ANS pharmacology Flashcards
M1 receptor location
neural –> CNS, peripheral ganglia
M1 receptor function
CNS excitation, gastric secretion
M2 receptor location
cardiac –> atria, conducting tissue, presynaptic terminals
M2 receptor function
cardiac inhibition, presynaptic inhibition
M3 receptor location
glandular –> exocrine gland, smooth muscle, vascular endothelium
M3 function
gland secretion, smooth muscle contraction, vasodilation
Carbachol
muscarinic receptor agonist with long lasting effect, carbamoyl group replacing acetyl group on acetylcholine
methacholine
muscarinic receptor agonist with methyl side chain, higher selectivity towards muscarinic than nicotinic receptor
bethanechol
muscarinic receptor agonist with carbamyl group + methyl side chain –> long lasting + higher selectivity towards muscarinic receptors than nicotinic receptors
What is glaucoma?
increased intraocular pressure e.g. accumulation of aqueous humour, obstruction of canal of schlemm
Pilocarpine
Treating glaucoma: M3 muscarinic receptor agonist
- induce contraction of iris circular muscle improve aqueous humour outflow by expanding filtration angle
- induce contraction of ciliary muscle exerting tension –> opening trabecular network and promoting fluid movement into canal of schlemm
- muscarinic receptors are widespread –> agonist have many side effects and thus seldomly used
atropine
muscarinic antagonist
- too long lasting
tropicamide
atropine-like muscarinic antagonist
- block M3 receptors to inhibit constriction of iris circular muscle –> mydriasis, abolishing light reflex –> easy viewing of retina during eye exam and surgery
- also inhibit constriction of ciliary muscle –> abolish eye accommodation
tiotropium
inhibit M3 receptor to suppress reflex airway constriction
- given by aerosol to treat asthma and obstructive pulmonary disease
atropine
block M2 receptor to treat sinus bradycardia e.g. after MI
pirenzipine
M1-selective antagonist reducing gastric acid secretion –> treat peptic ulcer
hyoscine butylbromide
quaternary agents used as antispasmodic to treat GI hypermotility
- not absorbed well and tend to stay in GI
hyoscine, scopolamine
block M1-3
Anaesthetic premedication
- reduce secretion and reflex bronchoconstriction –> ensure clear airway
- prevent bradycardia
- go through BBB - weak sedative effect in addition to anaesthetics
- also treat motion sickness
benztropine
- selective M1 antagonist –> block central cholinergic activity –> treat parkinsonism
trimetaphan
blocking ganglionic nicotinic receptor –> produce short-term lowering of blood pressure
- receptor antagonism –> bind to agonist binding domain
hexamethonium
block ganglionic nicotinic receptor by block opening of Na+ channel
- reduce sympathetic tone of blood vessel and heart –> reduce BP
- no longer used
Botulinum toxin
- bind to presynaptic membrane of cholinergic synapse –> degrade SNAP-25 of SNARE protein –> inhibit exocytosis of acetylcholine
- progressively paralysis parasympathetic and motor system –> respiratory failure
- antitoxin only effective if given before symptoms appear
small dose of botulinum toxin can treat
- upper motor neurone syndrome –> cause abnormal muscle tone
- focal hyperhidrosis (excess sweating)
- blepharospasm - persistent and disabling eyelid spasm
- strabismus - cross eye
- chronic migraine - unilateral headache
- bruxism - teeth grinding
- botox - reduce skin wrinkles
butyrylcholinesterase
- widely distributed with broad substrate specificity
- hydrolyze ester-containing drugs e.g. procaine, suxamethonium
edrophonium
short-duration antiAchE - form readily reversible ionic bond with esteratic site
neostigmine
medium duration antiAchE
forming carbamate ester - slowly hydrolysed from esteratic site
dyflos
long duration antiAchE
phosphate ester is very stable
pralidoxime
AchE reactivator given in case of moderate to severe antiAchE poisoning –> only effective before aging occur
Benzodiazepine
diazepam, lorazepam, midazolam prevent convulsion
myasthenia gravis
weakness and fatigue of muscle caused by reduction of nicotinic receptor at skeletal neuromuscular junction
diagnosis of myasthenia gravis
short-acting edrophonium produce improvement on muscle strength
treatment of myasthenia gravis
medium-duration neostigmine
reverse non-depolarising neuromuscular block e.g. tubocurarine
neostigmine - medium acting
long acting insecticides and nerve gases
dyflos –> severe poisoning
anticholinesterase poisoning
!!
muscarinic
- M1/3 - sludge
- M2 - slow heart rate, bradycardia and hypotension
- M3 - bronchoconstriction, vasodilation via NO production, miosis
CNS
- convulsion, depression, unconsciousness, respiratory failure
nicotinic
- initial stimulation increase sympathetic tone –> hypertension –> later become depolarisation block leading to hypotension
- initial skeletal muscle twitch (fasciculation) –> later become depolarisation block and paralysis at neuromuscular junction
a1-adrenoreceptor mechanism
Gq protein –> activate phospholipase C –> increase intracellular Ca2+ –> vasoconstriction
a2-adrenoreceptor mechanism
Gi protein –> lower cAMP –> lower [Ca2+]i –> lower [K+] –> inhibit noradrenaline release (autoreceptor)
b1/2/3-adrenoreceptor mechanism
Gs protein –> increase cAMP –> increase heart rate and contractility / bronchodilation + vasodilation / lipolysis
a1-adrenoreceptor agonist
phenylephrine
a2-adrenoreceptor agonist
clonidine –> reduce further release of NA
b1-adrenoreceptor agonist
dobutamine
b2-adrenoreceptor agonist
salbutamol
terbutaline
b2-adrenoreceptor agonist
competitive reversible a1 antagonist
phentolamine
irreversible a1 antagonist
phenoxybenzamine
long acting a1 antagonist
terazosin
selective a1a antagonist
tamsulosin
a2 antagonist
yohimbine
propanolol
block b1 and b2 adrenoreceptor
cardioselective b-blockers
metoprolol and atenolol - higher affinity for b1 than b2
3rd generation b-blocker
carvedilol - block b1,b2 and a1 blocking leading to vasodilation –> extra effect on reducing BP
biosynthesis of catecholamine
tyrosine - tyrosine hydroxylase –> DOPA - DOPA decarboxylase –> dopamine –> dopamine b-hydroxylase –> noradrenaline - PNMT –> adrenaline
NET
noradrenaline transporter –> for reuptake of noradrenaline from synapse to presynaptic terminal
monoamine oxidase
catalysing conversion of noradrenaline to metabolites in presynpatic terminal
VMAT
vesicular monamine transporter –> reuptake noradrenaline from cytoplasm to vesicle in presynaptic terminal
reserpine
!!!
inhibit VMAT –> more NA is metabolised by MAO –> deplete storage granules of NA
Guanethidine
!!!
taken up into presynpatic terminal through NET –> inhibit exocytosis + displace NA from vesicle –> more NA being metabolized by MAO
- weak local anaesthetic effect
a-methy-DOPA
enter the NA biosynthetic pathway as a false transmitter a-methyl-NA
- activate a2 to inhibit further release of NA
- do not activate adrenoreceptor at end organ
tyramine
sympathomimetics
uptaken into presynaptic terminal through NET - reduce NA reuptake
- displace NA from vesicle –> more release
- competitive inhibition to MAO
- weak adrenoreceptor agonist location
cocaine
!!!
noradrenaline reuptake inhibitor (NRI) –> local anaesthetics
phenoxybenzamine
Noradrenaline reuptake inhibitor and a a-blocker
imipramine
!!!
weak a1-blocker
effect of NRI
- block reuptake –> prolong action of NA and other agonist which are substrates for NET
Cheese-reaction
cheese is rich in tyramine –> substrate for MAO
- should be properly metabolized in gut and liver
when MAO inhibitor is present –> cannot be metabolised –> reach sympathetic terminal and show sympathomimetic effect –> provoke sudden and dangoerous rise in BP
anaphylactic shock / acute anaphylaxis
!!!
type I hypersensitivity reaction - second exposure to antigen cause release of inflammatory mediators from mast cells –> wide spread urticaria, edema, bronchospasm, hypotension –> laryngeal edema, bronchospasm, cardiovascular collapse
!!!treat acute anaphylaxis
intramuscular injection of adrenaline
- a1 and b2 improve cardiovascular function
- b2 dilate airway
phaeochromocytoma
tumour of adrenal cortex –> releasing large amount of catecholamine
premedication of surgical removal of phaeochromocytoma
phenoxybenzamine - irreversible a-blocker to reduce BP + atenolol (B1-blocker)
benign prostate hyperplasia treatment
tamsulosin (a1a antagonist) - prostatic / urethral smooth muscle relaxation to facilitate urination
treat nasal congestion
phenylephrine - a1 agonist to contract blood vessel in nasal cavity to exert nasal decongestant action
asthma treatment
salbutamol - b2-adrenoreceptor agonist relieve bronchospasm
premature labour treatment
!!!
ritodrine - B2- agonist given by IV to reduce uterine contraction
opthalmological exam
!!!
tropicamide to inhibit M3 receptor –> relax circular iris muscle
phenylephrine to activate a1 receptor to contract radial iris muscle
- produce mydriasis
parkinsonism
!!!
clinical syndrome characterized by tremour, bradykinesia, rigidity, postural instability
- due to increased Ach level and degeneration of dopaminergic nigrostriatal pathway
side effect of a-adrenoreceptor blocker
sexual dysfunction, dizziness, tachycardia, postural hypotension
