Drugs that Affect Parasympathetic Activity Flashcards
In the parasympathetic nervous system what types of receptors do we find?
- pre-ganglionic nerve - nicotinic receptor- post ganglionic nerve- muscarinic receptors
- Using acetyl choline
- Affecting salivary glands and many others
What is the role of the parasympathetic nervous system
Rest and digest:
- Pupil constriction, near point accommodation (able to focus close objects), bronchiole constriction, bradycardia (causing hypotension), more GI motility and contraction, contraction of bladder, exocrine secretions (salivation, lacrimation/ tears)
In muscarinic receptors explain the mode of action and what is this called? Is this a slow or fast process?
- Muscarinic receptor- ACh binds
- Metabotropic= G- coupled protein and secondary messenger system
Vs ionotropic (nicotinic acetylcholine receptors) - Slow process
How are muscarinic receptors activated? How does this differ in comparison to nicotinic receptors?
- Activated through muscarine
- Alkaloid mimicking action of ACh- causing sweating, salivation, weeping, blurred vision
- Not nicotine (like nicotinic receptors)
Explain the 3 types of muscarinic receptor and how they differ- including details of mAChR signalling mechanisms
M1: brain (more complicated- various cations)
M2: heart- decrease cAMP, decrease PKA (protein kinase A or cAMP- dependent protein kinase), less phosphorylation of Ca2+ channels so inactivated (less Ca in)
Also activation of K channels (more K out)
Hyperpolarisation of membrane
Causing less cardiac muscle contraction and bradycardia
M3: Glandular- increase Ca2+ causing exocrine secretion and smooth muscle contraction
Explain effects on certain organs mediated by M2 and M3
M2: heart
- SA node- decreasing rate
- Atrial muscle- less force
M3: Glandular (smooth muscle and exocrine gland)
Bronchi
- Smooth muscle constrict
- Glands secrete
GI tract
- Smooth muscle more motile and contract
- Glands secrete
Bladder
- Contract
Eye
- pupil (circular muscle of iris) constricts
- Ciliary muscle contracts
Salivary Glands
- secretion
Lacrimal glands (tears) - secrete
Muscarine activates them ALL- no selectivity- therefore no therapeutic uses in body
Outline molecular mechanism in M3 activation
In M3 activation: G coupled protein receptor activated Increase in phosphatidylinositol Ca released from intracellular stores Can combine with calmodulin- increasing interaction with myosin light chain kinase
Outline molecular mechanism in M2 activation
In cardiac muscle- M2 receptors causing Gi- coupled protein to be activated to decrease levels of cAMP- Less PKA produced- Ca2+ channels so inactivated (less Ca in)
Activation of Gi causes activation of G- protein regulated K channel (more K out)
Hyperpolarisation of membrane
Causing less cardiac muscle contraction and bradycardia
How does the parasympathetic system control bladder function? What is incontinence?
- afferent, sensory fibre in walls of bladder transfer impulse thalamus
- Thalamus delivers sensation to cerebral cortex (higher brain areas) Then post ganglionic relay neuron up to the bladder wall where short postganglionic neuron in walls of bladder release acetylcholine stimulating smooth muscle tissue
Therefore in the autonomic reflex arc there is a higher function override- loss of this can cause incontinence (MS or diabetic neuropathy)
What type of drug can help with unwanted bladder contractions?
Muscarinic receptor antagonist at target organ (M3)
Atropine or oxybutynin- M2/M3 mAChR antagonists (non-selective parasympatholytic/ anti-muscarinic) hence prevents unwanted bladder contractions but causes blurred vision, tachycardia, dry mouth
Explain which muscarinic drugs can control the contraction and the relaxation of the iris circular muscle
M3 agonist pilocarpine- mimics PNS actions causing contraction (constriction miosis)
Useful in glaucoma (build up of intraocular pressure)
M3 antagonist atropine blocks receptor causing relaxation (dilation mydriasis)
Useful in ocular examination
Explain the action of another muscarinic receptor antagonist- hyoscine?
- Non- selective antagonist
- lipophilicity > atropine therefore readily crosses blood brain barrier
- > CNS effects and > duration of action
- CNS depressant and inhibits smooth muscle motility (used in sedation, CNS depressant, travel sickness- reduce spasms associated with travel sickness, alleviate bowel colic- spasms of intestinal smooth muscle causing pain)
What are indirectly acting parasympathomimetic? Give e,g,
Mimic effects of the parasympathetic agonist by causing neurotransmitter release/ preventing breakdown of neurotransmitters
- Anti-ChE- block all AChE
- Affect all cholinergic neurotransmission
- Prolong and elevate ACh at receptors
Explain in further detail anti-cholinesterases
Competitive inhibitors
- Increase in ACh at the synapse
- More binding to M3 receptors
- physostigmine- causing more miosis (contraction) in treatment of glaucoma
- stimulate bladder in urinary retention (as more contraction)
- Used in treatment of atropine poisoning (M3 antagonist- causing dilation pupils)
- Neostigmine- polar, less lipophilic, acting peripherally, more effective at NMJ
- Myasthenia gravis- AChR antibodies
Explain in further detail irreversible anti-cholinesterases
- Organophosphorus compounds (in insecticides) e.g. dyflos or Novachok
- irreversibly covalently modify AChE
- Therefore esterase enzyme needs to be synthesised again
- Some highly lipid soluble so rapidly cross insect cuticles
