Adrenergic Drugs (updated 2016) - drdhrit

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An updated PowerPoint presentation on Adrenergic Drugs suitable for UG MBBS level Medical students

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  • Vmax – maximum velocity of reaction; Km – rate constant of reaction
  • Normally 700 ml of blood is pooled to legs when a person stands up, and threfore syncope should occur. But do not occur in case of normal person because of Baroreceptor reflex which stimulates VMC and sympathetic system is activated and contraction of veins occur via alpha-1 receptor. Blockade of such receptor may therefore may lead to Postural hypotension.
  • Nasal stuffiness is due to blockade of alpha receptors which normally maintains tone of blood vessels of nose. Blockade may lead to vasodilatation and stuffiness.
    Na retention
  • CA Levels are measured after3 hours after a 0.3 mg/kg oral test dose has been given to a patient. A positive test occurs if there is no decrease in plasma levels – positive test
  • Membrane stabilizing activity: Direct myocardial
  • Adrenergic Drugs (updated 2016) - drdhrit

    1. 1. Antiadrenergic Drugs Dr. D. K. Brahma Department of Pharmacology NEIGRIHMS, Shillong
    2. 2. Introduction • Drugs which antagonize the receptor action of Adrenaline and other related drugs at the receptor level • They occupy adrenergic receptors (α and β ) but do not produce signal transduction – affinity is there but without IA - - competitive antagonists • Antiadrenergics Vs Adrenergic Neurone Blockers ! • For pharmacologic research, adrenoceptor antagonist drugs have been very useful in the experimental exploration of autonomic nervous system function • Effects vary according to the drug's selectivity for and receptors - α and its subtype specific or β and its subtype specific
    3. 3. Antiadrenergic Drugs - Background  Clinically – to modify the responses of endogenous catecholamines (Adrenaline and Noradrenaline) - physiologic and pathophysiologic  Nonselective α-antagonists: have been used in the treatment of pheochromocytoma (tumors that secrete catecholamines), and α-1 selective antagonists are used in primary hypertension and benign prostatic hyperplasia (BHP)  β-receptor antagonist: hypertension, ischemic heart disease, arrhythmias, endocrinologic and neurologic disorders, and many other conditions  Blockade of peripheral dopamine receptors is of no recognized clinical importance at present  In contrast, blockade of central nervous system dopamine receptors is very important – antiemetic, antipsychotic and TCAs
    4. 4. α – receptor adrenergic Blockers
    5. 5. Drugs – Classification  Nonequilibrium type:  β-haloalkylamines: Phenoxybenzamine  Equilibrium: I. Nonselective: 1. Ergots: Ergotamine and Ergotoxine 2. Hydrogenated ergot alkaloids: DHE, Dihydroergotoxine 3. Imidazolines: Tolazoline, Phentolamine 4. Miscellaneous: Chlorpromazine, Histamine and Serotonin II. Selective α-1: Prazosin, Terazosin, Doxazosin and Tamsulosin III. Selective α-2: Yohimbine
    6. 6. Ergot Images (Claviceps purpurea) Sclerotium – St Anthony`s Fire Ergotism
    7. 7. Ergots  Natural: considered derivatives of Lysergic acid (LSD) – cognition enhancer  Amine alkaloid: Ergometrine (ergonovine)  Amino acid alkaloids: Ergotamine and ergotoxine – vasoconstrictor, partial agonist and antagonist at α receptors and 5-HT receptors (1 and 2)  Semisynthetic derivatives: Dihydroergotamine (DHE) and Dihydroergotoxine – more α- receptor blocking property
    8. 8. General Effects of alpha Blockade - CVS  Arteriolar and venous tone are determined to a large extent by receptors on vascular smooth muscle  Reduction in Blood Pressure: Blockade of α-1 (also α- 2) receptor causes – pooling of blood in capacitance vessels – reduced venous return and Cardiac output – fall in mean BP  Postural Reflex is interfered – dizziness and Syncope on standing  Reason: Normally 700 ml of blood is pooled to legs when a person stands up, and therefore syncope should occur. But do not occur in case of normal person because of Baroreceptor reflex which stimulates VMC and sympathetic system is activated. Contraction of veins occur via α-1 receptor. Blockade of such receptor may therefore may lead to Postural hypotension  Vasopressor effects of Adrenaline is not found - Vasomotor reversal of Dale
    9. 9. Effects of alpha Blockade - Others  Reflex tachycardia due to fall in - BP and increased NA release due to presynaptic alpha-2 blockade  Nasal stuffiness and Miosis  Increased Intestinal Motility - diarrhoea  Reduced GFR: Sodium retention and increase in blood volume – also reflex renin release  Tone of the Bladder trigone, sphincter and prostate is maintained by α1A sympathetic  Blockade produces increased urine flow  Inhibition of Ejaculation – due to inhibition of contraction of vas deferens and others
    10. 10. Individual Agents - Phenoxybenzamine  Non specific, long acting irreversible alpha antagonist  MOA: Spontaneously cyclizes in the body to give ethyleniminium intermediate – forms a strong covalent bond with α receptors – blockade of alpha receptor (lasts for 3 – 4 days)  Also blockade of 5-HT, histaminergic and cholinergic receptors  Clinically:  Postural hypotension: Venodilatation>arteriolar  In recumbent position, however:  Blood flow to many organ increased due to reduction in peripheral resistance and increased venous return  Shifts blood from pulmonary to systemic circulation  Shifts blood from extravascular to vascular compartment  CNS stimulation – nausea, vomiting on IV injection but oral doses cause depression, tiredness and lethargy
    11. 11. DRC 100% _ 50% _ 0.1 1 10 100 Log dose A A+1XC A+10XC A = Agonist C = antagonist
    12. 12. Phenoxybenzamine  Pharmacokinetics:  Erratic oral absorption and painful on IM or SC injections  Most of the administered drug Excretes in urine in 24 Hrs  Small amount may remain in tissue bound covalently – leading to accumulation in adipose tissue  ADRs: Postural hypotension, nasal stuffiness, miosis and inhibition of ejaculation  Uses:  Phechromocytoma, Secondary shock and Peripheral vascular disease (Raynaud`s disease)  Preparation and dosage:  20-60 mg orally  1 mg/kg IV infusion for 1 Hr.
    13. 13. Phentolamine  Non specific, short acting reversible alpha antagonist  Potent competitive antagonist at both 1 and 2 receptors  Quick acting (in minutes)  Reduction in Peripheral Resistance - blocking both α-1 and α-2 receptors - causes NA release and venodilatation more than arteriolar  Cardiac stimulation:  Enhanced NA release due to alpha-2 blockade  Inhibits serotonin release – muscarinic agonist (?)  Uses: Pheochromocytoma, clonidine withdrawal, cheese reaction and in extravasations of NA and Adr injection  Dose: 5 mg IV injection as and when needed
    14. 14. Prazosin  Highly selective alpha-1 blocker (1:1000)  Non-specific blockade of all subtypes - α1A, α1B and α1D  Blockade of sympathetic vasoconstriction - fall in BP  NA is not released as α-2 is not blocked (only mild tachycardia)  Dilates arterioles more than veins – Postural hypotension is less – only 1st dose effect (dizziness and fainting)  Also inhibits PDE – rise in smooth muscle cAMP - vasodilatation  Kinetics: effective orally (70%), metabolized in liver and half life is 6-8 Hrs  Uses:  Hypertension  Raynaud`s disease  BHP  Dose: start with 0.5 mg bed time and then 1- 4 mg tds.
    15. 15. Other alpha Blockers  Terazosin:  Similar to Prazosin but better bioavailability (90%)  Duration of action is longer – 24 Hrs  Use: Preferred in BHP – single dose and apoptosis, also in hypertension  Similar is Doxazosin  Tamsulosin:  Uroselective (vasicoselective) - α1A and α1D but not α1B  No change in BP and HR at therapeutic doses and Postural hypotension  Preferred drug in BHP  Only once dosing regime (MR caps)  ADRs: Retrograde ejaculation and dizziness
    16. 16. Comparison of alpha blockers Receptor affinity
    17. 17. Uses of α-blockers Pheochromocytoma:  Tumor of medullary cells of Adrenals  VMA and normetanephrine estimation is diagnostic  Phentolamine test: Injection of 5 mg IV over 1 minute (recumbent)  35 mm (Systolic) and 25 mm (Diastolic) of Hg  Treatment:  Surgery  Phenoxybenzamine in preoperatively and intra-operative because:  To Normalize blood volume: Excess CA shifts blood from vascular to extra vascular  To prevent outpouring of CA during surgery  To prevent unwanted hypotension due to dilatation of blood vessels following removal of tumor (Previously - Clonidine suppression test – Measurement of plasma CA levels)
    18. 18. Uses of α-blockers – contd. Hypertension:  Not useful except Prazosin due to  Compensated cardiac stimulation  Postural hypotension, Impotence, nasal blockage etc.  Phentolamine and Phenoxybenzamine – in clonidine withdrawal and cheese reaction BHP:  Static component: Size of prostate (5-alpha reductase)  Dynamic component: Tone of Prostate and bladder neck (alpha-1 mediated)  Converts testosterone to active dihydrotestosterone)  Effects of α blocking – relaxation of neck and prostate structures – reduction in obstruction  5-α reductase inhibitors like Finesteride decreases size of the prostate – better voiding  α blockers – 2 weeks and 5-alpha reductase inhibitors – 6 months  Remember – BHP is a progressive disease
    19. 19. Other uses of α-blockers  Secondary Shock – Phenoxybenzamine  Peripheral vascular disease – beneficial in Raynaud`s disease  Congestive Heart Failure – short term  Papaverine/Phentolamine induced penile erection (PIPE) for impotence
    20. 20. Postural Hypotension and 1st dose effect Remember !
    21. 21. Next Class β-adrenergic Receptor Blockers
    22. 22. β - adrenergic Blockers  Cardioselective:  Metoprolol, atenolol, acebutalol, bisoprolol, esmolol, betaxolol, celiprolol, nebivolol  Nonselective (β1 and β2):  Without intrinsic sympathomimetic activity: Propranolol (membrane stabilizing action), Sotalol and Timolol  With intrinsic sympathomimetic activity (ISA): Pindolol and Oxprenolol  Additional alpha blocking property: Labetolol and Carvedilol
    23. 23. Actions – Propranolol  Heart:  Decrease in Heart rate, decrease in cardiac output, decrease in force of contraction  Prolongs systole - synergy of contraction disturbed in ventricles  Not prominent in Normal persons, but in presence of sympathetic over activity (exercise, emotion)  Decreased ventricular size in normal subject – dilatation in low cardiac reserve patients  Cardiac work and oxygen consumption - reduced  Total coronary flow reduction (aortic pressure) – subepicardial region but not subendocardial region – benefit in angina  Delayed AV conduction  At high doses membrane stabilizing and direct depressant action
    24. 24. Propranolol – Blood Pressure  No direct and acute action on Blood Pressure  In fact blocks vasodilatation fall in BP by Isoprenaline and enhances rise in BP by adrenaline – re-reversal of vasomotor reversal  But beneficial in hypertensives on prolonged administration  Normally, propranolol would block CA induced vasodilatation and cause increase in TPR and decrease in cardiac output – but negligible change in BP  ADAPTATION: But chronic exposure will lead the resistance vessels to adapt to chronically low CO – TPR falls (Most possible explanation of antihypertensive effect)  Other explanations may be:  Decreased Renin release (β1)  Central reduction of sympathetic outflow  Blockade of NA release – blockade of beta recptors
    25. 25. Re-reversal of Vasomotor reversal
    26. 26. Actions - Propranolol  Respiratory:  Bronchoconstriction due to blockade of dilator beta-2 receptors  Not considerable in normal individual - May be dangerous in presence of asthma (avoid)  Beta-1 selective drugs are preferred  Contrary: COPD patients tolerate  Eye: Decreases IOP by reducing production of aqueous humor – glaucoma  CNS: No considerable CNS effect except – behavioural, forgetfulness and nightmare etc. Suppresses anxiety  Skeletal Muscle:  Reduction of Tremor  Reduction of exercise capacity: reduction in blood flow, glycogenolysis and lipolysis
    27. 27. Propranolol Actions – Metabolic  Lipid: Inhibits sympathetic stimulation of lipolysis and consequent increase in free fatty acid level – triglyceride level increased. LDL/HDL ratio increases  Carbohydrate: Inhibition of glycogenolysis in heart, muscle and liver – β2 mediated  Recovery from insulin action delayed  Warning signs are masked  But, Glucagon is the main hormone that responses to hypoglycaemia  Still, beta blockers should be used in caution in patients with diabetes and low glucagon reserve patients and in pancreatectomized patients  β1 selective are much safer
    28. 28. Pharmacokinetics (Propranolol as prototype) - absorption  Most of the drugs are well absorbed after oral administration; peak concentrations occur 1–3 hours after ingestion including propranolol  Propranolol undergoes extensive hepatic (first-pass) metabolism  High oral:parenteral ratio – 40:1  Interindividiual and equieffective dose bioavailability variation  Metabolism dependent on hepatic blood flow – itself decreases hepatic blood flow – higher bioavailability on chronic administration – saturation of hepatic extraction mechanism  Higher bioavailability if taken with food  Dose available as 10-80 mg tabs. (40 – 160 mg /day)  Sustained-release preparations of propranolol and metoprolol are available
    29. 29. Propranolol – ADRs and CI 1. Precipitation of CCF/Oedema – loss of sympathetic support – careful addition of beta-1 selective 2. Bradycardia 3. Respiratory: COAD and Bronchial asthma (life threatening asthma) 4. Risk of Coronary Heart Disease (triglyceride and LDL increase and fall in HDL) 5. Tiredness and reduced exercise capacity – beta-2 muscle 6. Variant angina exacerbation – unopposed coronary constriction by alpha receptor 7. Cold hands and feet – worsening of Peripheral vascular disease 8. Withdrawal 9. Others: GIT upset, nightmare, forgetfulness and sexual distress
    30. 30. Drug Interactions  Propranolol and insulin:  Delayed recovery of hypoglycemia by insulin  Warning signs are suppressed  Propranolol + alpha agonists: Rise in BP  NSAIDs + Propranolol: Attenuation of antihypertensive action of beta-blockers
    31. 31. Other Drugs – beta blockers  Cardioselectivity: More selective in blocking β1 receptors than β2  Advantages:  Lower propensity to cause Bronchoconstriction  Lesser interference with carbohydrate metabolism – safer in diabetics  Lower incidence of cold hand and feet – no/less β2 block  Lesser suppression of essential tremor  Lesser impairment of exercise capacity  Intrinsic sympathomimetic activity: Pindolol, celiprolol  Advantages: Partial agonist action  Lesser bradycardia and depression of contractility – preferred in elderly, sick sinus syndrome etc.  Favourable withdrawal  Less/no interference with lipid profile not effective in migraine prolhylaxis
    32. 32. Other beta blockers – contd.  Membrane stabilizing effect: like lidocaine  Local anaesthetic action  Typically blocks Na+ channel – antiarrhythmic action  Lipid insolubility: Atenolol, celiprolol, bisoprolol etc.  Less likely to produce sleep disturbances  Longer acting – incompletely absorbed, no first pass metabolism, excreted unchanged in urine – t1/2 – 6-2 Hrs Vs 2-6 Hrs
    33. 33. Other Beta Blockers  Metoprolol:  Prototype of cardioselective blockers - β1 selective (also inverse agonist)  Safer in patients with bronchoconstriction and preferred in patients with insulin  Less first pass metabolism  Slow and fast hydroxylators (CYP2D6 substrate)  Used:  In Diabetics and patients in OHs  Cold hands and feet with Propranolol  Available as tab – 25/50/100/ mg and IV injection  Atenolol:  Selective β1 and low lipid solubility, less 1st pass metabolism  Longer duration of action – once daily dosing  No lipid profile adverse effects - Hypertension and angina
    34. 34. Other Beta Blockers  Partial beta-agonist: Pindolol and celiprolol, carteolol, bopindolol, oxprenolol, and penbutolol:  Major CVS applications – less plasma lipid action and bradycardia  Intrinsic sympathomimetic activity  However, doubtful clinical benefit  Esmolol: partial agonist and MSA  Ultra short acting (less than 10 minutes) - inactivated by esterases in blood  Degree of blockade can be titrated - Steady dose can be maintained  Given as IV infusion in SVT, AF, Atrial flutter, arrhythmia during anaesthesia and cardiac surgery etc.  Available as injections IV: 100 – 500 mg/10 ml inj.
    35. 35. Other Beta Blockers  Celiprolol:  Selective beta-1 with additional beta-2 agonistic activity  Safe in asthmatics  Causes vasodilatation by NO production (NA receptor mediated) – additional benefit as antihypertensive. Dose: 200-600 mg  Nebivolol:  Highly selective beta-1 blocker  Acts as NO donor - Improves endothelial function and delay of atherosclerosis  No deleterious effects on carbohydrate, lipid metabolism  In CHF and hypertension  Dose: 2.5/5 mg
    36. 36. Uses of Beta Blockers 1. Hypertension: 1st line of agent (JNC 7) 2. Angina pectoris – not in vasospastic 3. Myocardia infarction:  Prophylaxis: Prevent reinfarction and Prevent ventricular fibrillation  Myocardial salvage: reduction in infarct size 1. Cardiac arrhythmias: Class II type of agent – Propranolol IV (digitalis and anaesthesia induced) 2. Congestive Heart failure 3. Phaeochromocytoma 4. Hyperthyroidism: T4 - T3 + sympathetic symptoms 5. Migraine 6. Anxiety: social phobia 7. Essential Tremor 8. Glaucoma
    37. 37. α + β blockers  Labetolol: Alpha + beta blocker (4 diastereomers)  Commercially – α1 + β1 + β2 block + β2 agonistic  Beta blockade – 1/3rd of Propranolol and alpha – 1/10th of Phentolamine  Beta: alpha = 1: 5  Clinically: Low dose – like propranolol and high dose like Propranolol + Prazosin  Fall in BP (Syst + diast) + vasodilatation (beta-2)  Limb blood flow increases - propranolol does not  Also inhbition of NA uptake  Moderately potent and Used in Phaechromocytoma, clonidine withdrawal  ADRs: Postural hypotension, failure of ejaculation and others but no change in lipid profile  Carvedilol: β1 + β2 and α1 blocker and also Ca+ channel block  Vasodilatation – α + Ca++ channel block + antioxidant  Uses: Hypertension and especially preferred in CHF as cardioprotective
    38. 38. Summary  Usefulness and actions of β blockers shall be discussed later - in relation to their use in the particular CVS disease conditions  Remember:  Effects of alpha blockade - Phenoxybenzamine, Phentolamine Test (Phaechromocytoma)  Selective alpha-1 blockers and uses - Prazosin, Terazosin and Tamsulosine  Name with selectivity of β blockers as per classification given  Pharmacological actions and ADRs of Propranolol as discussed  Overall therapeutic uses of beta-blockers – general Idea  Individual drugs - Metoprolol, atenolol, esmolol, Labetolol and carvedilol etc.
    39. 39. THANK YOU

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