adrenergic drugs ii
DESCRIPTION
Adrenergic DrugsTRANSCRIPT
Adrenergic Drugs II
AimsTo 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]
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
CH2NH2
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
CH2
OH
CH3
N CH3
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
CH2NH2
HO
Cocaine
• Blocks noradrenaline reuptake into nerve terminalBlocks most biogenic amine transporters
• Rapidly enters the CNS like amphetamine shorter actingmore 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
DH
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-selectivePhentolamine -adrenoceptorsPropranolol -adrenoceptors
• -selectivePrazosin -adrenoceptors
• -selectiveAtenolol -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 - structureOH
N
H3C
CH2
NH
N
CH2
NH
N
O
NCl
CH3
NCH2
CH2+
Cl-
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 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
N
N N N C
O
NH2
CH3O
CH3O
O
Adrenaline “reversal”
adrenaline adrenaline
Prazosin
Blo
od
Pre
su
reBlockade of vasoconstrictor 1-adrenoceptors reveals vasodilator -adrenoceptors
Time Time
Blood pressure recordings in anaesthetised dog
Alpha antagonists: Uses
• Hypertension – 1-selective only PrazosinDoxazosin
• Phaeochromocytomatumor of adrenal medullahigh levels of adrenaline and NEhypertension, sometimes fatalalpha blockers used before surgery
• Treat vasoconstrictor toxicity
• Benign prostatic hypertrophy - prazosin (relax sphincter)
Beta antagonists: Types
• Nonselective - block 1 and 2 receptorsPropranolol
• Relatively selective - in high doses block both 1and receptorsMetoprololAtenolol
• Relatively selective ButoxamineICI 118551
• intrinsic activity - block and stimulatePindolol
Beta antagonists - structure
Propranolol (non-selective)
Atenolol (1-selective)
ICI 118551 (2-selective)
Pindolol (intrinsic activity)
O
OH
NH
CH3
CH3
H2N O NH
OHCH3
CH3O
O NH
OHCH3
CH3CH3
CH3
O NH
OHCH3
CH3HN
Effect of a beta-antagonist on heart rate
Non-selective -antagonistPropranolol
• 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
Blo
dd
Pre
ssu
reBlockade of vasodilator -adrenoceptors reveals vasoconstrictor -adrenoceptors
Time Time
Propranolol Bioavailability
Peripheral Circulation
propranolol
Intestine Portalvein
liver
100 %
30 %
metabolites70 %
Selective -antagonistAtenolol
• 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
• Cardiovascularlowered heart rate and stroke volume - cardiac output lesslowered renin releaseinitial increase in peripheral resistance possiblelong-term reduction in BP
•Respiratoryincreased airway resistance - blockadeoften fatal increase in asthmaticsall beta blockers contraindicated in asthma
•Metabolicincreased triglycerides increased fatigue (lowered glucose mobilization)
Relative Contraindications
• Congestive heart failure
• Sinus bradycardia
• AV block
• Diabeteslack of tachycardia with hypoglycemiainhibits 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• Hypertensionalong or with a diuretic &/or calcium channel blockerespecially good in patients with high cardiac output
• Ischaemic heart diseasedecreases cardiac work and O2 demandprolongs survival
• Cardiac arrhythmiassupraventricular and ventricularincreases AV conduction time - protects ventricle from high atrial rates
• Heart failureprolongs 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 atcarbon enhances adrenoceptor activating properties
R2
R1
CH2CH2 NH R3
Cartoon of adrenergic receptors showing the 7 transmembrane spanning domains
GS
Family
Gi/o
Family
Adenylyl cyclase
+ve -ve
ATPcAMP
-adrenoceptors 2-adrenoceptors
Biological responsecAMP 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
DH
Reserpine-ve
Guanethidine-ve
MethylDOPA
-Methyl tyrosine-ve
Indirect sympatholytics:
•Affect noradrenaline synthesis-methyl-p-tyrosineInhibits tyrosine hydroxylaseOccasionally used in pheochromocytoma
Side effects Hypotension and sedation
MethyldopaPrecursor of false transmitter MethylnoradrenalineHypertension in pregnancySide effects – hypotension and sedation
Reserpine
Prevents vesicular uptake of noradrenalineHypertension (obsolete)Side effects – hypotension, sedation, depression
Indirect sympatholytics:
Inhibit noradrenaline release Guanethidine Hypertension (obsolete) Side effects – hypotension and sedation