autocrine and endocrine system pharmacology

what are the principal transmitters in the ANS

ACh and NA

what do ACh and NA act on

NAChRs mAChRs alpha and beta adrenoreceptors

how can drugs target ANS receptors

indirectly or directly

indirect drug targeting via

synthesis, storage or breakdown

direct drug ANS targeting via

agonists, antagonists

which neurotransmitter do most organs if the sympathetic organs use

NA

which neurotransmitter do sweat glands use in the sympathetic system

ACh

what neurotransmitter do postganglionic neurons of the parasympathetic nervous system use

ACh

what receptors do organs that are innervated by postganglionic parasympathetic neurons express

muscarinic ACh receptors

what are muscarinic receptors antagonised by

atropine

what does atropine do

blocks the effect of ACh or muscarine on muscarinic receptors

how many muscarinic subtypes are there

5

what does curare do?

blocks nicotinic ACh receptors

what are the nicotine like effects caused by blocking muscarinic receptors with atropine and larger doses of ACh

stimulation of all autonomic ganglia

stimulation of voluntary muscle

secretion of adrenaline from adrenal medulla

how can nicotine-like effects be caused

blocking muscarinic effects with atropine and larger doses of ACh

what are the 5 subtypes of muscarinic receptors

M1 to 5

what type of receptors are muscarinic receptors

G protein coupled receptors

what G protein are M1, M3 and M5 coupled to

Gq

where are M3 receptors found

endothelial cells

what do M3 receptors do

regulate the production of NO which leads to vasodilation and a drop in blood pressure

where are M1 receptors found

glands and GI system

what do M1 receptors regulate

acid secretion

what G protein are M2 and M4 receptors coupled to

Gi

where are M2 receptors found

in the pacemaker cells and atrial muscle of the heart

what do M2 receptors regulate in the heart

the rate of contraction

what is the downstream cascade of M2 receptor agonist binding

inhibits adenylyl cyclase and cAMP

activates GIRK via beta gamma subunit

inhibits L-type calcium channels

what is a muscarinic receptor agonist of M2 receptor

pilocarpine

how does agonist binding lead to decreased contractility of the heart

adenylyl cyclase inhibited = decreased cAMP

decrease in PKA activity

decreased phosphorylation of L type calcium ions

decreased contractility

what does opening of GIRK channels do to the heart

increase in potassium

hyperpolarisation opposing pacemaker

slows heart rate

how do M2 receptors slow heart rate

mediates the effects of pilocarpine and slows heart rate by opening GIRK channels

what is the downstream cascade of M2 receptor agonist binding

activates GIRK via beta gamma subunit and inhibits L type calcium channels

how does agonist binding of M2 inhibit L type calcium channels

M2 receptors negatively coupled to adenylyl cyclase through Gi

less cAMP formation acting to inhibit the opening of L-type calcium channels

what does activation of M2 receptors do

cardiac slowing

decreased force of contraction in the atria

inhibition of atrioventricular conduction

how do M2 receptors slow heart rate

mediates the effects of pilocarpine and slows heart rate by opening GIRK

where would you find M1 and M3 receptors

smooth muscle and gland cells

what does activation of M1 and M3 receptors do

increase in calcium and contraction of smooth muscle

stimulate emptying of bladder

stimulate crying through tear glands

what receptors are in the smooth muscle lining the lungs

M1

what receptor increases the production of mucus in the lungs

M3

what do drugs that inhibit muscarinic receptors lead to

dry mouth

why does inhibition of muscarinic receptors lead to dry mouth

because they are involved in the release of saliva

what is an agonist of choline

muscarine

what does muscarine do to blood pressure

decreases

how does muscarine decrease blood pressure

activates muscarinic receptors on endothelial cells lining blood vessels

activates production of NO increasing vasodilation

decrease in cardiac output form M2 receptors

increased production of NO via M3 activation in endothelial cells

how do muscarine receptors increase salivary production

activation of M3 receptors

what does muscarine do to the heart

slows down the heart and decreases contractility

neural mAChR subtype

M1

cardiac mAChR subtype

M2

gladular/smooth muscle mAChR subtype

M3

main location of M4 mAChR subtype

CNS

main location of 5 mAChR subtype

iris, salivary glands, substantia nigra

example of clinical mAChr agonists

cevimeline, pilocarpine

what is cevimeline selective to

M3 receptors

effect of cevimeline

improves salivary and lacrimal secretions in sjogren’s syndrome

what is pilocarpine selective to

it is non-selective

how is pilocarpine applied

as eye drops

what treats glaucoma

pilocarpine

what is sjogrens syndrome

autoimmune destruction of minor salivary and lacrimal glands characterised by dry mouth and eyes

what is glaucoma

drainage tubes within the eye become slightly blocked and prevents aqueous humor from draining properly causing vision loss

why is pilocarpine not ingested

removes unwanted side effects

what is atropine

non-selective muscarinic antagonist

atropine effects on glands

inhibits salivary, lacrimal, bronchial and sweat secretion

what does atropine do to the urinary tract

relaxes

what does atropine do to the eyes

dilates

atropine on heart rate

increases

atropine effect on GI tract

reduces GI motility and acid secretion

atropine on smooth muscle

relaxes it

what is the use of atropine

asthma

atropine on the CNS

agitation and disorientation

atropine on body temperature

increases

what is pirenzepine

M1 selective muscarinic antagonist

what is darifenacin

M3 selective muscarinic antagonist

use of pirenzipine

treats peptic ulcers

use of Darifenacin

treats overactive bladder

green mamba snake venom

antagonist of muscarinic receptors

cholinomimetic drugs

mimic ACh by directly or indirectly activating the receptors which which ACh interacts

what do cholinomimetic drugs affect

preganglionic sympathetic and parasympathetic nicotinic ACh receptors as well as post ganglionic parasympathetic

physostigmine

acetylcholinesterase, increases levels of ACh

how is pysostigamine applied

locally in the form of eye drops

what is sarin

cholinergic agonist

how does sarin work

binds to acetylcholinesterase and makes an irreversible bond preventing it from being flushed out leading to a significant build up of ACh and activation of ACh receptors throughout the body

what are cholinomimetic

drugs acting indirectly to enhance cholinergic trasnmission

how do anticholinesterase drugs act

long acting

where are anticholinesterases found

in nerve gas, organophosphates and pesticides

clinical uses of anticholinesterase drugs

reverse action of neuromuscular blocking drugs after an operation

treatment of myasthenia gravis

alzheimers disease

glaucoma

what is sarin used in

nerve gas

where are adrenoreceptors found

on tissues responding to postganglionic sympathetic neurons smooth muscle and cardiac muscle

catecholamines

noradrenaline, adrenaline and dopamine

what type are receptors for noradrenaline and adrenaline

GPCRs

where are B2 selective agonists used

treats asthma

alpha 1 receptors effects q

vasoconstriction of blood vessels and kidney

what is more potent to alpha 1 receptors

noradrenaline

what g protein do alpha 1 receptors couple to

Gq

beta 2 receptors effects

vasodilation and bronchodilation

beta 1 receptor effect

increased heart rate and contractility

what neurotransmitter is most potent for beta receptors

isoprenaline

what g protein do beta receptors couple to

Gs

Alpha 2 receptors effect

clot formation

where are alpha 2 receptors found

blood cells

g proteins coupled to alpha 2 receptors Gi and Go

Gi and Go

which neurotransmitter is most potent for alpha 2 receptors

adrenaline