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Adrenergic Drugs II
- 1. Adrenergic Drugs IIAims 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: [email protected]
- 2. Sympathomimetics: Types Directacting - drugs that interact directly with adrenoceptors Noradrenaline Adrenaline Isoprenaline Phenylepherine Indirect acting - drugs that activate adrenergic receptors indirectly displace stored catecholamines from nerve terminals (e.g. amphetamine) inhibit uptake of catecholamines already released (e.g. cocaine) Mixed - both direct and indirect
- 3. Amphetamine - indirectagonist Non-catechol Good oral bioavailability CNS stimulant - more so than ephedrine Peripheral actions mainly through release of catecholamines from nerve terminals
- 4. Amphetamine - indirectagonist
- 5. Ephedrine Produced byvarious plants (Ma-huang) Noncatechol with good oral bioavailability Long acting Releases catecholamines from nerve terminal Some direct stimulation of and receptors Penetrates brain to produce CNS stimulation Traditional asthma remedy
- 6. Tyramine Releases noradrenalinefrom nerve terminals Found in fermented foods (e.g. cheese) Normally destroyed by MAOs in gut wall May produce hypertensive crisis in patients taking MAO inhibitors
- 7. Cocaine Blocks noradrenalinereuptake into nerve terminal Blocks most biogenic amine transporters Rapidly enters the CNS like amphetamine shorter acting more intense than amphetamine Most CNS effects non-adrenergic (5HT, dopamine) smoked, snorted and injected for rapid onset Peripheral sympathomimetic effects prominent Acute hypertension may cause heart failure, death
- 8. Close up ofAdrenergic 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. Sympathomimetic Uses hypotensionshock haemostasis nasal decongestion acute heart failure bronchial asthma anaphylaxis mydriasis premature labor weight reduction
- 10. Sympatholytics: Types Directacting - drugs that interact directly with adrenoceptors Propranolol Atenolol Phentolamine Prazosin Indirect acting - drugs that interfere with noradrenaline release affect noradrenaline synthesis Methyldopa, reserpine inhibit released Guanethidine
- 11. Directly acting sympatholytics- antagonists Non-selective Phentolamine -adrenoceptors Propranolol -adrenoceptors -selective Prazosin -adrenoceptors -selective Atenolol -adrenoceptors ICI 118551 -adrenoceptors
- 12. Adrenergic antagonists Alphablockers Not as clinically useful as beta blockers Mostly anti-hypertensives Selective 1 blockers are most the useful Competitive and and non-competitive types Beta blockers Many clinical uses All competitive Selective blockers available Some with intrinsic (agonist) activity
- 13. Non-selective alpha antagonistsPhentolamine Compeditive antagonist (reversible) Duration dependent upon elimination rate Generally fairly short acting Blocks both and receptors Tolazoline Similar to phentolamine Better absorbtion Phenoxybenzamine Irreversible - alkylates the receptor Long acting (14-48 hours) Blocks receptors
- 14. Non-selective alpha antagonists- structure Phentolamine Tolazoline Phenoxybenzamine Active intermediate (ethyleneimonium)
- 15. Effect of tolazolineand phenoxybenzamine on noradrenergic contraction in cat splenic strips + Tolazoline + Phenoxybenzamine Competitive vs non-competitive antagonism
- 16. Problems with non-selectivealpha antagonists Severe first dose hypotension on standing Reflex tachycardia Water retention Nasal congestion Some tolerance develops
- 17. Selective alpha antagonistsPrazosin Competitive Blocks receptors only Less tachycardia than phentolamine May be used in ambulatory patients May produce severe hypotension after the first dose (First Dose Phenomenon) Short acting doxazosin - longer half-life
- 18. Adrenaline “reversal” adrenalineadrenaline Prazosin Blood Presure Blockade of vasoconstrictor 1 -adrenoceptors reveals vasodilator -adrenoceptors Time Time Blood pressure recordings in anaesthetised dog
- 19. Alpha antagonists: UsesHypertension – 1 -selective only Prazosin Doxazosin Phaeochromocytoma tumor of adrenal medulla high levels of adrenaline and NE hypertension, sometimes fatal alpha blockers used before surgery Treat vasoconstrictor toxicity Benign prostatic hypertrophy - prazosin (relax sphincter)
- 20. Beta antagonists: TypesNonselective - block 1 and 2 receptors Propranolol Relatively selective - in high doses block both 1 and receptors Metoprolol Atenolol Relatively selective Butoxamine ICI 118551 intrinsic activity - block and stimulate Pindolol
- 21. Beta antagonists -structure Propranolol (non-selective) Atenolol ( 1 -selective) ICI 118551 ( 2 -selective) Pindolol (intrinsic activity)
- 22. Effect of abeta-antagonist on heart rate
- 23. Non-selective -antagonist Propranolol Blocks 1 and 2 receptors First -antagonist approved High first pass metabolism e.g. 70% Parenteral doses much lower than oral doses Lipid soluble and passes the blood/brain barrier Some effects do not correlate with blood levels
- 24. Adrenaline with andwithout propranolol adrenaline adrenaline propranolol Blodd Pressure Blockade of vasodilator -adrenoceptors reveals vasoconstrictor -adrenoceptors Time Time
- 25. Propranolol Bioavailability Peripheral Circulation propranolol Intestine Portal vein liver 100 % 30 % metabolites 70 %
- 26. Selective -antagonist Atenolol Blocks 1 –receptors > 2 -receptors Most prescribed adrenergic antihypertensive 9,700 DDD/day Lipid soluble and passes the blood/brain barrier Less side effects than propranolol
- 27. Effects of BetaBlockade Cardiovascular lowered heart rate and stroke volume - cardiac output less lowered renin release initial increase in peripheral resistance possible long-term reduction in BP Respiratory increased airway resistance - blockade often fatal increase in asthmatics all beta blockers contraindicated in asthma Metabolic increased triglycerides increased fatigue (lowered glucose mobilization)
- 28. Relative Contraindications Congestiveheart failure Sinus bradycardia AV block Diabetes lack of tachycardia with hypoglycemia inhibits physiological response to hypoglycemia Peripheral vascular disease Asthma
- 29. Antagonists with IntrinsicSympathomimetic Activity Pindolol Interacts with 1 and 2 receptors Blocks the interaction of noradrenaline and adrenaline with the beta receptors Turns on the receptors slightly Substitutes high beta activity for a more modest beta activity Reduces high beta receptor activity; functionally a blocker
- 30. Clinical uses of -antagonists Hypertension along or with a diuretic &/or calcium channel blocker especially good in patients with high cardiac output Ischaemic heart disease decreases cardiac work and O 2 demand prolongs survival Cardiac arrhythmias supraventricular and ventricular increases AV conduction time - protects ventricle from high atrial rates Heart failure prolongs survival with angiotensin converting enzyme inhibitors
- 31. Clinical uses of -antagonists (cont) Glaucoma - applied topically Hyperthyroidism symptomatic relief only lowers beta receptor activation inhibits conversion of thyroxine to triiodothyronine Migraine prophylaxis Recent myocardial infarction (?)
- 32. Agonist structure-activity relationshipsWhen R1+2 groups are OH’s - catecholamine and decreases oral bioavailability Substitution on amine group R3 - increased selectivity Substitutions on the carbon blocks metabolism by MAO OH at carbon enhances adrenoceptor activating properties
- 33. Cartoon of adrenergicreceptors 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. Structure-activity relationships Lookingdown 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. Structure-activity relationships close up of binding site with adrenaline TM6 TM6 TM3
- 36.
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- 38. Indirect sympatholytics NANA 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. Indirect sympatholytics: Affectnoradrenaline synthesis -methyl-p-tyrosine Inhibits tyrosine hydroxylase Occasionally used in pheochromocytoma Side effects Hypotension and sedation Methyldopa Precursor of false transmitter Methylnoradrenaline Hypertension in pregnancy Side effects – hypotension and sedation Reserpine Prevents vesicular uptake of noradrenaline Hypertension (obsolete) Side effects – hypotension, sedation, depression
- 40. Indirect sympatholytics: Inhibitnoradrenaline release Guanethidine Hypertension (obsolete) Side effects – hypotension and sedation