Wk9 Autonomic Pharmacology Flashcards
Nicotinic cholinergic receptor
- depolarisation and firing up of APs when this occurs
- ligand gates
- they all have different alpha subunits
What is hexamethonium?
• Selective antagonist for the neuronal sub-type of nicotinic receptor
• Not competitive
• Blocks all the effects of autonomic stimulation - blocks ion channel - na+ cant move through, but ACh still binds
• One of the methonium derivatives (like decamethonium)
- sympathetic and parasympathetic stopped - opposite and so not effective
- first drug to lower BP
- injection
What are muscarinic receptors?
Parasympathetic Postganglionic Transmission:
ACh is released onto Muscarinic Receptors:
•7 transmembrane segments. (M1, m2, m3, m4, m5)
•5 subtypes, of which the first 3 (M1-3) are particularly important in the periphery - G-protein coupled receptors
- conducts muscle
- mediate transmission from parasympathetic post ganglionic neurones onto the tissues
What are muscarinic agonists?
Such drugs are “Parasympathomimetic drugs” because exposure mimics the effects of parasympathetic nervous system activation
Effects of parasympathomimetics
Cardiovascular - decreased heart rate
Smooth muscle - contracts, although vascular smooth muscle dilates via endothelium (EDRF = NO) endothelium derived relaxing factor
Exocrine glands - secrete - sweating, lacrimation, salivation,
bronchial secretion
What is muscarine poisoning?
• Muscarinicagonist
• Source:many mushrooms
• Adverse Effects:
– bradycardia, vasodilation (secondary to NO), leading to falling BP
– increased gut motility (colicky pain), bronchoconstriction, pupillary constriction (miosis).
– Salivation, lacrimation, airway secretions
• Treatment:
– muscarinic antagonist (atropine).
What is pilocarpine?
• Use: to treat glaucoma (some forms)
• Route of administration: topical to the
eye
• Action: On M3 receptors on ciliary muscle, improving aqueous humor drainage, dropping intraocular pressure.
Improves drainage in anterior component of eye
What are muscarinic antagonists?
5 subclasses (M1-5) - 3 are important peripherally
Less specific antagonists: atropine (from Belladonna), hyoscine, cyclopentolate.
M1
Stomach, salivary glands
M2
Cardiac
M3
Smooth muscle
Clinical Uses of Antimuscarinic Drugs
- Asthma (ipratropium)
- To treat bradycardia (atropine)
- During operations: decrease secretions, decrease AChEI side-effects (atropine)
- To dilate pupils (tropicamide)
- Urinary incontinence (oxybutynin or tolterodine)
- Motion sickness (hyoscine)
Pharmacology of Adrenergic Transmission: Overview
- α-adrenoceptor agonists and antagonists
- β-adrenoceptor agonist and antagonists
- Noradnrenaline transporter blockers
- Monoamine oxidase inhibitors
- Indirectly acting sympathomimetic amines
Adrenoreceptors
• 5 main sub-types
–a1
• contract smooth muscle (eg. vasoconstriction)
–a2
• Pre-synaptic auto-inhibition, direct vasoconstriction, central inhibition of sympathetic outflow
–b1
• increase heart rate and contractility
–b2
• relax smooth muscle (eg. bronchodilation,
vasodilation)
–b3
• Relax smooth muscle (bladder); simulate lipolysis
Main uses of a-adrenoceptor receptor agonists
• vasoconstrictors with local anaesthetics (mainly a1)
– adrenaline, noradrenaline
• nasal decongestants (mainly a1)
– phenylephrine
• hypertension (central a2)
• Facial erythema in rosacea
– Brimonidine1 (a2; direct vasoconstriction)
a1 Adrenoceptors: coupled to phospholipase C-ß
Noradrenaline binds to receptor activating an accessory G protein bound to an intracellulaire loop on the receptor
Gq protein dissociates
Phospholipase C activated, releasing signalling molecules
IP3 receptor - sarcoplasmic reticulum increases release of Ca2+ and contraction stimulated
α1- adrenoceptor
Gq
PLC
Increased IP3/DAG
α2- adrenoceptor
Gi
Decreased AC
Decreased cAMP
β- adrenoceptor (all)
Gs
Increased AC
Increased cAMP
M1, M3
Gq
PLC
Increased PI3/DAG
M2
Gi
Decreased Ac
Decreased cAMP
Main uses of a-adrenoceptor antagonists
- Hypertension (a1; doxazosin)
* Benign prostatic hyperplasia – tamsulosin (a1)
Main uses of b-adrenoceptor agonists
• Cardiogenic shock (b1) – adrenaline, dobutamine • Anaphylactic shock (a/b) – adrenaline (increase cardiac output) • Asthma (b2) – salbutamol – also delay of premature labour
e.g. metoprolol (b1) • angina, cardiac arrhythmias • hypertension • anxiety states • (chronic) heart failure (give the heart a holiday ...!) • locally for glaucoma (timolol)
Uptake of catecholamines: Uptake 1
Neuronal; due to the secondary active transporter NAT (Noradrenaline transporter)
Main mechanism for terminating the actions of Nad
Cotransports Na+, Cl- and catecholamine
Inhibitedby: cocaine tricyclic antidepressants (desipramine)
