Adrenergic Drugs II

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

Sympathomimetics: Types ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Amphetamine - indirect agonist ,[object Object],[object Object],[object Object],[object Object]

Amphetamine - indirect agonist

Ephedrine ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Tyramine ,[object Object],[object Object],[object Object],[object Object]

Cocaine ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

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

Sympathomimetic Uses ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Sympatholytics: Types ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Directly acting sympatholytics - antagonists ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Adrenergic antagonists ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Non-selective alpha antagonists ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Non-selective alpha antagonists - structure Phentolamine Tolazoline Phenoxybenzamine Active intermediate (ethyleneimonium)

Effect of tolazoline and phenoxybenzamine on noradrenergic contraction in cat splenic strips + Tolazoline + Phenoxybenzamine Competitive vs non-competitive antagonism

Problems with non-selective alpha antagonists ,[object Object],[object Object],[object Object],[object Object],[object Object]

Selective alpha antagonists Prazosin ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Adrenaline “reversal” adrenaline adrenaline Prazosin Blood Presure Blockade of vasoconstrictor  1 -adrenoceptors reveals vasodilator  -adrenoceptors Time Time Blood pressure recordings in anaesthetised dog

Alpha antagonists: Uses ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Beta antagonists: Types ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Beta antagonists - structure Propranolol (non-selective) Atenolol (  1 -selective) ICI 118551 (  2 -selective) Pindolol (intrinsic activity)

Effect of a beta-antagonist on heart rate

Non-selective  -antagonist Propranolol ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Adrenaline with and without propranolol adrenaline adrenaline propranolol Blodd Pressure Blockade of vasodilator  -adrenoceptors reveals vasoconstrictor  -adrenoceptors Time Time

Propranolol Bioavailability Peripheral Circulation propranolol Intestine Portal vein liver 100 % 30 % metabolites 70 %

Selective   -antagonist Atenolol ,[object Object],[object Object],[object Object],[object Object],[object Object]

Effects of Beta Blockade ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Relative Contraindications ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Antagonists with Intrinsic Sympathomimetic Activity Pindolol ,[object Object],[object Object],[object Object],[object Object],[object Object]

Clinical uses of  -antagonists ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Clinical uses of  -antagonists (cont) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Agonist structure-activity relationships ,[object Object],[object Object],[object Object],[object Object]

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

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

Structure-activity relationships close up of binding site with adrenaline TM6 TM6 TM3

Agonist structure-activity relationships

Antagonist structure-activity relationships

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

Indirect sympatholytics: ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Indirect sympatholytics: ,[object Object],[object Object],[object Object],[object Object]

Adrenergic Drugs II

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