cholinomimetics: cholinoreceptor-activating & cholinesterase-inhibiting drugs synchronous

pharm synchronous lecture

cholinergic agonists

anything that mimics ACh

AChE inhibitor

breaks down ACh

indirect acting types

reversible

irreversible

reversible indirect acting

AChE inhibitors

irreversible indirect acting

anticholinesterases

nicotinic

high affinity to nicotine

muscarinic

high affinity to alcohol

where is ACh used as a neurotransmitter?

released from the pre-ganglionic neuron in sympathetic innervation for adrenal medulla, sympathetic, and parasympathetic

released from the post-ganglionic neuros in parasympathetic

released from the neuron in somatic

steps in cholinergic neurotransmission

Steps in Cholinergic Neurotransmission:

1. Synthesis of Acetylcholine (ACh)

2. Storage of Acetylcholine

3. Action Potential & Depolarization

4. Calcium Influx

5. Release of Acetylcholine

6. Binding to Receptors

7. Degradation of Acetylcholine

8. Reuptake of Choline

Synthesis of Acetylcholine (ACh)

ACh is synthesized in the nerve terminal from choline and acetyl-CoA through the enzyme choline acetyltransferase

Storage of ACh

once synthesized, ACh is stored in vesicles within the pre-synaptic neuron

action potential and depolarization

an AP reaches the presynaptic terminal, causing depolarization of the neuron and opening of voltage gated calcium channels

calcium influx

calcium enters the neuron, triggering fusion of ACh-containing vesicles with the presynaptic membrane

release of ACh

ACh is released into the synaptic cleft via exocytosis

binding to receptors

ACh binds to cholinergic receptors on post-synaptic membrane, leading to a physiological response

degradation of ACh

ACh is rapidly broken down in the synaptic cleft by the enzye AChE into choline and acetate

reuptake of choline

choline is taken back into the presynaptic terminal via a high-affinity choline transporter for reuse in synthesizing more ACh

7 potential sites of drug action

1. inhibition of ACh synthesis

2. inhibition of ACh storage

3. inhibition of ACh release

4. Modulation of calcium channels

5. receptor agonists/antagonists

6. inhibition of AChE

7. reuptake inhibition

indirect acting cholinergic agonists

not directly acting on receptor

high affinity Na-choline co-transporter

ACh-H+ antiport channel

exocytosis of synaptic vesicles

synaptic cleft: Ach is degraded via AChE

direct acting cholinergic agonists

mimic ACh

botox

acts as a cholinergic blocker

muscarinic ACh receptors

GPCR

slower than nAChR

nicotinic ACh receptors

ion-channel (ligand gated)

fast acting

M1, M3, M5

Gq (excitatory)

increase Ca2+ intracellularly

M2, M4

Gi (inhibitory)

increases K+ channel (efflux)

causes hyperpolarization

nicotinic receptors

opens Na+/K+

excitatory

5 subunit receptor

Nm or Nn

Nm

aka N1

at NMJ: 2alpha, B, gamma, eplison

Nm

N2

autonomic ganglia

adrenal medulla

CNS

made of 2alpha, 3 beta

muscarinic M1

autonomic ganglia

CNS

Gq→ IP3 and DAG formation, increases intracellular Ca2+

EPSP, increased cellular excitability

muscarinic M3

smooth muscle

Gq→ IP3 and DAG formation, increases intracellular Ca2+

contraction

muscarinic M5

CNS, vascular endothelium

Gq→ IP3 and DAG formation, increases intracellular Ca2+

contraction

muscarinic M2

myocardium

Gi→ inhibition of AC

B gamma→K+ channel opening

hyperpolarization, suppress excitability

muscarinic M4

CNS

Gi→ inhibition of AC

B gamma→K+ channel opening

suppress excitability

nicotinic Nm

skeletal muscle

NMJ

alpha1/2, beta1gamma pentamers

opening of Na+,K+ channels

depolarization, skeletal muscle contraction

nicotinic Nn

autonomic ganglia

adrenal medulla

CNS

pentamers with alphabeta only

opening of Na+, K+ channels

depolarization and firing of post ganglionic neuron

secretion of catecholamines

cholinergic agonists help to promote

SLUDD

contraction of eye (pupil constriction)

miosis

side effects of generalized cholinergic stimulation

diarrhea

miosis

urinary urgency

diaphoresis

nausea

types of cholinergic agonists

direct acting

indirect acting

direct acting

choline esters

alkaloids

indirect acting

reversible AChE inhibitors

irreversible AChE inhibitors

block ACh release; Botulinum toxin

clinical uses for reversible AChE inhibitors

myasthenia gravis

serious muscle weakness

affects:

• eyelid movement

• facial expression

• swallowing

• arms and legs

reversible AChE inhibitors

prolongs ACh in the synaptic cleft

prolonged effect on both M and N cholinergic receptors

edrophonium

short acting reversible AChE inhibitor

indirect acting cholinergic agonist

neostigmine

non-depolarizing NM blocking

post surgery to increase muscle contraction

indirectly increase ACh

WARNING: bradycardia, blocks affect of muscarinic, blocks sympathetic

alzheimer’s disease

associated with loss of cholinergic neurons

decrease in ACh

ACh is important for

cognition

donepezil

AChE inhibitor

increase ACh levels indirectly

can cause delay in disease progression of alzheimer’s

WARNING: bradycardia, increase in urinary retention

irreversible AChE inhibitors

produce long lasting increase in ACh levels

developed as nerve agents

some are insecticides

antidote to nerve agents

atropine

acute intoxication by an irreversible AChE

muscarinic excess

CNS disturbances (cognitive disturbances, convulsions, coma)

peripheral (depolarizing NM blockade)

what do soldiers use to block excess ACh uptake?

pyridostigmine

neostigmine

indirect acting reversible cholinergic agonist

blocks AChE

will use when want muscles to work faster (muscle contraction)

can cause bradycardia bc will increase ACh which slows down HR

donepezil

indirect acting, reversible cholinergic agonist

used for delaying alzheimer’s symptoms

increase ACh since it blocks AChE

can cause bradycardia since ACh and decrease HR

can cause urinary retention bc ACh can activate sympathetic side and cause sphincter to contract and bladder to relax

organophosphate poisoning

N+ of PAM is attracted to the anionic site of AChE

PAM binds to the organophosphate, regenerating AChE

PAM + Atropine antidote

PAM CANNOT cross BBB

Atropine CAN cross BBB

effects of direct acting agonists (cholinergic)

EYE→ contraction (miosis)

HEART → vasodilation, decrease HR

BVs→ dilation; HIGH DOSE=contraction

LUNG→ bronchoconstriction

GI TRACT→ increase motility; relax sphincter; increase secretion

URINARY BLADDER → increase contraction of bladder, decrease sphincter (voiding)

GLANDS→ increase secretion

side effects of direct acting cholinergic agonists

diarrhea

miosis

increase urination

nausea

diaphoresis

pilocarpine

direct-acting muscarinic receptors

use for tx of dry mouth (increase salivation) and causes pupil constriction

can cause issues with driving at night→ bc constriction of the pupils can make it hard to see at night

WARNING: visual disturbances

three classes of anticholinergics

antimuscarinics

ganglionic blockers

neuromuscular blocking agents

where do anticholinergics act?

drugs that block and inhibit the activity of the neurotransmitter acetylcholine (ACh) at both central and peripheral nervous system synapses

antimuscarinic drugs

oppose SLUDD

inhibit muscarinic receptors on effector organs innervated by cholinergic parasympathetic neurons

atropine

acts centrally and peripherally

readily absorbed

EYE→ pupillary dilation, ciliary muscle dilation

GI→ reduced GI motility

URINARY SYSTEM→ reduces bladder motility

CV→ low dose: blocks presynaptic M1, increase ACh release; decrease HR

high dose: blocks M2, increases HR

SECRETIONS→ decrease salivary, sweat, lacrimal

• drying agent

therapeutic uses of atropine

ophthalmic→ mydriasis and cyclopegia

antispasmodic→ GI and urinary bladder relaxation

antidote for cholinergic agonists→ to treat OD of AChE inhibitors

antisecretory→ to block respiratory tract secretions before surgery

adverse effects of antimuscarinics

blurred vision

mydriasis (pupil dilation)

urinary retention

confusion

constipation

scopolamine

antimuscarinic

greater action on CNS

produce euphoria at higher dose (ABUSE)

USE: prophylactic use in motion sickness

adjunct in anesthetic procedures

tolterodine

muscarinic receptor antagonist

used to treat overactive bladder with urinary incontinence, urgency, and frequency

dry mouth is a side effect, bc OPPOSITE OF SLUDD

tiotropium

muscarinic receptor antagonist

M3 receptor antagonist

used for bronchodilation

can also be in nasal spray→ goes right to lungs

ganglionic blockers

act on nAChR on autonomic ganglia

rarely used therapeutically

nicotine

ganglionic blockers

USE: smoking suppressant

activated nicotinic receptors

increase BP and HR, and increased peristalsis and secretions

AT HIGH doses, can decrease BP

neuromuscular blocking (NM) drugs

work by blocking transmission between motor nerves and skeletal muscles

at the NMJ

prevent muscle contractions

types of neuromuscular blockers

non-depolarizing

depolarizing

non-depolarizing NM blockers

nAChR antagonists

end in -onium/-curiums

achieves skeletal muscle relaxation

these compete with ACh and precent binding

prevent depolarization, and inhibit contractions

competitive blockers

depolarizing NM blockers

nAChR agonists

mimic ACh

stimulate receptor for a long time

succinylcholine

phase I and phase II

end result: flaccid paralysis

rapid onset, profound relaxation, short duration

good for endotracheal intubation

choice of NM blocker depends on . . .

how quickly and how long muscle relaxation is needed

anticholinergic adverse effects

ABCDs

agitation

blurred vision

constipation and confusion

dry mouth

statis of urine and sweating