Week 9

Question 1

What is the best way to target action potential propagation

Answer 1

you can interfere with transmission with synapses
Best way to target ANS peripherally is at the level of tissue it’s innervating at level of junction

Question 2

What to target on parasympathetic nervous system

Answer 2

Target muscarinic receptors of effector organ

Question 3

What to target sympathetic nervous system

Answer 3

Target noradrenergic transmission

Question 4

Cholinergic modification

Answer 4

Synthesis ACh
Packaged into vesicles
Released by exocytosis
Act on receptors
Action being terminated by an enzyme- aceytylcholinesterase
Each step can be targeted with drugs, inhibitors for each pathway
Inhibitors/activators of receptors

Question 5

nicotinic cholinergic receptor

Answer 5

Ligand gated ion channel
Binding site for ACh
When open lots Na+ and Ca2+ in
Excitatory neurotransmitter acting at nicotinic receptors

Question 6

Hexamethonium

Answer 6

Used to be used as a anti hypertensive drug, had to be injected, lots of side effects and difficult to use
Selective antagonist for the neuronal subtype of nicotinic receptor, pore blocker blocks channels for Na+ and Ca2+
Not competitive at receptor
Blocks all effects of autonomic stimulation as ganglia all release ACh onto nicotinic receptors
Blocks enteric system as they have cholinergic synapses. Chromaffin cells in adrenal medulla have nicotinic receptors

Question 7

Muscarinic receptors

Answer 7

Located on target organs
GPCRs
Parasympathetic postganglionic transmission M1-5
ACh is released onto muscarinic receptors
7 transmembrane segments
5 subtypes of which the first 3 M1-3 are particularly important in periphery

Question 8

Muscarinic agonists

Answer 8

Parasympathomimetics
Because exposure mimics the effects of parasympathetic nervous system activation
Allows you to predict effects drugs will have
Extreme effects, poisoning: cramping abdominal pains, excessive salivation, excessive secretion, bronchoconstriction, bradycardia

Question 9

Effects of parasympathomimetics

Answer 9

Cardiovascular-decreased heart rate
Smooth muscle- contracts although vascular smooth muscle dilates via endothelium
Exocrine glands- secrete, sweating , lacrimation, salivation, bronchial secretion
If add muscarinic agonist directly on smooth muscle them muscarinic receptor on smooth muscle will cause it to contract. Within circulatory system

If add muscarinic agonist directly on smooth muscle then Muscarinic receptor on smooth muscle will cause it to contract. Within circulatory system the endothelial cells which line blood vessels have muscarinic receptors and when these activated produce nitric oxide tends to cause relaxation of blood vessels. Paracrine signalling sometimes indirect

Question 10

Muscarine: poisoning

Answer 10

Muscarinic agonist
Source many mushrooms
Adverse effects: bradycardia, vasodilation (secondary to NO), leading to falling BP
Increased gut motility (colicky pain), bronchoconstriction, pupillary constriction(mioisis), salivation, lacrimation, airway secretions
Treatment:
Muscarinic antagonist (atropine)

Question 11

Pilocarpine

Answer 11

Use: to treat glaucoma (some forms)
Route of administration: topical to the eye, local action
Action: on M3 receptors on ciliary muscle, improving aqueous humor drainage, dropping intraocular pressure

Question 12

Muscarinic antagonists

Answer 12

Can target drugs to particular organ systems by targeting receptor subtypes
M1-stomach, salivary glands
M2-cardiac
M3- smooth muscle
Less specific antagonists:atropine (from belladonna), hyoscine, cyclopentolate. Mainly used in practice

Question 13

Clinical uses of antimuscarinic drugs (muscarinic antagonists)

Answer 13

Asthma (ipratropium, dont use atropine because of side effects and not easy top deliver to lungs)
Bradycardia (atropine)
During operations, decrease secretions, decrease AChEI (acetylcholinesterase inhibitor, neostigmine) side effects (atropine)
Dilate pupils (tropicamide), applied locally to eye, parasympathetic NS tends to cause constriction of eye
Urinary incontinence (oxybutynin or tolterodine)
Motion sickness (hyoscine)-over counter, mixed CNS and PNS action

Question 14

Paralysis in operation

Answer 14

Nicotinic receptor antagonist
An anaesthetist will give you skeletal neuromuscular junction blocking agent
To reverse paralysis quickly they give AChEI to amplify amount of ACh at skeletal NMJ but no have excessive ACh in lungs& heart- fluid in lungs, bradycardia
So they then give neostigmine with atropine to prevent problem of neostigmine

Question 15

Pharmacology of adrenergic transmission overview

Answer 15

Alpha-adrenoceptor agonists and antagonists
Beta-adrenoceptor agonist and antagonists
Noradrenaline transporter blockers
Monoamine oxidase inhibitors
Indirectly acting sympathomimetic amines

Question 16

Adrenoceptors

Answer 16

5 main subtypes:
A1- contract smooth muscle (vasoconstriction)
a2- presynaptic auto-inhibition, direct vasoconstriction, central inhibition of sympathetic outflow
B1-increase heart rate and contractility
B2- relax smooth muscle (vasodilation, bronchodilation)
B3-relax smooth muscle (bladder), simulate lipolysis

Question 17

Main uses of a-adrenoceptor receptor agonists

Answer 17

Vasoconstrictors with local anaesthetics so causes local vasoconstriction, keeps LA local stops it being absorbed systemically, acts on a1 receptors found in blood vessels in skin (mainly a1)
-adrenaline, noradrenaline
Nasal decongestants (mainly a1), phenylephrine
Hypertension (central a2, multiple locations for a2)
Facial erythema in rosacea- brimonidine (a2; direct vasoconstriction)

Question 18

A1-adrenoceptors; coupled to phospholipase C-beta

Answer 18

All adrenoceptors are GPCRs
When G proteins activated will stimulate or inhibit an enzyme on plasma membrane
Particular effects depend on what target is- smooth muscle or glands
Noradrenaline binds to a1 receptor, activating attached Gq protein stimulating phospholipase C causing intracellular cascade. DAG(diacylglycerol) often activates protein kinase C-> other effects. IP3 causes release of Ca2+ from intracellular stores into endoplasmic reticulum

Question 19

Signal transduction mechanisms for autonomic receptors

Answer 19

Receptor- G-protein -target- transduction effect
A1- Gq- PLC(phospholipase C)- increase IP3/DAG
A2-Gi- inhibits AC(adenyl cyclase)-decrease cAMP
B-Gs- stimulates AC-increase cAMP
M1,M3-Gq-PLC-increase IP3/DAG
M2-Gi-AC-decrease cAMP

Question 20

Main uses of a-adrenoceptor antagonists

Answer 20

Hypertension (a1;doxazosin)
Benign prostatic hyperplasia (a1; tamsulosin), enlargement of prostrate, reduce tone in prostrate gland

Question 21

Main uses of b-adrenoceptor agonists

Answer 21

Cardiogenic shock (B1)-adrenaline, dobutamine
Anaphylactic shock (a/B)- adrenaline-activates B receptors , if blood pressure every low
asthma (B2)-salbutamol, also delays premature labour by stopping contraction of uterus
Epi-pen contains epinephrine-adrenaline

Question 22

Main uses of B-adrenoceptor antagonists

Answer 22

E.g. metoprolol(b1) -present in heart
Angina, cardiac arrhythmias
Hypertension
Anxiety states
(Chronic) heart failure
Locally for glaucoma (timolol)

Question 23

Drugs target process of noradrenergic transmission

Answer 23

Tyrosine synthesises NAd-> dihydroxyphenylalanine(DOPA)-> dopamine-> VMAT(vesicular monoamine transporter) packages NAd into vesicle, released by exocytosis, recycled into nerve terminals
NAT(noradrenaline transporter responsible for ‘uptake 1’) takes NAd back into cells where monoamine oxidase MAO breaks down NAd

Question 24

Uptake of catecholamines:uptake 1

Answer 24

Neuronal; due to secondary active transporter NAT
Main mechanism for terminating the actions of NAd
Cotransports Na+, Cl- and catecholamine
Inhibited by cocaine(inhibits NAT), tricyclic antidepressants (desipramine)

Question 25

Inhibitors of noradrenaline uptake

Answer 25

NAT inhibitors enhance the effects of sympathetic activity, NAd once released not recycled so stays in extracellular space where it can activate its receptors. Amplifying transmission
NAT is closely related to the dopamine and serotonin transporters (DAT and SERT)
Desipramine: tricyclic antidepressant, major action on CNS, adverse effects: tachycardia, dysrhythmia
Cocaine: euphoria and excitement CNS action, tachycardia and increased BP PNS, also local anaesthetic

Question 26

Monoamine oxidase inhibitors

Answer 26

MAO blocks breakdown NAd
Most blocks MAO irreversibly
Used clinically as antidepressants 2nd and 3rd line
Increase levels of NAd, dopamine and 5-HT in brain and peripheral tissues
Peripheral actions:increase or make BP unstable
Adverse effects include postural hypotension, weight gain, restlessness, insomnia, cheese reaction (hypertensive episode following ingestion of tyramine-containing food, e.g. cheese)
Examples: phenelzine, tranylcypromine, iproniazid, moclobemide(reversible, competitive inhibitor)

Question 27

Indirectly acting sympathetic amines

Answer 27

Mimic sympathetic activation
Act like NAd, structurally related, substrates for NAT, enter nerve terminals via transporter, enter vesicles so displace NAd by reverse transport. So NAT takes NAd out cell into extracellular space where it can activate its receptors
E.g.amphetamine, ephedrine, tyramine
Similar effect on dopamine and 5-HT in CNS
Long lasting effects that mimic those of NAd: bronchodilation, vasoconstriction, positive inotropy (strengthening function of cardiac tissue), raised BP
CNS effects underlie their use as substances of abuse