Adrenergic Drugs II
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Adrenergic Drugs II

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Adrenergic Drugs

Adrenergic Drugs

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Adrenergic Drugs II Adrenergic Drugs II Presentation Transcript

  • 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
    • Direct acting - 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
  • Amphetamine - indirect agonist
    • Non-catechol
    • Good oral bioavailability
    • CNS stimulant - more so than ephedrine
    • Peripheral actions mainly through release of catecholamines from nerve terminals
  • Amphetamine - indirect agonist
  • Ephedrine
    • Produced by various 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
  • Tyramine
    • Releases noradrenaline from 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
  • Cocaine
    • Blocks noradrenaline reuptake 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
  • 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
    • hypotension
    • shock
    • haemostasis
    • nasal decongestion
    • acute heart failure
    • bronchial asthma
    • anaphylaxis
    • mydriasis
    • premature labor
    • weight reduction
  • Sympatholytics: Types
    • Direct acting - 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
  • Directly acting sympatholytics - antagonists
    • Non-selective
      • Phentolamine  -adrenoceptors
      • Propranolol  -adrenoceptors
    •  -selective
      • Prazosin   -adrenoceptors
    •  -selective
      • Atenolol   -adrenoceptors
      • ICI 118551   -adrenoceptors
  • Adrenergic antagonists
    • Alpha blockers
      • 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
  • Non-selective alpha antagonists
    • Phentolamine
      • 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
  • 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
    • Severe first dose hypotension on standing
    • Reflex tachycardia
    • Water retention
    • Nasal congestion
    • Some tolerance develops
  • Selective alpha antagonists Prazosin
    • 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
  • 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
    • Hypertension –  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)
  • Beta antagonists: Types
    • Nonselective - 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
  • 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
    • 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
  • 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
    • 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
  • Effects of Beta Blockade
    • 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)
  • Relative Contraindications
    • Congestive heart failure
    • Sinus bradycardia
    • AV block
    • Diabetes
      • lack of tachycardia with hypoglycemia
      • inhibits physiological response to hypoglycemia
    • Peripheral vascular disease
    • Asthma
  • Antagonists with Intrinsic Sympathomimetic 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
  • 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
  • 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 (?)
  • Agonist structure-activity relationships
    • When 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
  • 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:
    • Affect noradrenaline 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
  • Indirect sympatholytics:
    • Inhibit noradrenaline release
      • Guanethidine
        • Hypertension (obsolete)
        • Side effects – hypotension and sedation