Adrenergic drugs
- 1. Adrenergic Drugs PREPARED BY ; ZARNA PATHAK M.PHARM SEM - 1
- 2. List of contents Introduction Biosynthesis of Catecholamines Classification Response of effector organs Individual drugs List of abbreviations References
- 4. Introduction • Major NT involved in the SNS are ; • Norepinephrine • Epinephrine (hormone secreted by adrenal medulla) • Dopamine • SNS is mainly involved in the fight or flight response. • Mainly 3 types of adrenergic receptors are identified till now . i.e. • Alpha receptors • Beta receptors • Dopamine receptors
- 6. Classification Receptor Location G-protein 2nd messeng er Function α1 Vascular smooth muscle, salivary gland, Bronchi, Uterus, radial muscle of iris, urinary bladder, Liver cells, Intestine Gq Increas e IP3, DAG Increase Ca conc.of smooth muscle, increase secretions α2 Presynaptic on adrenergic and cholinergic nerve terminals, post synaptic in brain, B-pancreatic cells Gi Decrea se cAMP Decrease NE release, central sym.out flow, insulin release,V.C.
- 7. Response of effector organs
- 8. Drugs Sympathomimetic Drugs ; this drugs mimic the actions of endogenous catecholamines. these are categorized into 3 groups i.e. Directly acting Indirectly acting Mixed action
- 9. M/A of Directly acting drugs
- 10. M/A of indirectly acting drugs
- 11. Directly acting sympathomimetics Catecholamines Non catecholamines Endogenous synthetic Alpha 1 selective Phenylephrine Methoxamine Naphazoline Oxymetazoline Xylometazoline Midodrine Epinephrine Norepinephrine Dopamine Isoprenaline Dipivefrine Dobutamine Dopexamine Fenoldopam Alpha 2 selective Clonidine Apraclonidine Alpha -methyldopa
- 12. Indirectly acting sympathomimetics Releasing agents : Amphetamine Tyramine Uptake inhibitors Cocaine MAO inhibitors Selegilline Rasagilline COMT inhibitors Entacapone Tolcapone
- 13. Mixed acting sympathomimetics Ephedrine Mephentermine
- 14. Endogenous catecholamines Epinephrine : 1. Cardiovascular effects: Very potent vasoconstrictor and cardiac stimulant On Heart IncreaseHR, FC, CO, conductionvelocity,speed of relaxation,increaseO2 consumption,and Excitabilityandhighincidenceof arrhythmia On blood vessels Constriction of artery in skin, mucous membrane, Splanchnic BV, dilation of coronaries, contraction of veins and splanchnic capsule On BP Increase systolic BP, decrease diastolic (dilation of skeletal muscle BV), Rise in mean BP
- 15. 2. On Smooth muscles : Bronchial smoothmuscles Bronchodilatation, decreasebronchialsecretions, andD'sbronchialresistance GIT Gut relaxation, constriction of sphincters Urinary Tract Contraction of Trigone and sphincters, hindered micturition uterus • Non pregnant uterus : Contraction • Pregnant Uterus : Relaxation
- 16. 3. Metabolic Effects Hyperglycemia (glycogenolysis in liver and skeletal muscles) I’es free fatty acids due to lipolysis in adipose tissue Inhibition of insulin release Calorigenic effects 4. Miscellaneous effects Thick salivary secretions Active mydriasis Anxiety and tremors Piloerection and sweating of palms and soles
- 17. Therapeutic uses Allergy (Anaphylactic shock) Bronchial asthma Cardiac resuscitation To prolong the duration of local anesthetic action To control epistaxis Adams-stokes syndrome S/E Cerebral haemoerrhage Coronary insufficiency may leads to angina, palpitation, arrhythmias CNS S/E : tremors, anxiety, headache
- 18. Contraindications Hyperthyroidism Angina and Hypertension MAOIs Halothane group of general anaesthetics ( I’es sensitivity of myocardium towards catecholamines)
- 19. Nor epinephrine (levarterenol) It is chemical mediator liberated from postganglionic sympathetic nerve endings, adrenal medulla. Receptor affinity : α1=α2>β1>>β2 Cardiovascular actions ; • It I’es systolic as well as diastolic BP due to cardiac stimulation (β1) and I’es PVR(α1). CO is unchanged. • It causes greater vasoconstriction than does epinephrine, because it doesn’t include compensatory vasodilation. • Reflex bradycardia (due to compensatory I’es in vagal discharge) • If atropine is given prior to NE, hypertension is followed with tachycardia. • It doesn’t exhibit Dale’s vasomotor reversal.
- 20. Therapeutic Actions Cardiogenic shock as it I’es vascular resistance and decrease blood flow to vital organs (but dopamine is more preferred because it doesn’t reduce blood flow to kidney) Adverse effects Same as epinephrine Infusion should be tapped off to avoid sudden fall in BP Tissue necrosis at the site of injection
- 21. Dopamine It is an endogenous catecholamine which is immediate precursor of E and NE It occurs naturally in the CNS in the basal ganglia. Cardiovascular effects At lower doses it mainly acts on renal, mesenteric and coronary beds.it leads to smooth muscle vasodilation.(via Gs- adenylyl cyclase-cAMP pathway) At higher doses it acts on β1 receptors to produce a positive inotropic effect.it also causes release of NE from nerve terminals. which contributes its effect on heart. It I’es systolic BP and pulse pressure. At high conc. It activates vascular α1 receptors, leading to more general vasoconstriction.
- 22. Effects on CNS It has generally no effects on CNS, because it generally doesn’t cross BBB. Therapeutic uses Treatment of severe CHF particularly in patients with oliguria and low peripheral vascular resistance In cardiogenic and septic shock It improves renal and cardiac functions in severe cases of chronic heart disease or renal failure.
- 23. Side effects Nausea, vomiting Tachycardia, ectopic beats Gangrene of fingers and toes (on prolonged infusion) Contraindications It should be avoided if patient is on treatment of MAOIs
- 24. Synthetic catecholamines Isoprenaline (Isoproterenol) It predominantly stimulates β1 and β2 receptors. Receptor affinity order : β1=β2>>β3>>>>α Cardiovascular effects Positive inotropic and chronotropic effect. So it I’es cardiac output It slightly I’es systolic BP, but mean arterial and diastolic BP are greatly reduced. Dilates arterioles of skeletal muscles. So it D’es peripheral resistance.
- 25. Effect on smooth muscles It relaxes bronchial and GIT smooth muscles. It relieves bronchoconstriction (β2 effect and due to inhibition of antigen induced histamine release) Pharmacokinetics It is metabolized by COMT present in liver and other tissue. Therapeutic uses In emergency situations to stimulate HR in patients with bradycardia or heart block particularly in anticipation of inserting an artificial cardiac pacemaker In ventricular arrhythmias In asthma and shock
- 26. Side effects Palpitations Sinus tachycardia Serious arrhythmias Cardiac ischemia Marketed formulations Isolin Isoprin Neo-epinine isosol
- 27. Dipivefrine It is prodrug of E with enhanced corneal permeability. USES ; Treatment of glaucoma S/E ; Photosensitivity Conjunctival hyperaemia Marketed formulations PROPINE(1% eye drops)
- 28. Dobutamine It is used clinically as a racemic mixture of two enantiomeric forms The l- form is a potent agonist for α1 receptor and the d- form is a potent α1 antagonist and also a powerful β1 agonist. Thus CV effects are counterbalancing It has more inotropic effect than chronotropic effect. At equivalent inotropic dose it enhances automaticity of sinus node.
- 29. Therapeutic uses For short term treatment of cardiac decompensation post cardiac surgery In CHF Dobutamine with combination with echocardiography is useful in noninvasive assessment of patients with CAD. Side effects Sharp rise in BP and HR Myocardial O2 demand increases. So angina or MI may be precipitated. Tolerance (on prolonged use) Shouldn’t be use in patients with arterial fibrillation.
- 31. Dopexamine It stimulates β1 receptors and peripheral DA receptors and inhibits neuronal uptake of NE. Which results in I’es CO, peripheral vasodilation, I’es in renal and mesenteric blood flow. USES To provide hemodynamic support in CHF and shock. S/E Tachycardia Transient hypotension Dyspnoea Shouldn’t use in patients with phaeochromocytoma
- 32. Fenoldopam Selective D1 receptor agonist Has no α or β receptor activity 0it is peripheral arteriolar dilator and causes vasodilation in coronaries, renal, and mesenteric arteries. USES Short term management of severe hypertension patients with impaired renal functions. When rapid reduction in BP is desired.
- 33. Side effects Reflex tachycardia I’es intraocular pressure Headache Hypokalaemia
- 34. Non catecholamines α1agonist drugs Phenylephrine Selective α1 agonist It lacks a OH group at 4th position on the benzene ring of E(thus it is a non catecholamine) P’cological effects I’es in peripheral vascular resistance and BP
- 35. USES As a nasal decongestant Mydriatic In some patients of hypotension and shock
- 36. Midodrine It is a prodrug Used in treatment of postural hypotension S/E Hypertension in supine position .
- 37. Naphazoline, Oxymetazoline, Xylometazoline Used as Nasal decongestant in rhinorrhea and to check epistaxis.
- 38. Phenylpropanolamine Most commonly used in common cold oral preparations for nasal congestion. It has been withdrawn because it I’es risk of hemorrhagic stroke in young women and hypersensitives
- 39. α2 agonist drugs Clonidine : Imidazoline group of antihypertensive After i.v injection it produces a transient rise in BP followed by hypotension, but after oral dose it only produces fall in BP M/A Stimulates α2 receptors at vasomotor centers, so central sympathetic outflow is reduced Recently two Imidazoline receptors have been identified in brain and periphery, drug binds to it and it is a GPCR which uses IP3 and DAG to modulate central sympathetic activity It activates presynaptic α2 receptors present on sympathetic post ganglionic neurons , thus it suppress release of NE
- 40. Therapeutic uses Moderate hypertension To control diarrhoea in diabetic patients with autonomic neuropathy Prophylaxis of migraine Management of nicotine, opiate and alcohol withdrawal Preanaesthetic medication Menopausal hot flushes
- 41. Side effects Rebound hypertension (due to supersensitivity of newly formed α1 receptors) Dry mouth Sedation Nasal stuffiness Impotence Constipation Contact dermatitis
- 42. Apraclonidine & Brimonidine Are selective α2 agonists Used for treatment of glaucoma by reducing formation of aqueous humor Are potent ocular hypotensives Are used after laser trabeculoplasty
- 43. Alpha methyldopa It is converted to its active metabolite by L-aminoacid decarboxylase to α-methyldopamine It then enters to storage vesicle in place of DA and gets converted to N-methylnorepinephrine. And at releasing time N-methyl NE is released as a false neurotransmitter Though it has no peripheral action because released N-methyl NE is as potent to NE, but it mainly acts on brain to inhibit adrenergic neuronal outflow Renin secretion is also reduced and salt and water retention does occur
- 44. Advantages Reduction in renal vascular resistance, so useful in patients with renal insufficiency Reduction in ventricular hypertrophy S/E Sedation Dry mouth Gynaecomastia and galactorrhoea Hepatotoxicity Haemolytic anaemia
- 45. Indirectly acting drugs These are taken up by neuronal cytoplasm, enters to storage vesicle, displace NE and in turn activates adrenoceptors They cresses BBB Amphetamine CV effects Raises systolic as well as diastolic BP Effectson smoothmuscles Sphincter of urinary bladder constricts, results in difficulty in micturition Causes relaxation of gut and increases tone of uterus
- 46. Drugs having mixed action Ephedrine It directly stimulates receptor by binding to it and Indirectly stimulates receptors by causing release of stored NT from vesicles in nerve endings Mephentermine Used to control BP hypotensive states in spinal anaesthesia
- 47. Sympatholytics Reversible non-selective adrenergic blockers Mainly 2 drugs belongs to this category; Phentolamine Tolazoline CV actions Vasodilation D's PVR which leads to hypotension Since α1 receptors are blocked sympathetic discharge stimulates β1 receptors , which leads to tachycardia
- 48. Being a non selective drug it blocks α2 receptor presyneptically, which causes neuronal NE release, ultimately leads to palpitations and tachycardia postural hypotension Cerebral hypoxia, fainting : in absence of efficient peripheral Vasoconstrictor in erect posture Which leads to peripheral pooling of blood Nasal stuffiness: due to vasodilation & congestion of nasal mucosa Miosis : loss of tone of radial muscles of iris & contraction of circular muscles
- 49. Improved urine flow : smooth muscle relaxation of bladder and neck Failure of ejaculation& impotence : inhibition of contraction of vas deferens & ejaculatory duct Nausea, vomiting and diarrhoea: I’es GI secretions Indications Diagnosis & management of phaeochromocytoma For peripheral vascular disorders ( Raynaud's syndrome and frostbite) To prevent dermal necrosis To prevent hypertensive crisis
- 50. Irreversible non selective blockers Phenoxybenzamine It binds covalently with α1 & α2 receptors (up to 20-48 hrs.) It inhibits reuptake of released NE Cresses BBB Upon administration it causes Vasodilation D’es PVR Tachycardia Dale’s vasomotor reversal
- 51. CV effects cant be reversed by I’es amount of agonist. Because the binding is covalent & irreversible S/E Reversible inhibition of ejaculation Salt & water retention Cardiac arrhythmia Sedation Fatigue
- 52. Uses Treatment of phaeochromocytoma Raynaud’s syndrome frostbite
- 53. Reversible selective α1 blockers Prazosin Pharmacological actions Peripheral vasodilation D’s arterial pressure with less tachycardia Because • It lacks α2 blocking properties, so it doesn’t promote NE release from nerve terminals • D’s cardiac preload • D’s central sympathetic outflow
- 54. Potent inhibitor of cyclic PDE enzyme I’es cAMP in vascular smooth muscles Vasodilation I’es HDL & D’s LDL Relaxes smooth muscles in bladder neck, prostate capsule, prostatic urethra Thus it improves urinary outflow USES Treatment of hypertension Treatment of benign prostatic hyperplasia Raynaud’s disease
- 55. S/E Postural hypotension Impotence nasal congestion GI upset Water retention Drug interactions Diuretic drug ( furosamide, hydrochlorothiazide) I’es S/E of drug PDE inhibitors ( sildenafil)
- 56. Terazosin and doxazosin Longer duration of action For treatment of BPH Treatment of hypertension
- 57. Bunazosin & alfuzosin Bunazosin is avoided in patients with hepatic impairment, because it is metabolized by liver Both drugs are used in treatment of benign prostatic hyperplasia
- 58. Tamsulosin & silodosin Tamsulosin is selective α1A antagonist, which are located on bladder neck & urethra These are uroselective drugs Used in treatment of benign prostatic hyperplasia S/E Abnormal ejaculation Intraoperative floppy iris syndrome
- 59. List of abbreviations CO: cardiac output BP : blood pressure FC : force of contraction I’es : increase D’s : decrease PDE : phosphodiesterase cAMP : cyclic adenosine monophosphate COMT : catecholamine o methyl transferace VC : vasoconstriction VD : vasodilation
- 60. References Sharma H.L, Sharma k.k, “principles of pharmacology”, 2013 Tripathi K. D “Essentials of MEDICAL PHARMACOLOGY” 7th edition, 2013 Rang & Dale’s PHARMACOLOGY, 8th edition https://en.m.wikipedia.org
- 61. Thank you
Editor's Notes
- #12: Responses are not decreased by prior treatment with reserpine and guanethidine. but may be potentiated with Cocaine, reserpine, guanethidine.
- #13: Responses are decrease by prior treatment with reserpine and guanehidine.
- #14: Response are abolished by prior treatment with guanethidine and reserpine.