parasympathetic nervous system drugs Flashcards
what type of receptors does the neuromuscular junction use?
nicotinic receptors?
what is the difference between the receptors used in the neuromuscular junction and the autonomic nervous system?
their sub-unit composition is different
nicotinic receptors of the autonomic nervous system: can be antagonised by hexamathenoium/tubocurarine
nicotinic receptors of the neuromuscular junction can be antagonised by decamethenoium/tubocurarine
what is the structure of a nicotinic receptor?
5 sub-unit / ionotropic receptors
what is the structure of a muscuranic receptor?
7 sub unit/ G -coupled proteins
what are the agonists of the musurinic receptors? and what are the anatagonists of the receptor?
agonists:
- LOW dosages of Ach
- muscuraine
antagonists:
-atropine
what are the agonists of nicotinic receptors? and what are the antagonists of the receptor?
agonists:
- HIGH dosages of Ach
- nicotine
antagonists:
- tubocuranine
- repeated dosages of nicotine
what are some of the therapeutic uses of muscurinic agonists
relief of xerostoma (dry mouth) - pilocarpine
reduction of intra-ocular pressure (by constricting pupil) - pilocarpine
relief of urinary retention - especially if retention is caused by failure of reflex pathway - bethanechol
what are the effects of the muscuranic antagonists on the CNS?
anti-emetic (hyoscine)
reduces the intention tremor in PD (atropine)
in high dosages atropine causes marked stimulation: with restlessness, disorentation, hallucinations and confusion and thus can lead to cognitive impairment in the elderly
what are the effects of the muscuranic antagonists on the eye?
cause pupil dilation - for retinal examinations
cause paralysis of accommodation, allows lens to heal post operation
tropicamide: usually the short lived muscuranic antagonist used in the cases of eye examinations
what are some of the therapeutic uses of the muscuranic antagonists?
anti-emetics (powerful CNS depressant, causing sleep and amnesia) hyoscine
eye examinations: tropicamide
treatment of anti cholinesterase poisoning
symptomatic relief of SM spasm in asthma: ipratropium
anaesthesia (as pre-medication)
to reduce effects of vagal stimulation and anti-cholinesterase given during GI surgery
hyoscine/scopolamine
what are the side effects of muscuraninc antagonists
reduced secretion reduced sweating reduction in tear production reduction in bronchial secretion urinary retention smooth muscle relaxation in the bronchus and bladder increase in heart rate, with no affect on blood vessels reduced GI motility and secretion
what are the effects of the muscurinic receptors in the heart?
they reduce heart rate, but have no negative ionotropic effect
the PS only spreads to the atria’s SAN and AVN
the M receptors slow the depolarisation of PM, meaning it takes longer for a threshold potential to be reached in order to generate an AP
why is the muscuranic agonist Ach not used clinically?
it is degraded too quickly by Che
what are the characteristics of the muscuranic agonists methacholine and carbacol?
have a long duration of action they're quaternary amines they're fully ionised no readily absorbed if given orally not readily absorbed if given through the conjunctiva
what are the characterstics of the muscuranic agonist pilocarpine?
long duration of action
partially ionised at physiological pH
absorbed topically
what are the main side effects of muscuranic agonists
bardycardia (Reducing BP and CO)
vasodilation
salivation, lacrimation and sweating
bronchoconstriction and increased bronchosecretion
contraction of bladder detrusor muscle
increased GI motility
miosis and accommodation of the eye (reducing intra-ocular pressure)
what is the characteristic feature of the muscuranic antagonists?
they’re all tertiary bases - therefore, easily cross into the brain
quaternary derivatives are used to minimise CNS effects, but those are less selective peripherally
give two specialisations of the NMJ
pre-synpatically: vesicles containing high concentration of Ach are located at the active zone
post-synpatically: the membrane is thrown into folds, increasing the surface area of the post-synaptic cell
Hemicholinium acts on the NMJ, how?
where is most effective? when is its affect seen?
it inhibits choline uptake into the pre-synpatic terminal, through competitive antagonism to the choline carrier.
the choline carrier has a higher affinity for hemicholinium than choline
it is more effective at highly active synapses. its effect is not seen immediately but post-synaptic response gradually decreases
name three drugs inhibiting acetylcholine release at the NMJ
botilinum toxin
tentanus toxin
aminoglycosides (hence they have a side effect of muscle weakness)
name three competitive antagonists to the acetylcholine receptor at the NMJ
tubocuranine
gallamine
pancuronium
explain how suxamethonium work
depolarising drug - blocks nerve transmission at the post-synpatic terminal
what are the CNS effects of nicotine?
they increase both sympathetic and parasympathetic outflow
this causes:
- tachycardia
- increase in BP
- reduced gastric motility
- increased salivation and bronchial secretion
- increased ADH release
what are the effects of ganglionic blocking drugs?
they indiscriminately block sympathetic and parasympathetic nervous system
CV effects: due to sympathetic blockage
- vasodilation and venodilation, huge reduction in BP
- loss of cardiovascular reflexes
GI tract effects: due to parasympathetic blockage
- inhibition of motility leading to severe constipation
genito-urinary tract: due to blockage of parasympathetic nervous system
- microturition
- failure of erection
- failure of ejaculation (this is sympathetic mediated)
eyes: parasympathetic
- dilated pupils and loss of pupillary reflex (photophobia)
- loss of accommodation reflex (blurred vision)
explain what a competitive neuromuscular block is? and give some of its feature?
- it prevents Ach binding to AchR
features:
- no fasiculuation
- no post operative pain
- no effect on the eye
- hypotensive
- increased effect in mysthania gravis
- effect can be reversed with anti ChE
- no change in plasma potassium concentration
explain what a non-competitive muscular block is? and give some of its features
- it depolarises the post-synpatic membrane, preventing the generation of an AP
- acts on end plate region, making the cell inexcitable
features:
- fasciculation
- post operative pain
- increased I.OP
- NO hypotension
- reduced effect in mysthania gravis
- effect cannot be reversed with anti - ChE (perhaps even increased)
- an increase in plasma potassium concentration
give examples of competitive drugs
tubocuranine
gallamine
pancuronium
give examples of a depolarising drug
suxamethonium
give the differences between butylcholinesterase and acetylcholine esterase
butylcholinesterase:
- soluble enzyme
- found in many tissues, liver and plasma
- hydrolsyses drugs
acetylcholinesterase:
- membrane bound enzyme
- found at cholinergic synapses (also found in RBC)
- only hydrolysizes acetylcholine and similar compounds
what is the dibucaine number?
why is it important?
this refers to the sensitivity of the enzyme butylcholinesterase to the inhibitor dibucaine
normal sensitivity: 70-90%
heterozygeous mutation to gene: 50-70% (show no altered sensitivity to suxamethonium
homozygous mutation to gene: 10-20% increased sensitivity to the drug suxamethonium
blood test routinely carried out, because of its implication when using anaesthetics
how does the enzyme cholinesterase work?
2 binding site:
anionic site:
esterac site (with OH serine)
acetylcholine binds to both sites, acetyl group binds to the OH of the serine group, this causes the release of choline
the acetylated OH is hydroylses, releasing acetic acid
hydrolysis is at the rate of 10^4 molecules per second
how do short acting reversible anti ChE work?
example: edrophonium
drug has a quaternary ammonium group, acts to the anionic site of the enzyme
competitive antagonism
how do long acting reversible anti- ChE work?
example: neostigimine
drug binds to the OH serine group of the enzyme, forming an ester bond
drug ALSO binds to the anionic site
the hydrolysis of the acetylated drug takes a while –
rate of hydrolysis is 0.1 molecules per minute
how do non reversible anti-ChE work?
example: DYFLOS and DFP
- those are organophosphate compounds
- irreversibly bind to the serine OH
- recovery of the OH group requires the synthesis of a new enzyme
these drug do NOT have a quaternary group, so inhibit other enzyme containing serine OH apart from ChE
What are the peripheral effects of anti Che
NMJ:
- repeated firing at the junction
- reversal of nerve transmission due to muscular block or mysathenia gravis
- in high dosages Ach could build up, this would lead to a depolarising muscular block
parasympathetic effect:
- pupil constriction
- bronchoconstriction and secretion
- increased motility
- bradycardia
what are the central effects of anti - ChE drugs?
excitatory –> agitation and convuslion –> respiratory depression
what are the therapeutic uses of anti ChE?
glaucoma: physostigmine
- reduced intra-ocular pressure
myasthenia gravis: neostigimine and pyrdiostygimine
- those are quaternary compounds, used to minimise central effects
- atropine used in conjunction to reduce peripherial actions
- those drugs enhance synaptic transmission at end plate
GI tract: neostigimine
reversal of neuromuscular block after analgesia
how do organophosphates cause damage? how is their action reversed?
they’re anti ChE inhibitors
their toxic effects are mediated by causing demyleination leading to paralysis and sensory loss (probably due to interfering with myelin synthezing enzymes)
cholinesterase activators are used:
- oxime group (pralidoxime)
- they bind to anionic site, and they entice the release of the phosphate from the esteraic site
give an example of a non selective N/M receptor agonist?
acetylcholine and carbachol
when is carbachol used?
used as eye drops in the treatment of raise intra-ocular pressure
has a long half - life because not hydrolysed by chE
give examples of selective M receptor agonists?
methacholine (quaternary amine)
pilocarpine (tertiary amine - absorbed topically- xerostermia and reduction in I.O.P)
bethanachol (urinary retention)
when is tropamide used? why not homatropine?
druring eye examination to cause cycloplegia and pupil dilation. it is used because it is shorter acting
what agents would you use to induce cycloplegia after surgery?
long acting muscuraninc antagonists
e.g. atropine or hyscocine (probably atropine because hyscocine induces more drowsiness)
what’s the difference between atropine and hyscocine?
hyscocine is used to reduce nausea, it also induces far more drowsiness
what are parasympathomimetic drugs?
- those which act directly on the AchR (muscarnic agonists)
2. those that inhibit cHE therefore prolong and enhance the action of released Ach at the synapse
what happens to HR and BP when using muscarinic antagonists?
BP does not change
- no inneveration to most BV through parasympathetic system
- HR increases (particularly in young and fit, because their HR is under vagal control)
