) Synaptic vesicle membrane Other substrates Tyramine guanethidine (+)-Noradrenaline Histamine Dopamine 5-HT Inhibitors Cocaine Tricyclic Antidepressants (e.g. desipramine Steroid hormones (e.g. corticosterone) Phenoxybenzamine Reserpine
  10. 10. 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 non-neuronal 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).
  11. 11. DEAMINATION DEAMINATION ALDEHYDE DEHYROGENASE ALDEHYDE REDUCTASE 3,4-DIHYDROXYPHENYL GLYCOL 3,4-DIHYDROXYMANDELIC ACID 3-METHYL,4-HYDROXYPHENYLGLYCOL ALCOHOL DEHYROGENASE ALDEHYDE DEHYROGENASE VANILLYL MANDELIC ACID
  12. 12. ADRENERGIC RECEPTORS • All belong to superfamily of G-protein-coupled receptors
  13. 13. α1 α2 β1 β2 β3 Second messengers and effectors PLC activation ↓cAMP ↑cAMP ↑cAMP ↑cAMP ↑ IP3 ↑DAG ↑Ca2+ Selective agonists Phenylephrine, methoxamine Clonidine, clenbuterol Dobutamine, xamoterol Salbutamol, terbutaline, salmeterol, formoterol BRL 37344 Selective antagonists Prazosin, doxazocin Yohimbine, idazoxan Atenolol, metoprolol Butoxamine
  14. 14. Effects of receptor activation Tissues and effects α1 α2 β1 β2 β3 Blood vessels Constrict Constrict Dilate Bronchi Constrict Dilate GI tract Relax Relax (presynaptic effect) Relax GI sphincters Contract Uterus Contract Relax Bladder Relax detrusor
  15. 15. α1 α2 Β1 Β2 β3 Bladder sphincter Contract Seminal tract Contract Relax Iris (radial muscle) Contract Ciliary muscle Relax Heart: Rate Increase Force of Increase contraction
  16. 16. α1 α2 β1 β2 β3 Liver Glycogenolysis Glycogenolysis Fat Lipolysis Thermogenesis Pancreatic islets Decrease insulin secretion
  17. 17. α1 α2 β1 β2 β3 Nerve Terminal: Adrenergic Decrease release Increase release Cholinergic Decrease release Salivary gland K+ release and watery secretion Amylase secretion Mast cells Inhibition of histamine release
  18. 18. Receptor Regulation • Responses mediated by adrenoceptors are not constantly same. • Three processes have considerable clinical significances. 1. Desensitisation 2. Up – Down regulation 3. supersensitivity
  19. 19. DRUGS THAT AFFECT ADRENERGIC RECEPTOR
  20. 20. DRUGS THAT AFFECT ADRENERGIC NEURONS
  21. 21. Therapeutic Classification of Adrenergic Drugs • Pressure agents Noradrenaline Ephedrin Dopamine Phenylephrine Methoxamine • Cardiac stimulants Adrenalin Dobutamine Isoprenaline • Bronchodilators Isoprenal Salbutamol Salmeterol Formoterol • Nasal Decongestants Phenylephrine Xylometazoline Oxymetazoline Naphazoline • CNS Stimulants Amphetamine Methamphetamine Dexamphetamine • Anorectics Fenfluramine Sibutramine Dexfluramine • Uterine relanxant & vasodilators Ritodrine Isoxsuprine Salbutamol Terbutaline
  22. 22. Clinical uses of adrenoceptor agonists • Cardiovascular system – cardiac arrest: adrenaline – cardiogenic shock: dobutamine (β1-agonist) – heart block: β-agonists (e.g. isoprenaline) can be used temporarily while electrical pacing is being arrange • Anaphylactic shock (acute hypersensitivity) – adrenaline is the first-line treatment along with steroids & antihistaminics • Respiratory system – Asthma : selective β2-receptor agonists (salbutamol, terbutaline, salmeterol, formoterol) – nasal decongestion: drops containing oxymetazoline or ephedrine for short-term use
  23. 23. • Miscellaneous indications – adrenaline can be used to prolong local anaesthetic action – miscellaneous indication for α2-agonists (e.g. clonidine) include hypertension , menopausal flushing, lowering intraocular pressure & migraine prophylaxis – Obesity – CNS uses • Hyperkinetic children • Narcolepsy
  24. 24. TOXICITY OF ADRENERGIC DRUGS • Restlessness, palpitation, anxiety, tremor, may occur after s.c. /i.m. injection of Adr. • Marked rise in BP leading to cerebral haemorrhage. • Ventricular tachycardia/fibrillation, angina, myocardial infarction are the hazards of large doses of Adr. • CNS toxicity is rarely observed with adr. drugs – In moderate doses, amphetamines commonly cause restlessness, tremor, insomnia, & anxiety; in high doses, a paranoid state may be induced.
  25. 25. ADRENERGIC ANTAGONISTS • These are drugs which antagonize the receptor action of adrenaline and related drugs. • They are competitive antagonists at α or β or both α and β. 1. α ADRENERGIC BLOCKING DRUGS 2. β ADRENERGIC BLOCKING DRUGS
  26. 26. α ADRENERGIC BLOCKING DRUGS I. Nonequilibrium type  B-Haloalkylamines - Phenoxybenzamine. ll. Equilibrium type A. Nonselective (i) Ergot alkaloids-Ergotamine, Ergotoxine (ii) Hydrogenated ergot alkalolds-Dihydroergotamine(DHE), Dihydroergotoxine (iii) Imidazolines-- Phentolamine (iv) Miscellaneous - Chlorpromazine B. α1 selective- Prazosin, Terazosin, Doxazosin, Tamsulosin C. α2 selective- Yohimbine
  27. 27. Pharmacological properties  Cardiovascular effect • Blockade of α receptors → vasodilatation → decrease in peripheral vascular resistance → fall in BP → Hypotension. • Resultant fall in BP → baroreceptor reflex → sympathetic discharge since α receptors are blocked, stimulates β1 receptor in heart → tachycardia • α receptors blocked → absence of efficient peripheral vasoconstriction in erect posture → peripheral pooling of blood → cerebral hypoxia , vertigo and fainting → postural hypotension
  28. 28. • Nasal stuffiness due to blocked of α receptor in nasal blood vessels. • Miosis due to loss of tone of radial muscles of iris. • Tone of smooth muscle in bladder trigone, sphincter and prostate is reduced by blockade of α1 receptor → urine flow in patients with benign hypertrophy of prostate (BHP) is improved. • Inhibition of contractions of vas deferens and ejaculatory duct → failure of ejaculation → impotence • Intestinal motility is increased due to partial inhibition of relaxant sympathetic influences → diarrhoea
  29. 29. β ADRENERGIC BLOCKING DRUGS Nonselective (β1 and β2 ) a. Without intrinsic sympathomimetic activity Propranolol, Sotalol, Timolol. b. With intrinsic sympathomimetic activity Pindolol c. With additional α blocking property Labetalol, Carvedilol Cardioselective (β1) Metoprolol, Atenolol, Acebutolol, Bisoprolol Esmolol, Betaxolol, Celiprolol, Nebivolol
  30. 30. Classifying B blockers into 3 generations
  31. 31. Pharmacological properties Cardiovascular system • ↓ heart rate, ↓ myocardial contractility, ↓ conduction velocity,↓ myocardial oxygen demand Though β1 receptor blockade is the main mechanism responsible for antihypertensive effect : - ↓ renin release - ↓ decrease in central sympathetic outflow - Chronic ↓ in c.o - Blockade of facilitatory effect of presynaptic β2 receptor on NE release.
  32. 32. Pulmonary system – Least affect on bronchial muscle of normal individuals. – In asthmatic or COPD pts→ severe bronchoconstriction. Metabolic effects – Inhibits stress or adrenaline induced glycogenolysis in type 1 DM to overcome episodes of hypoglycaemia. – Masks the sympathetic manifestation (tremor, tachycardia, sweating) of hypoglycemia. – Adverse effect on lipid profile : ↓ HDL,↑ LDL & Triglycerides.
  33. 33. CNS effects – ↓ decrease in central sympathetic outflow – Chronic use leads to sedation, lethargy and disturbances in sleep. Ocular effects – decreases formation of aqueous humour  ↓ intraocular pressure
  34. 34. Therapeutic uses Cardiovascular use – Hypertension – Congestive heart failure – Angina pectoris : C/I in prinzmetals angina. – Cardiac arrythmias. – Myocardial infarction: ↓ incidence ,recurrence and mortality after long term use
  35. 35. Non cardiovascular use : – Migraine prophylaxis – Anxiety provoking situations – Glaucoma – Hyperthyroidism – Pheochromocytoma – Bleeding oesophageal varices associated with portal hypertension
  36. 36. Adverse effects – Bronchoconstriction – Bradycardia – Cold extremities – CNS side effects: fatigue ,sleep disturbance and depression – Heart failure – Hypoglycemia – Adverse serum lipid profile
  37. 37. THANK YOU
  38. 38. REGULATION OF TRANSMITTER RELEASE • The release of cotransmitters can be modulated by prejunctional autoreceptors and heteroreceptors. • Following their release from sympathetic terminals, all three cotransmitter norepinephrine, neuropeptide Y (NPY), and ATP can feedback on prejunctional receptors to inhibit the release of each other. • Enhancement of sympathetic neurotransmitter release can be produced by activation of b2 adrenergic receptors
  39. 39. DRUGS THAT AFFECT ADRENERGIC NEURONS
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ADRENERGIC RECEPTORS AND MODULATORS

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