Adrenoceptor agonists

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Adrenoceptor agonists

  1. 1. Adrenoceptor agonists
  2. 2. Overview The study of the sympathetic nervous system is important from a clinical perspective. The SNS is involved in controlling heart rate, contractility, blood pressure, vasomotor tone, carbohydrate and fatty acid metabolism etc. Stimulation of the SNS occurs in response to physical activity, psychological stress, allergies etc. Drugs influencing the SNS are used in treatment of hypertension, shock, cardiac failure and arrhythmias, asthma and emphysema, allergies and anaphylaxis.
  3. 3. Sites of Drug Action – Modulation of Neurotransmission ↓1 2. intake of precursor 3. synthesis 4. storage 5. metabolism 7. reuptake 6. release 8. degradation 9. receptor
  4. 4. Direct acting adrenergic drugs:
  5. 5. Sympathomimetics: Drugs that mimic or facilitate the actions of the sympatho-adrenal system.a) Direct acting: – Drugs that can act directly or specific adrenergic receptors – Mimic the effects of NE and Epib) Indirect acting: – Drugs that do not activate the adrenergic receptor directly i. Facilitate release of NE ii. Block neuronal uptake of NE iii. Block metabolism of NE
  6. 6.  classifications α-R agonists: NA, metaraminol α, β-R agonists: AD,ephedrine α, β, DA-R agonists: dopamine β-R agonists: Isop,dobutamine
  7. 7. Location Receptor type Effect ↑ heart rate Heart β1 ↑ force of contractionVascular Smooth Muscle:Skin and splanchnic vessels α constriction Skeletal muscle vessels α and β2 constriction or dilation Other smooth muscle: Bronchiole β2 dilation Uterus: α1 contraction pregnant β2 relaxation non-pregnant β2 relaxation GI tract α and β relaxation Eye: radial pupillary dilator α1 contraction (mydriasis) ciliary muscle β relaxation
  8. 8. Receptor Location Effect typeExocrine glands: Pancreas α ↓ release of insulin Salivary glands α and β increase secretionMetabolic effects: ↑ glycogenolysis Liver β2 ↑ gluconeogenesis Adipose tissue β1 lipolysis
  9. 9. Direct Acting Sympathomimetics:Ahlquist designated the receptors as α or β based on observations that catecholamines act on 2 principal receptors: α1: Epi ≥ NE >> INE α2: β1: INE > Epi = NE β2: INE > Epi >> NE
  10. 10. Chemistry and Pharmacokinetics ofSympathomimetics:
  11. 11. α-R agonistsnoradrenaline(norepinephrine,NA,NE)pharmacokinetics :pharmacological actions: strongly activate α- R, slightly activate β1-R.
  12. 12. pharmacological actions of NA 1.vessels: contract(α-R) coronary vessels dilate (adenosine) 2.heart: excited(β1-R) 3.BP: small dose: SBP↑ DBP large dose: SBP↑ DBP↑ 4.others: metabolism, CNS
  13. 13. clinical uses 1.shock 2.hypotension caused by drugs’ intoxication 3.upper digestive tract hemorrhage
  14. 14. adverse reactions 1.local ischemia and necrosis 2.acute renal failure contraindications HT In pregnant females, NE should not be used because it stimulates alpha 1 receptors in the uterus that cause contraction
  15. 15. Effect of NE to intact CVSMean arterial pressure(MAP) = DBP + 1/3 of (SBP-DBP) α 1 ,α 2 ,β 1
  16. 16. metaraminol (aramine ) Mechanisms: 1.direct actions 2.indirect actions Characteristics: 1.action is weaker and longer than NA 2.little adverse reactions: renal failure, arrhythmias 3.stable, im. 4.tachyphylaxis Uses: substitute for NA in treatment of shock
  17. 17. phenylephrine(neosynephrine) and methoxamine 1.selective α1-R agonists: shock, hypotension 2.paroxysmal atrial tachycardia 3.renal vasoconstriction significant 4.phenylephrine→mydriasis
  18. 18. Adrenaline (epinephrine,AD) source Stress hormone released from the adrenal medulla Pharmacokinetics: comt mao pharmacological actions: activate1.heart: strongly excited (β1-R)2.vessels: contract(α-R),dilate(β2-R)3. smooth muscle: bronchial smooth muscle relax4.metabolism: ↑ 20%-30%; blood Glu ↑, blood fatty acid ↑
  19. 19. Epinephrine: Dose-dependent effects: α β Dose of epinephrine →
  20. 20. Effect of Epi to intact CVSa1 ,a2 ,b1,b2
  21. 21. Epinephrine Reversal (m m H g ) 200 180 M e a n Arte ri a l Pre s s u re 160phenoxybenzamine] 140 120 Epi PBZ Epi 100 80 0 1 2 3 4 5 6 7 8 9 10 Tim e (re lative )
  22. 22.  5.BP Low doses: β-adrenergic effects predominate  ↑ HR, vasodilation of vascular smooth muscle in skeletal muscle, other smooth muscle effects High doses: α-adrenergic effects predominate  Vasoconstriction of blood vessels in skin and peritoneal cavity  ↑ BP and reflex slowing of the heart (baroreceptor reflex)
  23. 23. clinical uses 1. Relief of bronchospasm 2. Relief of hypersensitivity reactions and anaphylaxis 3. To prolong the duration of action of local anesthetics. 4. As a topical hemostatic to control superficial bleeding from skin and mucosae 5. To restore cardiac rhythm in patients with cardiac arrest.
  24. 24.  Adverse effects:  Extensions of their effects in the CVS and the CNS  Anxiety, tenseness, headache and paranoia  tachycardia, dysrhythmias  Large dose IV – cerebral hemorrhage, pulmonary edema Route of administration:  Inhalation  Injection (IM, SC, IV), not PO  Topical application  Rapidly degraded
  25. 25. Phenylephrine: Acts on α receptors Vasoconstriction (↑ BP) Longer lasting than epinephrine Clinical use:  Hypotension and shock  Nasal decongestantSalbutamol: Selective β agonist 2 Dilates bronchial smooth muscle Clinical use:  Antiasthmatic
  26. 26. Adrenergic Drugs cont’d: Ephedrine Acts directly and indirectly  Acts on α and β receptors and causes release of NE  Less potent and longer acting than epinephrine  Available OTC  Orally administered  Clinical use  Bronchodilation  Nasal decongestant
  27. 27. α, β,DA-R agonists dopamine (DA) Pharmacokinetics: ivd, MAO/COMT; short t1/2, not across BBB pharmacological actions activate DA, α, β1-R
  28. 28. actions 1.Cardiovascular system: dilate (DA- R),contract(α-R) 10µg/kg·min SBP→ DBP↓ 20µg/kg·min SBP↑ DBP↑→ >25µg/kg·min SBP↑ DBP↑ 2. Ren: renal vessels small dose dilate large dose contract
  29. 29. Effect of DA to intact CVS DA1, Beta1 Moderate Dose
  30. 30. clinical uses 1.shock 2.chronic heart failure(CHF) 3.acute renal failure(ARF) toxicity high doses of DA is similar to that noted above for NE. Since the drug has an extremely short half life in plasma, DA toxicity usually disappear quickly if the administration is terminated.
  31. 31. β-R agonists--isoprenaline Pharmacokinetics: pharmacological actions: activate β1, β2-R 1.heart: excited (β1-R) 2.vessels: dilate (β2-R) 3.BP: small dose: SBP↑ DBP↓ large dose: SBP↓ DBP↓ 4.bronchial smooth muscle: relax 5.others; metabolism, CNS
  32. 32. Effect of Iso to intact CVS b1,b2
  33. 33. clinical uses 1.bronchial asthma 2.atrial ventricular block(AVB) 3.cardiac arrest 4.shockadverse reactions and contraindication
  34. 34. dobutamine 1.selective β1-R agonist 2.inotropic effect>chronotropic effect in therapeutic dose 3.short-term treatment for CO↓ following cardiac surgery or CHF caused by AMI 4.tachyphylaxis
  35. 35. Clinical Use of Adrenergic Agonists:α – agonists:  Anaphylactic shock  Hypotension  Nasal congestion  Hemorrhage  Co-administration with local anestheticsβ – agonists:  Congestive heart failure – short term  Asthma – bronchial dilation  Tocolytic – stopping premature labour
  36. 36. Adrenoceptor antagonists Section 1 α-R antagonists Ⅰ. α1, α2-R antagonistsClassification 1.short-term acting phentolamine tolazoline competitive α-R antagonists 2. long-term acting phentoxybenzamine noncompetitive α-R antagonists Ⅱ. α1-R antagonists prazosine Ⅲ. α -R antagonists yohimbine
  37. 37. Epinephrine Reversal (m m H g ) 200 180 M e a n Arte ri a l Pre s s u re 160phenoxybenzamine] 140 120 Epi PBZ Epi 100 80 0 1 2 3 4 5 6 7 8 9 10 Tim e (re lative )
  38. 38. phentolamine (regitine)pharmacological actions 1.vessels : vessels dilate; BP ↓ “adrenaline reversal ” 2.heart: excited, CO ↑ HR ↑ a. vessel relaxation>BP ↓, baroreflex (+) b. alpha2 blockade , NE release↑ 3.other effects: cholinergic action histamine-like action
  39. 39. Clinical uses 1.peripheral vasospasmatic disorders 2.local vasoconstrictor excess (eg, NA) 3.diagnosis and treatment of pheochromocytoma 4.shock 5.CHF and AMI 6.others: male sexual dysfunction
  40. 40. adverse reactions 1.cardiovascular reaction: hypotension, tachycardia, angina, arrhythmia 2.gastrointestinal reaction: stomachache, diarrhea, vomiting, ulceration 3.histamine-like reaction:
  41. 41. tolazoline The action of blocking α1-R is more weakly than regitine. While cholinergic action and histamine- like action are stronger than regitine.
  42. 42. phenoxybenzamine Pharmacokinetics: only iv, high liposolubility pharmacological actions: similar to phentolamine, but slow, strong and long. it also can block the receptors of 5-HT and HA.
  43. 43. Prazosin the prototype of a family of potent and very selective alpha 1 receptor antagonists. It has 1000X greater affinity for alpha 1 vs alpha 2 receptors. It blocks all alpha one receptor subtypes equipotently. It is a short acting drug with a duration of action of about 7 to 10 hours. Prazosin causes a decrease in total peripheral resistance, but not an increase in heart rate (since alpha 2 receptors are not inhibited).
  44. 44. phenoxybenzamine clinical uses: 1.peripheral vasospasmatic disorders 2.pheochromocytoma 3.shock 4. Urinary obstruction caused by benign prostatic hyperplasia adverse reactions: Postural hypotension, tachycardia (palpitation), arrhythmia, nasal congestion
  45. 45. Section 2 β-R antagonists pharmacological actions: 1. β1-R blocking action: 1) cardiovascular effects: heart depressed, BP↓ 2)bronchial smooth muscle 3)metabolism 4)renin release↓ 2.intrinsic sympathominetic activity(ISA) 3.membrane stabilizing action at high dose 4.other effects: antiplatelet aggregative(propranolol) ↓intraocular pressure (timolol)
  46. 46. clinical uses 1.arrhythmias 2.angina pectoris, myocardial infarction 3.hypertension 4.CHF 5.others: hyperthyroidism, glaucoma, migraine
  47. 47. adverse actions andcontraindications 1.nausea, vomiting, PLT↓ 2. cardiovascular reaction 3. bronchial asthma 4.withdrawal syndrome 5.others
  48. 48. classification β 1,β2-R antagonist Propranolol, Timolol: most potent,glaucoma; pindolol β 1-R antagonist atenolol , metoprolol, Acebutolol α, , β -R antagonist Labetalol, carvedilol
  49. 49. Thank you for your attention
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