W7: Pharmacology Of The ANS Flashcards
What does hexamethonium do?
Selective antagonist for the neuronal subtype of nicotinic receptor (not at the NMJ). Not competitive and blocks all effects of autonomic stimulation.
Where do you find muscarinic receptors?
At parasympathetic postganglionic synapses
What effects to parasympathomimetics have?
Mimic effects of the parasympathetic nerve stimulation acting as muscarinic agonists
Cardiovascular - decreased HR and CO
Smooth muscle - contracts (vascular smooth muscles dilate via endothelial influences so difficult to predict)
Exocrine glands - secrete - e.g., sweating, lacrimation, salivation, bronchial secretion
Examples of muscarinic agonists
ACh, muscarine, pilocarpine
What are the effects of muscarine poisoning?
Adverse effects (same symptoms of muscarinic activation):
- bradycardia, vasodilation (secondary to NO), so fall in BP
- increased gut motility, bronchoconstriction, pupillary constriction
- salivation, lacrimation, airway secretions
What is the source and treatment of muscarine poisoning?
Source: Many mushrooms
Treatment: Muscarinic antagonist - atropine
What is pilocarpine (muscarinic agonist) used for?
To treat glaucoma
How is pilocarpine administered?
Topically applied to the eye
What is the action of pilocarpine?
Acts on M3 receptors on ciliary muscles improving aqueous humor drainage, dropping intra-ocular pressure.
Common muscarinic antagonists
Less specific ones, e.g., atropine, hyoscine
Clinical uses of antimuscarinic drugs (muscarinic antagonists)
- asthma - PNS causes narrowing of airways so antagonists reverse
- treatment of bradycardia - PNS causes slower HR, so blocking this speeds HR
- to decrease gut motility
- to decrease secretions during operations
- dilate pupils
- urinary incontinence
- motion sickness - there are lots of muscarinic receptors in the enteric NS
What do activated alpha1 adrenoceptors do?
Contract smooth muscle (e.g., vasoconstriction)
What do alpha2 adrenoceptors do?
Pre-synaptic auto-inhibition, direct vasoconstriction, central inhibition of sympathetic outflow
What do beta1 adrenoceptors do?
Increase heart rate and contractility
What do beta2 adrenoceptors do when activated?
Relax smooth muscle (bronchodilation, vasodilation)
What do beta3 receptors do when activated?
Relax smooth muscle (bladder); stimulate lipolysis
What are the main uses of alpha receptor agonists
Vasoconstrictors with LA (mainly alpha1)
Nasal decongestants (mainly alpha 1)
Hypertension (central alpha2)
Facial erythema in rosacea (alpha2)
How does adrenaline work in LA?
Adrenaline causes a local vasoconstriction, contracting smooth muscles meaning the licocaine (LA) stays where it is put, causing a better action.
How does NA cause alpha adrenoceptor activation?
NA binds to g-protein coupled receptors
Alpha receptor uses the Gq protein, which is linked to phospholipase C
Phospholipase C produces DG and IP3
IP3 mediates effects on smooth muscle, activating its receptor (ligand-gated ion channel) found on the ER. Allows Ca2+ out of the ER to cause contraction, so constrict blood vessels.
Does not have to cross a membrane to activate the receptor
What is the G-protein, target and transduction effect for alpha1 adrenoceptor?
Gq
PLC
Increased production of IP3/DAG
What is the G-protein, target and transduction effect for alpha2 adrenoceptor?
GI
Decreased AC
Decreased cAMP
What is the G-protein, target and transduction effect for beta adrenoceptors?
Gs
Increased AC
Increased cAMP
What is the G-protein, target and transduction effect for M1, M3?
Gq
PLC
Increased IP3/DAG
What is the G-protein, target and transduction effect for M2 receptors?
Gi
Decreased AC
Decreased cAMP
Main uses of beta-receptor agonists with examples
Mimic the action of sympathetic activation (NA released from sympathetic nerve terminals)
- cardiogenic shock (beta1) - e.g, adrenaline
- anaphylactic shock (alpha/beta) - e.g., adrenaline
- asthma (beta2) - e.g., salbutamol
Main uses of alpha antagonists
Reversing sympathetic symptoms
- hypertension (alpha1 - dozazosin)
- benign prostate hyperplasia (alpha1 - tamsulosin)
How does a largened prostate affect the bladder?
Large prostate will press on urethra, causing bladder problems. Alpha antagonists reduces contraction of the prostate.
Main beta antagonists
Propranolol (beta1/2)
Metaprolol (beta1)
Main uses of beta antagonists
Beta 1 specific to the heart - to treat heart problems like angina, cardiac arrhythmias, hypertension
Treat anxiety states, chronic heart failure
Locally glaucoma - SNS would dilate the pupil so the antagonist would constrict the pupil
Uptake 1: what happens to noradrenaline once it’s released?
Once released, it is taken back up into the nerve terminal by noradrenaline transporter NAT (a secondary active transporter), to terminate its actions
Relatively selective for NAd
What does NAT cotransport?
Na+, Cl-, catecholamines
What is the NAT transporter inhibited by?
Cocaine, tricyclic antidepressants (desipramine)
What is the effect or NAT inhibitors?
They enhance the effects of sympathetic activity
What transporters is NAT closely related to?
Dopamine and serotonin transporters, DAT and SERT
What happens to DAT and SERT if NAT is inhibited
These ‘reward’ neurotransmitters, dopamine and serotonin, you will amplify the effect of their transmission centrally, producing pleasure.
What are the effects of desipramine?
A tricyclic antidepressant. Major action is on the CNS. Adverse effects: tachycardia, dysrhythmia (abnormal heart rhythms)
What are the effects of cocaine?
Euphoria and excitement (CNS action)
Causes tachycardia by increased drive to the heart and increased BP by causing peripheral vasoconstriction (peripheral)
Can be used as a local anaesthetic (by inhibition of Na+ channels)
What do mono-amine oxidase inhibitors do?
Block MAO irreversible
Increases levels of noradrenaline, dopamine, 5-HT, in the brain and peripheral tissues
What is the clinical use of MAO inhibitors?
Antidepressants
What does MAO do?
Terminates the action of NA by breaking it down
Adverse effects of MAO inhibitors
Postural hypotension, weight gain, restlessness, insomnia, cheese reaction (hypertensive episode following ingestion of tyramine-containing food, e.g., cheese; flushing)
Examples of MAO inhibitors
Phenelzine, moclobemide (reversible competitive inhibitor)
Give examples of indirectly acting sympathetic amines and what are they structurally related to?
Amphetamine, tyramine
Structurally related to adrenaline
Why are indirectly acting sympathetic amines indirectly acting?
Because they do not directly affect a receptor
They are transported into nerve terminals via NAT and into vesicles by VMAT, mimicking the route of NA
They displace NA, which leaks out via NAT, producing sympathetic like effects
What are the effects of indirectly acting sympathetic amines?
Long-lasting effects that mimic those of NA (sympathetic NS effects).
Bronchodilation, vasoconstriction, positive inotropy, raised BP
