Drugs And The Neuromuscular Junction and adverse drug reactions Flashcards
ACh
Synthesised in neurones from acetyl-CoA and choline
Choline-acetyltranferase
Synthesise ACh from acetylcholine-CoA and choline
ACh is stored in
Vesicles and then released into the synaptic cleft following electrical stimulation
ACh in the synaptic cleft is metabolised
Rapidly by the enzyme acetylcholinesterase into acetate and choline
Nicotinic cholinergic receptor
Opens in presence of ACh but only for microseconds -> will then close, causes depolarisation of the membrane
Botulinum toxin
Toxin produced by the anaerobic soil bacterium - C. Botulinum
Muscle paralyser
Protease enzyme that selectively attacks and breaks down proteins required for docking of synaptic vesicles with presynaptic membrane -> this inhibits the release of neurotransmitter release, lowering conc of transmitter in the synaptic cleft
Non depolarising neuromuscular blockers
Competitive antagonists of the nicotinic cholinergic receptor
Atracurium, rocuronium, vecuronium, pancuronium
Depolarising blockers
Initial agonists which are followed by continued binding and shutting of the ion channel
Suxamethonium -> two linked ACh molecules which are less favourable for breakdown by acetylcholinesterase
Anticholinestersases
Reduce the rate of breakdown of ACh and therefore potentials cholinergic transmission
Reversible anticholinesterases
Are used in the treatment of conditions like myasthenia gravis and Alzheimer’s
Can also be ides as a anaesthetic
Reversible as rapidly hydrolysed
Irreversible anticholinesterases
Contain a phosphate ester bond so can resist hydrolysis
Dangerous -> can cause muscle paralysis and respiratory failure and a cholinergic crisis in the autonomic nervous system
Agents are extremely poisonous -> nerve agent ‘sarin’ and organophosphates
Skeletal muscle relaxants
Differ fundamentally in cartoon from the neuromuscular junction blocking agents used in anaesthesia
Can relieve chronic muscle spasm
Drugs acting centrally in the CNS to reduce descending stimulators signals to the muscles
Baclofen, diazepam
Drugs that act peripherally - directly on the muscles
Dantrolene
Drugs acting at both CNS and directly on muscles
Cannabis extract
Dantrolene sodium
Inhibits calcium release from sarcoplasmic reticulum which is a prerequisite for the interaction of the contractile proteins actin and myosin
Diseases that result in spasm of voluntary muscles
Stroke, MS, cerebral palsy
The actions of ACh are terminated by
Enzymatic breakdown by the enzyme acetylcholinesterase in the synaptic cleft
Many adverse drug reactions are
Avoidable
Type A adverse drug reactions
Predictable from the known pharmacology of the drug and dose-related
Type B adverse drug reactions
Unrelated to the known pharmacology of the drug and idiosyncratic
Teratogenesis
Drugs which effect embryo development
-Affect cell division or protein/DNA synthesis
Pharmacovigilance
The scientific study concerned with the detection and evaluation of adverse effects of drugs
Detecting adverse drug reactions
Animal (pre-clinical) studies
Phase I-III clinical studies
Voluntary reporting systems e.g. yellow cards
Prescription event monitoring
Population statistics/record linkage
Medical literature
What the yellow card scheme can detect
Unrecognised ADRs (signal generation
Identification of predisposing factors
Comparing ADR profiles of drugs
Continual safety monitoring
What changes might follow the yellow card scheme
Restriction in use
Reduction in dose
Special warnings and precautions
Product withdrawn
Weakness of spontaneous reporting
Low reporting rates
Relies on ADR being recognised
Reporting rate is high early after launch but then falls rapidly
Reporting rate influenced by publicity and reports tend to arise after reaction established
Cannot provide an estimate of risk
Black triangle
Signifies that a drug I’d new and that all adverse reactions should be reported
Many adverse drug reactions are not known until
After licensing and distribution has begun -> implies a careful review of accumulating data in the post licensing period
