Adrenergic Drugs II

4,883
-1

Published on

Adrenergic Drugs

0 Comments
4 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
4,883
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
264
Comments
0
Likes
4
Embeds 0
No embeds

No notes for slide

Adrenergic Drugs II

  1. 1. Adrenergic Drugs II Aims To understand the actions and side effects of major adrenergic drugs, and their clinical applications Read: Chapter 8, Rang and Dale comments to Dr Ian Musgrave (336S) Email: Ian.Musgrave@adelaide.edu.au
  2. 2. Sympathomimetics: Types <ul><li>Direct acting - drugs that interact directly with adrenoceptors </li></ul><ul><ul><li>Noradrenaline </li></ul></ul><ul><ul><li>Adrenaline </li></ul></ul><ul><ul><li>Isoprenaline </li></ul></ul><ul><ul><li>Phenylepherine </li></ul></ul><ul><li>Indirect acting - drugs that activate adrenergic receptors indirectly </li></ul><ul><ul><li>displace stored catecholamines from nerve terminals </li></ul></ul><ul><ul><ul><li>(e.g. amphetamine) </li></ul></ul></ul><ul><ul><li>inhibit uptake of catecholamines already released </li></ul></ul><ul><ul><ul><li>(e.g. cocaine) </li></ul></ul></ul><ul><li>Mixed - both direct and indirect </li></ul>
  3. 3. Amphetamine - indirect agonist <ul><li>Non-catechol </li></ul><ul><li>Good oral bioavailability </li></ul><ul><li>CNS stimulant - more so than ephedrine </li></ul><ul><li>Peripheral actions mainly through release of catecholamines from nerve terminals </li></ul>
  4. 4. Amphetamine - indirect agonist
  5. 5. Ephedrine <ul><li>Produced by various plants (Ma-huang) </li></ul><ul><li>Noncatechol with good oral bioavailability </li></ul><ul><li>Long acting </li></ul><ul><li>Releases catecholamines from nerve terminal </li></ul><ul><li>Some direct stimulation of  and  receptors </li></ul><ul><li>Penetrates brain to produce CNS stimulation </li></ul><ul><li>Traditional asthma remedy </li></ul>
  6. 6. Tyramine <ul><li>Releases noradrenaline from nerve terminals </li></ul><ul><li>Found in fermented foods (e.g. cheese) </li></ul><ul><li>Normally destroyed by MAOs in gut wall </li></ul><ul><li>May produce hypertensive crisis in patients taking MAO inhibitors </li></ul>
  7. 7. Cocaine <ul><li>Blocks noradrenaline reuptake into nerve terminal </li></ul><ul><ul><li>Blocks most biogenic amine transporters </li></ul></ul><ul><li>Rapidly enters the CNS </li></ul><ul><ul><li>like amphetamine </li></ul></ul><ul><ul><li>shorter acting </li></ul></ul><ul><ul><li>more intense than amphetamine </li></ul></ul><ul><li>Most CNS effects non-adrenergic (5HT, dopamine) </li></ul><ul><li>smoked, snorted and injected for rapid onset </li></ul><ul><li>Peripheral sympathomimetic effects prominent </li></ul><ul><li>Acute hypertension may cause heart failure, death </li></ul>
  8. 8. Close up of Adrenergic terminal NA NA NA NA Tyrosine Dopamine DOPA NA MAO NA NA Metabolites Uptake 1 Vesicular transporter TH DDC D  H Vesicular transporter Cocaine
  9. 9. Sympathomimetic Uses <ul><li>hypotension </li></ul><ul><li>shock </li></ul><ul><li>haemostasis </li></ul><ul><li>nasal decongestion </li></ul><ul><li>acute heart failure </li></ul><ul><li>bronchial asthma </li></ul><ul><li>anaphylaxis </li></ul><ul><li>mydriasis </li></ul><ul><li>premature labor </li></ul><ul><li>weight reduction </li></ul>
  10. 10. Sympatholytics: Types <ul><li>Direct acting - drugs that interact directly with adrenoceptors </li></ul><ul><ul><li>Propranolol </li></ul></ul><ul><ul><li>Atenolol </li></ul></ul><ul><ul><li>Phentolamine </li></ul></ul><ul><ul><li>Prazosin </li></ul></ul><ul><li>Indirect acting - drugs that interfere with noradrenaline release </li></ul><ul><ul><li>affect noradrenaline synthesis </li></ul></ul><ul><ul><ul><li>Methyldopa, reserpine </li></ul></ul></ul><ul><ul><li>inhibit released </li></ul></ul><ul><ul><ul><li>Guanethidine </li></ul></ul></ul>
  11. 11. Directly acting sympatholytics - antagonists <ul><li>Non-selective </li></ul><ul><ul><li>Phentolamine  -adrenoceptors </li></ul></ul><ul><ul><li>Propranolol  -adrenoceptors </li></ul></ul><ul><li> -selective </li></ul><ul><ul><li>Prazosin   -adrenoceptors </li></ul></ul><ul><li> -selective </li></ul><ul><ul><li>Atenolol   -adrenoceptors </li></ul></ul><ul><ul><li>ICI 118551   -adrenoceptors </li></ul></ul>
  12. 12. Adrenergic antagonists <ul><li>Alpha blockers </li></ul><ul><ul><li>Not as clinically useful as beta blockers </li></ul></ul><ul><ul><li>Mostly anti-hypertensives </li></ul></ul><ul><ul><li>Selective  1 blockers are most the useful </li></ul></ul><ul><ul><li>Competitive and and non-competitive types </li></ul></ul><ul><li>Beta blockers </li></ul><ul><ul><li>Many clinical uses </li></ul></ul><ul><ul><li>All competitive </li></ul></ul><ul><ul><li>Selective    blockers available </li></ul></ul><ul><ul><li>Some with intrinsic (agonist) activity </li></ul></ul>
  13. 13. Non-selective alpha antagonists <ul><li>Phentolamine </li></ul><ul><ul><li>Compeditive antagonist (reversible) </li></ul></ul><ul><ul><li>Duration dependent upon elimination rate </li></ul></ul><ul><ul><li>Generally fairly short acting </li></ul></ul><ul><ul><li>Blocks both    and   receptors </li></ul></ul><ul><li>Tolazoline </li></ul><ul><ul><li>Similar to phentolamine </li></ul></ul><ul><ul><li>Better absorbtion </li></ul></ul><ul><li>Phenoxybenzamine </li></ul><ul><ul><li>Irreversible - alkylates the receptor </li></ul></ul><ul><ul><li>Long acting (14-48 hours) </li></ul></ul><ul><ul><li>Blocks     receptors </li></ul></ul>
  14. 14. Non-selective alpha antagonists - structure Phentolamine Tolazoline Phenoxybenzamine Active intermediate (ethyleneimonium)
  15. 15. Effect of tolazoline and phenoxybenzamine on noradrenergic contraction in cat splenic strips + Tolazoline + Phenoxybenzamine Competitive vs non-competitive antagonism
  16. 16. Problems with non-selective alpha antagonists <ul><li>Severe first dose hypotension on standing </li></ul><ul><li>Reflex tachycardia </li></ul><ul><li>Water retention </li></ul><ul><li>Nasal congestion </li></ul><ul><li>Some tolerance develops </li></ul>
  17. 17. Selective alpha antagonists Prazosin <ul><li>Competitive </li></ul><ul><li>Blocks   receptors only </li></ul><ul><li>Less tachycardia than phentolamine </li></ul><ul><li>May be used in ambulatory patients </li></ul><ul><li>May produce severe hypotension after the first dose (First Dose Phenomenon) </li></ul><ul><li>Short acting </li></ul><ul><ul><li>doxazosin - longer half-life </li></ul></ul>
  18. 18. Adrenaline “reversal” adrenaline adrenaline Prazosin Blood Presure Blockade of vasoconstrictor  1 -adrenoceptors reveals vasodilator  -adrenoceptors Time Time Blood pressure recordings in anaesthetised dog
  19. 19. Alpha antagonists: Uses <ul><li>Hypertension –  1 -selective only </li></ul><ul><ul><li>Prazosin </li></ul></ul><ul><ul><li>Doxazosin </li></ul></ul><ul><li>Phaeochromocytoma </li></ul><ul><ul><li>tumor of adrenal medulla </li></ul></ul><ul><ul><li>high levels of adrenaline and NE </li></ul></ul><ul><ul><li>hypertension, sometimes fatal </li></ul></ul><ul><ul><li>alpha blockers used before surgery </li></ul></ul><ul><li>Treat vasoconstrictor toxicity </li></ul><ul><li>Benign prostatic hypertrophy - prazosin (relax sphincter) </li></ul>
  20. 20. Beta antagonists: Types <ul><li>Nonselective - block  1 and  2 receptors </li></ul><ul><ul><li>Propranolol </li></ul></ul><ul><li>Relatively selective   - in high doses block both  1  and    receptors </li></ul><ul><ul><li>Metoprolol </li></ul></ul><ul><ul><li>Atenolol </li></ul></ul><ul><li>Relatively selective   </li></ul><ul><ul><li>Butoxamine </li></ul></ul><ul><ul><li>ICI 118551 </li></ul></ul><ul><li>intrinsic activity - block and stimulate </li></ul><ul><ul><li>Pindolol </li></ul></ul>
  21. 21. Beta antagonists - structure Propranolol (non-selective) Atenolol (  1 -selective) ICI 118551 (  2 -selective) Pindolol (intrinsic activity)
  22. 22. Effect of a beta-antagonist on heart rate
  23. 23. Non-selective  -antagonist Propranolol <ul><li>Blocks  1 and  2 receptors </li></ul><ul><li>First  -antagonist approved </li></ul><ul><li>High first pass metabolism e.g. 70% </li></ul><ul><li>Parenteral doses much lower than oral doses </li></ul><ul><li>Lipid soluble and passes the blood/brain barrier </li></ul><ul><li>Some effects do not correlate with blood levels </li></ul>
  24. 24. Adrenaline with and without propranolol adrenaline adrenaline propranolol Blodd Pressure Blockade of vasodilator  -adrenoceptors reveals vasoconstrictor  -adrenoceptors Time Time
  25. 25. Propranolol Bioavailability Peripheral Circulation propranolol Intestine Portal vein liver 100 % 30 % metabolites 70 %
  26. 26. Selective   -antagonist Atenolol <ul><li>Blocks  1 –receptors >  2 -receptors </li></ul><ul><li>Most prescribed adrenergic antihypertensive </li></ul><ul><ul><li>9,700 DDD/day </li></ul></ul><ul><li>Lipid soluble and passes the blood/brain barrier </li></ul><ul><li>Less side effects than propranolol </li></ul>
  27. 27. Effects of Beta Blockade <ul><li>Cardiovascular </li></ul><ul><ul><li>lowered heart rate and stroke volume - cardiac output less </li></ul></ul><ul><ul><li>lowered renin release </li></ul></ul><ul><ul><li>initial increase in peripheral resistance possible </li></ul></ul><ul><ul><li>long-term reduction in BP </li></ul></ul><ul><li>Respiratory </li></ul><ul><ul><li>increased airway resistance -   blockade </li></ul></ul><ul><ul><li>often fatal increase in asthmatics </li></ul></ul><ul><ul><li>all beta blockers contraindicated in asthma </li></ul></ul><ul><li>Metabolic </li></ul><ul><ul><li>increased triglycerides </li></ul></ul><ul><ul><li>increased fatigue (lowered glucose mobilization) </li></ul></ul>
  28. 28. Relative Contraindications <ul><li>Congestive heart failure </li></ul><ul><li>Sinus bradycardia </li></ul><ul><li>AV block </li></ul><ul><li>Diabetes </li></ul><ul><ul><li>lack of tachycardia with hypoglycemia </li></ul></ul><ul><ul><li>inhibits physiological response to hypoglycemia </li></ul></ul><ul><li>Peripheral vascular disease </li></ul><ul><li>Asthma </li></ul>
  29. 29. Antagonists with Intrinsic Sympathomimetic Activity Pindolol <ul><li>Interacts with  1 and  2 receptors </li></ul><ul><li>Blocks the interaction of noradrenaline and adrenaline with the beta receptors </li></ul><ul><li>Turns on the receptors slightly </li></ul><ul><li>Substitutes high beta activity for a more modest beta activity </li></ul><ul><li>Reduces high beta receptor activity; functionally a blocker </li></ul>
  30. 30. Clinical uses of  -antagonists <ul><li>Hypertension </li></ul><ul><ul><li>along or with a diuretic &/or calcium channel blocker </li></ul></ul><ul><ul><li>especially good in patients with high cardiac output </li></ul></ul><ul><li>Ischaemic heart disease </li></ul><ul><ul><li>decreases cardiac work and O 2 demand </li></ul></ul><ul><ul><li>prolongs survival </li></ul></ul><ul><li>Cardiac arrhythmias </li></ul><ul><ul><li>supraventricular and ventricular </li></ul></ul><ul><ul><li>increases AV conduction time - protects ventricle from high atrial rates </li></ul></ul><ul><li>Heart failure </li></ul><ul><ul><li>prolongs survival with angiotensin converting enzyme inhibitors </li></ul></ul>
  31. 31. Clinical uses of  -antagonists (cont) <ul><li>Glaucoma - applied topically </li></ul><ul><li>Hyperthyroidism </li></ul><ul><ul><li>symptomatic relief only </li></ul></ul><ul><ul><li>lowers beta receptor activation </li></ul></ul><ul><ul><li>inhibits conversion of thyroxine to triiodothyronine </li></ul></ul><ul><li>Migraine prophylaxis </li></ul><ul><li>Recent myocardial infarction (?) </li></ul>
  32. 32. Agonist structure-activity relationships <ul><li>When R1+2 groups are OH’s - catecholamine and decreases oral bioavailability </li></ul><ul><li>Substitution on amine group R3 - increased  selectivity </li></ul><ul><li>Substitutions on the  carbon blocks metabolism by MAO </li></ul><ul><li>OH at  carbon enhances adrenoceptor activating properties </li></ul>
  33. 33. Cartoon of adrenergic receptors showing the 7 transmembrane spanning domains G S Family G i/o Family Adenylyl cyclase +ve -ve ATP cAMP  -adrenoceptors  2 -adrenoceptors Biological response cAMP dependent protein kinase
  34. 34. Structure-activity relationships Looking down on the  -adrenoceptor from outside the membrane with adrenaline in the binding site between transmembrane domains 3,5 and 6 (model based on rhodopsin crystal structure) TM3 TM5 TM6
  35. 35. Structure-activity relationships close up of binding site with adrenaline TM6 TM6 TM3
  36. 36. Agonist structure-activity relationships
  37. 37. Antagonist structure-activity relationships
  38. 38. Indirect sympatholytics NA NA NA MeNA Tyrosine Dopamine DOPA NA NA NA Uptake 1 Vesicular transporter TH DDC D  H Reserpine -ve Guanethidine -ve MethylDOPA  -Methyl tyrosine -ve
  39. 39. Indirect sympatholytics: <ul><li>Affect noradrenaline synthesis </li></ul><ul><ul><li> -methyl-p-tyrosine </li></ul></ul><ul><ul><ul><li>Inhibits tyrosine hydroxylase </li></ul></ul></ul><ul><ul><ul><li>Occasionally used in pheochromocytoma </li></ul></ul></ul><ul><ul><ul><li>Side effects Hypotension and sedation </li></ul></ul></ul><ul><ul><li>Methyldopa </li></ul></ul><ul><ul><ul><li>Precursor of false transmitter Methylnoradrenaline </li></ul></ul></ul><ul><ul><ul><li>Hypertension in pregnancy </li></ul></ul></ul><ul><ul><ul><li>Side effects – hypotension and sedation </li></ul></ul></ul><ul><ul><li>Reserpine </li></ul></ul><ul><ul><ul><li>Prevents vesicular uptake of noradrenaline </li></ul></ul></ul><ul><ul><ul><li>Hypertension (obsolete) </li></ul></ul></ul><ul><ul><ul><li>Side effects – hypotension, sedation, depression </li></ul></ul></ul>
  40. 40. Indirect sympatholytics: <ul><li>Inhibit noradrenaline release </li></ul><ul><ul><li>Guanethidine </li></ul></ul><ul><ul><ul><li>Hypertension (obsolete) </li></ul></ul></ul><ul><ul><ul><li>Side effects – hypotension and sedation </li></ul></ul></ul>

×