BGDA - Autonomic Pharmacology

Sympathetic nervous system

division of the autonomic nervous system that triggers the body’s rapid "fight-or-flight" response to danger or stress.

Parasympathetic nervous system

division of the autonomic nervous system for the "rest and digest" or "feed and breed" functions.

Chemoreceptors

aortic arch receptor detecting low oxygen increases vagal activity, leading to a decrease in heart rate.

Baroreceptors

aortic arch receptor detecting increased blood pressure, triggering increased vagal activity, decreasing heart rate (and vis versa).

Autonomic nervous system

division of the peripheral nervous system under involuntary control, including smooth muscle, glands, heart, and metabolic processes.

Dual innervations

organs receive impulses sympathetic and parasympathetic motor neurons.

Antagonistic actions (physiological antagonism)

opposite actions from either divisions lead to physiological balance (i.e. homeostasis), e.g. excitatory vs. inhibitory

Acetylcholine

neurotransmitter released by parasympathetic preganglionic neuron.

Acetylcholine

neurotransmitter released by sympathetic preganglionic neuron.

Acetylcholine

neurotransmitter released by parasympathetic postganglionic neuron.

Noradrenaline (mostly)

neurotransmitter released by sympathetic postganglionic neuron.

Nicotinic cholinergic

ganglion receptor for both the parasympathetic and sympathetic nervous systems.

Muscarinic cholinergic

effector receptor for parasympathetic postganglionic neurotransmitters.

Adrenergic

effector receptor for sympathetic postganglionic neurotransmitters.

Cholinergic

neurons/axons that release acetylcholine (ACh) as their primary neurotransmitter.

Innervating sweat glands

What is the exception for sympathetic postganglionic neurons being cholinergic?

Synthesis, packaging, release, receptor activation, removal

What are the 5 steps to cholinergic neurotransmission?

Synthesis (1)

Choline is transported by choline transporter (CHT) and reacts with AcCoA to form ACh.

Packaging (2)

ACh is transported into vesicles by the vesicle associated transporter (VAT).

Release (3)

fusion of vesicles with membrane and expulsion of ACh into synaptic cleft (exocytosis).

Receptor activation (4)

ACh activates cholinergic receptors to produce cellular functions.

Removal (5)

Acetylcholinesterase (AChE) hydrolyses ACh into choline and acetate.

Choline transporter

transports choline from the synaptic cleft back into the presynaptic cholinergic nerve terminal, where it is reused to synthesise acetylcholine.

Vesicle-associated transporter (VAT)

transports acetylcholine from the cytoplasm into synaptic vesicles for storage and later release.

Acetylcholinesterase (AChE)

enzyme in the synaptic cleft that rapidly breaks down acetylcholine into choline and acetate, terminating the signal.

SNARE complex

group of proteins that dock and fuse acetylcholine-containing vesicles with the presynaptic membrane, allowing Ca²⁺-triggered release of acetylcholine into the synaptic cleft.

Muscarinic receptors

G-protein coupled receptors activated by muscarine.

M1, M3, M5

Gq coupled muscarinic receptors.

M2, M4, Gi coupled muscarinic receptors.

Gq coupled (”excitatory”) muscarinic receptors

muscarinic receptors that activate Gq/11-phosphatidyl inositol pathway to increase Ca2+ influx.

Gi coupled (”inhibitory”) muscarinic receptors

muscarinic receptors that activate Gi and adenylyl cyclase inhibition to reduce cAMP formation.

Nicotinic receptors

ligand-gated ion channels activated by nicotine, made up of a combination of α, β, γ, δ, and ε subunits.

Neuronal-types (Nn)

nicotinic receptors formed from α +/-β subunits.

Muscle-types (Nm)

nicotinic receptors formed from α, β, γ, δ, and ε subunits.

M1 muscarinic receptor

cholinergic receptor that mainly stimulates gland secretion and neuronal activity (e.g. gastric acid secretion in the stomach and CNS/autonomic ganglia signalling).

M2 muscarinic receptor

cholinergic receptor that slows the heart by decreasing heart rate and reducing AV node conduction.

M3 muscarinic receptor

cholinergic receptor that contracts smooth muscle and increases gland secretion (e.g. bronchoconstriction, increased GI motility, bladder contraction, salivation, pupil constriction).

Nn nicotinic receptor (neuronal)

cholinergic receptor that causes rapid depolarisation in autonomic ganglia and adrenal medulla, transmitting autonomic nerve signals and stimulating adrenaline release.

Nm nicotinic receptor (muscle)

cholinergic receptor that causes skeletal muscle contraction at the neuromuscular junction.

Neuromuscular junction (NMJ) blocking agents

drugs prevent transmission between motor nerves into nicotinic cholinergic receptors at skeletal muscle, causing skeletal muscle paralysis.

Neuromuscular junction (NMJ)

synapse where acetylcholine (ACh) is released from the nerve terminal, binds Nm nicotinic receptors on the muscle end plate, depolarises the muscle membrane, and triggers skeletal muscle contraction.

Tetanic fade

occurs for non-depolarising NMJ blockers, failure of ACh release at neuromuscular junction causes contraction of muscles under rapid stimulation to gradually become weaker.

Non-depolarising

NMJ blocking agent, competitive antagonists that act to block Nm nicotinic receptors at the NMJs, blocking pre and post synaptic nicotinic receptors. Increased ACh can reverse the effect.

Depolarising

NMJ blocking agent, agonists at nicotinic receptors that initially cause muscle twitching, followed by paralysis by maintaining muscle depolarisation.

Botulinum toxin

drug blocking presynaptic ACh release by cleaving SNARE complex with release of light chain subunit, preventing vesicle fusion at cholinergic nerve terminals.

Acetylcholinesterase (AChE) inhibitors

competes with ACh for binding to AChE, preventing ACh hydrolysis, increasing levels at the synaptic cleft.

Myasthenia gravis (MG)

autoimmune disorder in which antibodies destroy neuromuscular junctions by targeting and reducing nicotinic receptors at the NMJ.

Pancuronium/vecuronium

pure synthetic non-depolarising NMJ blockers with a fast onset, shorter duration of action and will not pass blood-brain barrier (less side effects).

Succinylcholine

depolarising NMJ blocker causing persistent depolarisation of the motor end plate, causing rapid-onset paralysis.

Miosis

constricted pupils, due to contraction of the iris sphincter muscle (M3).

Accommodation

ability to adjust its focus from distant to near objects by contraction of the ciliary muscle (M3).

Aqueous production

humour is produced by the ciliary epithelium (α2/β2).

Mydriasis

excessive dilation of the pupil, due to contraction of the radial muscle (α1).

Glaucoma

progressive optic nerve damage with irreversible vision loss due to increased intraocular pressure (IOP) due to reduced aqueous humour (produced by ciliary epithelium) drainage.

Intraocular pressure (IOP)

fluid pressure inside eye, can be reduced by increasing aqueous humour outflow, and decreasing aqueous humour production.

Open-angle

glaucoma where the drainage pathway is physically open but clogged.

Closed-angle

glaucoma where the iris physically blocks the drainage canals.

Muscarinic agonists

stimulate M3 receptors to contract ciliary and iris sphincter muscle treating open-angle glaucoma and acute closed-angle glaucoma, e.g. pilocarpine, carbachol.

Pilocarpine, carbachol

M3 receptor agonist contracting ciliary and iris sphincter muscle treating open-angle glaucoma and acute closed-angle glaucoma.

Beta-adrenoceptor antagonist

activates β receptors in ciliary epithelium to reduce aqueous humour production, treating chronic open-angled glaucoma or ocular hypertension, e.g. timolol.

Timolol

β adrenoreceptor antagonist activating β receptors in ciliary epithelium to reduce aqueous humour production, treating chronic open-angled glaucoma or ocular hypertension

alpha 2 adrenoceptor agonists

activates presynaptic α2 autoreceptors before ciliary epithelial cells to reduce aqueous humour production, e.g. apraclonidine.

Apraclonidine

α2-adrenoceptor agonists activating presynaptic α2 autoreceptors before ciliary epithelial cells to reduce aqueous humour production.

Overactive bladder (OAB)

condition characterised by urinary urgency, sometimes with urinary incontinence, increased daytime frequency, and nocturia.

Storage phase

sympathetic dominant; detrusor relaxes and urethra contracts when noradrenaline triggers β3 and α1 receptors (+voluntary external urethral sphincter closing).

Voiding phase

parasympathetic dominant; detrusor contracts and internal urethral sphincter relaxes when M3 receptors are triggered (+voluntary external urethral sphincter opening).

Alpha 1 and beta 3 adrenoceptors

receptor triggering relaxation of the detrusor muscle and contraction of the internal urethral sphincter during the bladder storage phase

M3 muscarinic receptor

receptor triggering detrusor muscle contraction during voiding via phospholipase and increased intracellular Ca²⁺.

M3 muscarinic receptor

receptor triggering relaxation of the internal urethral sphincter during voiding to allow urine flow.

M3 muscarinic receptor

receptor triggering contraction of the iris sphincter muscle, causing miosis (pupil constriction).

M3 muscarinic receptor

receptor triggering contraction of the ciliary muscle, allowing accommodation for near vision.

Alpha 2 and beta 2 adrenoceptors

receptor regulating aqueous humour production by the ciliary epithelium.

Alpha 1 adrenoceptor

receptor triggering contraction of the radial iris muscle, causing mydriasis (pupil dilation).

Muscarinic antagonists

block M3 receptors on detrusor muscle to prevent ACh-mediated contraction relax bladder, increase capacity, and reduce urgency/frequency.

Solifenacin

selective M3 antagonist with fewer cardiac side effects than non-selective agents

Beta 3-adrenoceptor agonists

stimulates β3 receptors on detrusor muscle causes bladder relaxation and increases urine storage capacity, e.g. mirabegron.

Mirabegron

β3-adrenoceptor agonist stimulating β3 receptors on detrusor muscle causes bladder relaxation and increases urine storage capacity, e.g. mirabegron.

Botulinum toxin (Botox)

destroyed SNARE complex, preventing vesicle fusion for ACh release, thus reducing M3 receptor-mediated detrusor muscle contraction.

Drug selectivity

drug’s ability to produce the intended effect by binding more strongly or exerting greater functional effects at one target, compared with other targets.

Selective drugs

bind preferentially to one type of receptor (100-fold selectivity = therapeutically selective).

Non selective drugs

bind to multiple receptors, usually receptors that are closely related.

Side effects

secondary effects that occur in addition to the intended therapeutic effect.

Adverse effects

undesired, harmful, or unpleasant side effects that occur when the treatment is administered correctly.

Clinical trials, pharmacovigilance reporting

What are the 2 ways in which adverse effects are detected?

On-target effects

side effects or adverse effects at the intended receptor in the intended or unintended tissue.

Off-target effects

side effects or adverse effects at the unintended receptor in the intended or unintended tissue.

Adrenaline (epinephrine)

hormone mostly produced by the adrenal glands.

Noradrenaline (norepinephrine)

neurotransmitter mostly produced by the sympathetic nervous system, with remaining produced by the adrenal glands.

Alpha 1 adrenoceptors

types A, B, D, Gαq-coupled receptors that increase calcium.

Alpha 2 adrenoceptors

types A, B, C, Gαi-coupled receptors that DECREASE cAMP production.

Beta adrenoceptors

types 1, 2, and 3, Gαs-coupled receptors that increase cAMP production.

-olol

conventional suffix for β adrenoceptor antagonists (β blockers).

-ol

conventional suffix for β adrenoceptor agonists.

-osin

conventional suffix for α adrenoceptor antagonists.

None

conventional suffix for α adrenoceptor agonists.

Alpha 1 adrenoceptor

receptor triggering smooth muscle contraction via phospholipase C → IP₃ + DAG → release of Ca²⁺.

Beta 2 and 3 adrenoceptors

receptor triggering smooth muscle relaxation via adenylyl cyclase → increase of cAMP → protein kinase activation → blocking myosin phosphorylation.

Beta 1 adrenoceptor

receptor triggering cardiac muscle contraction via adenylyl cyclase → increase of cAMP → protein kinase activation → release of Ca²⁺.

Selective beta 2 adrenoceptor agonist

drug causing relaxation of smooth muscle in bronchi used to relieve bronchospasms in asthma or chronic obstructive pulmonary disease.

Salbutamol

selective β2 adrenoceptor agonist causing relaxation of smooth muscle in bronchi used to relieve bronchospasms in asthma or chronic obstructive pulmonary disease.