Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Adrenal receptors antagonist

full lecture of Adrenal receptors antagonist pharmacologicaly

  • Login to see the comments

Adrenal receptors antagonist

  1. 1. Adrenal Antagonist By Dr. Sara Sami Yuzuncu Yil University 2015
  2. 2. Adrenoceptor Antagonist Drugs Classification – Alpha Antagonists • Non Selective • α1 Selective • α2 Selective – Beta Antagonists • Non Selective • β1 Selective • β2 Selective • Toxicity
  3. 3. Classification of adrenergic receptor antagonist.
  4. 4. Wording • Adrenoceptor Blocker • Adrenergic Antagonist • Subgroups in Sympathoplegic drugs • Alpha Blocker, Alpha Antagonist • Beta Blocker, Beta Antagonist
  5. 5. General effects of α blockers Blood vessels • α1-blockade reduces peripheral resistance Fall in BP Postural hypotension • α2-blockade in brain se vasomotor tone. • Block pressor action of adrenaline, fall in BP due toβ2. action- “vasomotor reversal of Dale” • Actions of selective α-agonists supressed.
  6. 6. Heart • Reflex tachycardia due to:-  fall in mean arterial pressure Blockade of presynaptic α2 receptors- ↑ NA release. Nose: nasal stuffiness Eye: miosis GIT: intestinal motility se Kidney: Hypotension se GFR NA+ & H2O reabsorption
  7. 7. Urinary bladder • α1A blockade- se tone of smooth muscle in trigone, sphincter & prostrate. • Improved urine flow, used in BPH. Reproductive system • Contraction of vas deferens result in ejaculation through α receptors. • Blockade results in impotence.
  8. 8. Alpha-Blocking Drugs A. Classification –based on: selective affinity for alpha receptors, reversibility 1. Irreversible, long-acting alpha blockers 2. Reversible, short-acting alpha blockers 3. a1-selective blockers 4. a2-selective blockers
  9. 9. Classification 1. Irreversible alpha blockers : Phenoxybenzamine –slightly a 1 -selective, long-acting 2. Reversible alpha blockers: Phentolamine (nonselective), tolazoline (slightly a 2 -selective) 3. a 1 blockers: Prazosin, Doxazosin, Terazosin 4. a 2 blockers: Yohimbine used primarily in researches
  10. 10. Pharmacokinetics • All active orally as well as parenterally • Phenoxybenzamine: short t1/2 but long duration-48 hr (covalent bond) • Phentolamine, tolazoline: parenteral, duration 20-40 min by parenteral route • Prazosin: oral, duration 8-10 hr
  11. 11. Irreversible non-selective α- blockers Phenoxybenzamine • Cyclizes spontaneously to highly reactive ethyleniminium intermediate. • Binds covalently to α-receptors- irreversible or non- equilibrium competitive block. • Blockade is slow onset & longer duration (3-4 days). • Also inhibits reuptake of NE. • Shifts blood from pulmonary to systemic circuit. • Shift fluid from extravascular to vascular compartment- relaxation of postcapillary vessels.
  12. 12. Reversible alpha blockers Yohimbine • Natural alkaloid from Pausinystalia yohimbe. • No established clinical role. Idazoxan • Has membrane stabilizing action. Ergot alkaloids • Ergotamine & Dihydroergotamine • Competitive α-receptor blockers. • Principal use is migraine.
  13. 13. Reversible, selective α1- blockers Prazosin • Highly selective α1-blocker , α1: α2 selectivity 1000:1 • Fall in BP with only mild tachycardia. • Dilates arterioles more than veins • Postural hypotension occurs as 1st dose effect, minimized by starting with low doses at bed time. • Also inhibits PDE- se cAMP in smooth muscle. PK • Effective orally, BA- 60%. • Highly bound to plasma proteins (α1 acid glycoprotein).
  14. 14. • Metabolized in liver, 1o excreted in bile. • t1/2 – 2-3hrs, effect lasts for 6-8hrs. Uses • Primarily as antihypertensive. • LVF not controlled by diuretics & digitalis. • Raynaud’s disease • BPH • Scorpion sting
  15. 15. PK • Preferred ROA- i.v. • Lipid soluble penetrates brain. • Mainly excreted through urine in 24 hrs. • Accumulates in adipose tissue on ch. Administration. Dose 20-60 mg/d oral 1mg/kg/1hr slow i.v infusion. Uses Pheochromocytoma, occasionally 2oshock, PVD.
  16. 16. Reversible non-selective α-blockers Tolazoline • Block is modest & short lasting. • Direct vasodilator & stimulates the heart. • Also blocks 5-HT receptors, histamine like gastric secretagouge & Ach like motor action on intestine. SE • N, V, cramps, diarrhoea, nervousness, chills • Tachycardia, Exacerbation of MI, peptic ulcer. Use • PVD • Pulmonary HT of newborn.
  17. 17. • Cause reflex tachycardia (due to decreased MAP) • Tachycardia may be exaggerated because a 2 receptors are also blocked. • e.g. phenoxybenzamine, phentolamine, tolazoline Effects of Alpha Blockers 1. Nonselective alpha blockers (cont)
  18. 18. Clinical Uses 1. Nonselective alpha-blockers Presurgery of pheochromocytoma: phenoxybenzamine During surgery: phentolamine (sometimes) Carcinoid tumor: phenoxybenzamine (5-HT blocking) Mastocytosis: phenoxybenzamine (H1 antihistamine)  Accidental local infiltration of alpha agonist: phentolamine Overdose of sympathomimetics (amphetamine, cocaine, phenylpropranolamine) Raynaud’ s phenomenon, erectile dysfunction (phentolamine)
  19. 19. 2. Selective a 1 blockers • The same effects as nonselective alpha blockers • But cause much less tachycardia than nonselective blocker • e.g. Prazosin, Doxazosin, Terazosin Effects of Alpha Blockers
  20. 20. Clinical Uses 2. Selective a 1 -blockers  Prazosin and others  Essential Hypertension  Urinary hesitancy  Prevention of urinary retention in benign prostatic hyperplasia (BPH)
  21. 21. Terazosin &Doxazosin • Long acting( t1/212 & 18hr) congener of prazosin. • Used in HTN & BPH as single daily dose. Tamsulosin & Silodosin • Uroselective α1A blocker • α1A –bladder base, prostrate. α1B- blood vessels. • Don't cause significant changes in BP & HR. • t1/2- 6-9hr, MR cap(0.2-0.4 mg) can be taken OD. • Efficacious in Rx of BPH. • SE: retrograde ejaculation, dizziness,, floppy iris syd. • Silodosin weaker(4-8mg/d) but longer acting.
  22. 22. Phentolamine • More potent α-blocker than tolazoline. • Other actions are less marked. • Duration of action is shorter (min). • Equally blocks α1 & α2 receptors- NA release sed. Uses • ∆sis & of pheochromocytoma. 5mg i.v- B.P falls by 25(D)or35(S)mmHg. • HTN due to clonidine withdrawl, cheese reaction. • Dermal necrosis due to extravasated i.v NA/DA. Given S.C as local infiltration.
  23. 23. Bunazosin & Alfuzosin • Orally effective α1 blockers similar to prazosin. • Alfuzosin t1/2 4hrs (2.5mgTDS or 10mg SR OD). • CI in hepatic impairment, metabolized in liver. • Bunazosin slightly longer t1/2. • Primarily used in BPH.
  24. 24. F Adverse effects of Alpha blockers  Orthostatic hypotension (venodilatation)  Reflex tachycardia (nonselective > selective)  First dose hypotension (take before going to bed)  Nausea/vomiting  Caution in patients with coronary artery disease (CAD or CHD): angina
  25. 25. Side effects of α-blockers • Palpitation • Postural hypotension • Nasal blockade • Diarrhea • Fluid retention • Inhibition of ejaculation & impotence.
  26. 26. Receptor Type a1 a2 Selective Agonist Phenylephrine Oxymetazoline Clonidine Clenbuterol Selective Antagonist Doxazosin Prazosin Yohimbine Idazoxan Agonist Potency Order A=NA>>ISO A=NA>>ISO Second Messengers and Effectors PLC activation via Gp/q causes inc. [Ca2+]i dec. cAMP via Gi/o causes dec. [Ca2+]i Physiological Effect Smooth muscle contraction Inhibition of transmitter release Hypotension, anaesthesia, Vasoconstriction
  27. 27. Beta-Blocking Drugs A. Classification and Mechanisms All are competitive antagonists Propranolol is prototype Classification is based on  Beta subtypes selectivity  Partial agonist activity  Lipid solubility  Local anesthetic action
  28. 28. 3. Propranolol is contraindicated in one of the following diseases: a) Hypertension b) Tachycardia c) Hyperthyroidism d) Angina pectoris e) Bronchial asthma
  29. 29. 4. Propranolol produces its antihypertensive action by: a) Vasodilatation b) Ganglionic blockade c) Decreased cardiac output d) A diuretic action e) Blockade of 1 receptors
  30. 30. Classification and Mechanisms 1. Receptor selectivity – b 1 -selective: metoprolol, atenolol – b 2 -selective: butoxamine (research only) – Nonselective: propranolol –Combined beta- and alpha- blocking: labetalol
  31. 31. A. Classification and Mechanisms Partial agonist activity –Intrinsic sympathomimetic activity, ISA –eg, pindolol, acebutolol –may be useful in patients with asthma
  32. 32. Classification and Mechanisms 3. Local anesthetic activity (membrane-stabilizing activity): –disadvantage when used topically in the eye –timolol: no this activity 4. Lipid solubility –responsible for CNS adverse effects: propranolol
  33. 33. Pharmacokinetics of Beta blockers • For systemic effects, developed for chronic oral use • Esmolol: short-acting--only used parenterally • Nadolol: longest-acting • Atenolol, acebutolol are less lipid- soluble
  34. 34. Effects and Clinical Uses • Predict from beta blockade –decreased HR, force of contraction –decreased A-V conduction –slow firing rate of SA node • Cardiovascular and ophthalmic applications are extremly important
  35. 35. Clinical Uses • CVS: hypertension, angina pectoris, arrhythmia prophylaxis after MI, supraventricular tachycardias, hypertrophic cardiomyopathy, congestive heart failure* • Glaucoma: reduce aqueous humor secretion (timolol)
  36. 36. Clinical Uses • Migraine: propranolol • Thyroid storm, thyrotoxicosis: propranolol • Famillial tremor, other types of tremor, “stage fright” : propranolol
  37. 37. Adverse effects • CVS: bradycardia, A-V blockade, congestive heart failure • Patients with airway disease: asthmatic attack • Mask sign of hypoglycemia in diabetic patients: tachycardia, tremor, anxiety • CNS effects: sedation, fatigue, sleep alterations
  38. 38. Receptor Type b1 b2 b3 b4 Selective Agonist Dobutamine xamoterol Salbutamol salmeterol BRL 37344 none Selective Antagonists Atenolol metoprolol Butoxamine SR59230A Bupranolol Agonist Potency Order ISO>A=NA ISO>A>>NA ISO=NA>A Second Messengers and Effectors Inc cAMP via Gs Inc cAMP via Gs Inc cAMP via Gs Inc cAMP via Gs Physiological Effect Inc heart rate and force Vasodilatation and broncho- dilation Lipolysis and thermogenesis Inc heart rate and force
  39. 39. SUMMARY
  40. 40. Selectivity Partial Agonist Activity Local Anesthetic Action Elimination Half- Life Approximate Bioavailability Acebutolol β1 Yes Yes 3-4 hours 50 Atenolol β1 No No 6-9 hours 40 Betaxolol β1 No Slight 14-22 hours 90 Bisoprolol β1 No No 9-12 hours 80 Carteolol None Yes No 6 hours 85 Carvedilol None No No 7-10 hours 25-35 Celiprolol β1 Yes No 4-5 hours 70 Esmolol β1 No No 10 minutes 0 Labetalol None Yes Yes 5 hours 30 Metoprolol β1 No Yes 3-4 hours 50 Nadolol None No No 14-24 hours 33 Penbutolol None Yes No 5 hours >90 Pindolol None Yes Yes 3-4 hours 90 Propranolol None No Yes 3.5-6 hours 30 Sotalol None No No 12 hours 90 Timolol None No No 4-5 hours 50