Drug Innov Week 8

What are the steps in the catecholamine synthesis pathway

Tyrosine → L-DOPA → Dopamine → Noradrenaline (norepinephrine) → Adrenaline (epinephrine)

What are catecholamines

Tyrosine-derived signalling molecules that drive sympathetic 'fight-or-flight' activity via adrenoceptors

What is epinephrine

Adrenaline – released from the adrenal medulla into the circulation

What is norepinephrine

Noradrenaline – the principal neurotransmitter at sympathetic nerve endings

What are the two receptor families for catecholamines

α (alpha) and β (beta)

What determines the effects of catecholamines

which receptor subtype a drug engages and where that receptor sits in the body – the same transmitter can constrict one vessel and dilate another

what happens when noradrenaline is released into the synapse

it acts on pre- and post-synaptic adrenoceptors, then is recaptured

what does noreadrenaline receptor binding trigger

intracellular second-messenger cascades (cAMPs)

what are all the Adrenoceptors

α1

α2

β1

β2

β3

Where are α1 receptors located

Arteries (vascular smooth muscle)

what do α1 receptors do

Vasoconstriction → increased blood pressure

what are the subtypes of α1 receptors

α1A, α1B, α1D

Where are α2 receptors located

Presynaptic nerve terminals; pancreas

what do α2 receptors do

Autoregulation - negative feedback that reduces noradrenaline release

inhibits insulin

what are the α2 subtypes

α2A, α2B, α2C

Where are β1 receptors located

Myocardium (heart muscle)

what do β1 receptors do

Increased rate and force of contraction (positive chrono- & inotropy)

Where are β2 receptors located

Bronchioles; vessels of skeletal muscle, heart, kidney, brain

what do β2 receptors do

Bronchodilation and increased tissue perfusion when stimulated

Where are β3 receptors located

Adipose tissue, gall & urinary bladder

what do β3 receptors do

Lipolysis; may also be present in heart and vessels

What is the clinical key about α & β receptors

α & β receptors are unevenly distributed – so selectivity for a subtype determines a drug's therapeutic target and side-effect profile

What are α1 stimulation clinical uses

Hypotension – nasal decongestion

What are β1 stimulation clinical uses

Shock – hypotension – cardiac arrest

What are β2 stimulation clinical uses

Asthma – COPD – preterm labour

What are examples of direct α1-agonists

Phenylephrine, midodrine, oxymetazoline, naphazoline, xylometazoline

What is the warning about topical decongestants

Topical decongestants not for prolonged use – rebound congestion

What are positive inotropes

Drugs that raise cardiac rate & force

What is dobutamine

Selective β1-agonist

What are β2-agonists often paired with

Antimuscarinic (tiotropium) ± inhaled corticosteroid

What is the warning about high-dose nebulised β2-agonists

High-dose nebulised → hypokalaemia

What does the presynaptic α2 autoreceptor do

negative feedback (autoinhibition) reducing further noradrenaline release

What does the post synaptic α2 autoreceptor on the pancreas do

inhibits insulin secretion

What are direct-acting sympathomimetics

Agonists that bind the adrenoceptor directly (e.g., adrenaline)

What are indirect-acting sympathomimetics

Trigger release of stored transmitter

What type of action do ephedrine/pseudoephedrine have

Mixed (direct + indirect) action

What are sympatholytics

Block release of, or deplete stores of, the adrenergic transmitter – e.g., tetrabenazine (central depletion)

Does the body have natural adrenergic antagonists

no

What are the clinical uses of α-antagonists

Hypertension – peripheral vascular disease – BPH

What are the clinical uses of β-antagonists ('β-blockers')

Hypertension – angina – arrhythmia – bronchospasm control

What are inotropes for circulatory shock

Dopamine and dobutamine (a direct-acting β1-agonist) raise cardiac output

Why is carvedilol used for heart failure

It blocks β receptors AND α1 – reducing afterload while protecting the failing myocardium

what are the types of cholinergic receptors

Nicotinic receptors

Muscarinic receptors

what are nicotinic receptors stimulated by

nicotine (not muscarine)

they are ligand gated channels

how do nicotinic receptors work

Na⁺ influx → depolarisation → muscle contraction

what are nicotinic receptors built from

α, β, ε, δ subunits - e.g. (α7)₅ and (α1)₂β1ε δ

what antagonises nicotinic receptors

Atracurium antagonises them - muscle relaxation for intubation

what are Muscarinic receptors stimulated by

Mainly stimulated by acetylcholine. G-protein coupled (M1-M5)

which muscarinic receptors are well characterised

M1, M2, M3

what does M2 do

on heart → decreases force of contraction

what is a muscarinic receptor agonist

Bethanechol → promotes bladder emptying

What are the key ligands & source for cholinergic receptors

Acetylcholine, muscarine, nicotine

what do AChE inhibitors Donepezil, galantamine, rivastigmine do

raise synaptic ACh - used for the cognitive symptoms of dementia (Alzheimer’s)

what are the 4 classes of Cholinergic receptor blockers

Depolarising NMJ blockers

Non-depolarising NMJ blockers

Muscarinic blockers (~20 drugs)

Ganglionic blockade & nerve blockade

what is an example of a Depolarising NMJ blocker

Suxamethonium

what does Suxamethonium do

causes sustained depolarisation, preventing repolarisation. Broken down by pseudocholinesterase, not AChE. Used to relax muscles in ECT

what are Muscarinic blockers used as

antispasmodics, antiemetics, premedication, antiasthma & for incontinence

what are examples of Ganglionic blockade & nerve blockade

Botulinum toxin blocks ACh release → muscle paralysis

what does blocking muscarinic receptors reverse

the 'rest-and-digest' effects – drying secretions, dilating pupils, relaxing smooth muscle and speeding the heart

How is schizophrenia treated

By blocking dopamine receptors – effects may take weeks to appear

how do First-generation (‘typical’) antipsychotics work

Block central dopamine D2 receptors

what is the problem with first generation antipsychotics

Many side effects, including sedation

how do 2nd generation antipsychotics work

D2 + 5-HT2A + α1 antagonism

how do MARTA antipsychotics work

Multi-acting receptor-targeted agents act on 5- HT2A, D2, H1, 5-HT1A/1C and M

however risk of fatal agranulocytosis

what are the dopamine receptor subtypes

D1-D5