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: 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

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