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Pharmacology 3
Autonomic NS
sympathetic
- thoraco-lumbar
- T1 - L2
- short pre-ganglionic myelinated B fibres enter sympathetic ganglion and act on nicotinic Ach receptors on post-ganglionic neurone (except fibres to the adrenal medulla, which go directly there without a ganglion and stimulate chromaffin cells to release adrenaline)
- long post-ganglionic unmyelinated C fibres mostly release noradrenaline and act on adrenoceptors (except to sweat glands and LIKELY also blood vessels in skeletal muscle, where they release Ach which act on muscarinic receptors)
- adrenoceptors
- alpha
- α1
- Gq
- activates phospholipase C, which controls breakdown of phosphoinositides to form inositol triphosphate (IP3) and diacylglycerol (DAG)
- IP3 causes Ca release from endoplasmic reticulum, which causes membrane hyper polarisation or enzyme release
- DAG activates protein kinase C
- activation
- vasoconstriction
- relaxation of gut smooth muscle
- hepatic glycogenolysis
- saliva secretion
- α2
- pre-synaptic (all others are post-synaptic)
- Gi
- inhibit adenylyl cyclase, which decreases cAMP
- activation
- inhibits noradrenaline release
- stimulates platelet aggregation
- decrease insulin resistance
- beta
- all Gs
- stimulate adenylyl cyclase, which increases cAMP, which activates protein kinase A
- β1
- activation
- positive inotropy and chronotropy
- relaxation of gut smooth muscle
- causes lipolysis
- β2
- activation
- bronchodilation
- vasodilation of skeletal muscle vessels
- relaxation of smooth muscle
- inhibition of histamine release
- renin release
- metabolic
- insulin release
- glycogenolysis
- gluconeogenesis
- β3
- dopamine
- all
- GPCR’s
- traverse cell membrane 7 times
- activate second messengers at expense of GTP
- agonists
- all: have a benzene ring with an amine side chain at C1
- catecholamines: have a hydroxyl group at C3 and C4
- adrenaline
- low dose: mainly β
- high dose (e.g. arrest): mainly α
- L-isomer 15x more potent
- noradrenaline
- dopamine
- low dose: dopamine receptors
- peripheral D1 activation: vasodilatation of renal and mesenteric beds
- D2 activation at CTZ: N&V
- middle: β ****& dopamine receptors
- high dose: α, β ****& dopamine receptors
- dobutamine
- mainly β1
- some β2 and α1
- T1/2: 2 minutes
- dopexamine
- β2 and dopamine receptors
- some β1
- isoprenaline
- non-specific β
- ideal for complete heart block
- non-catecholamines
- ephedrine
- mainly β
- some α
- also indirect
- causes increased release of catecholamines
- so get more of a tachycardia!
- tachyphylaxis can occur as noradrenaline stores are depleted
- does not reduce uterine blood flow
- exc. mostly unchanged
- metaraminol
- mainly α
- also indirect
- some β
- phenylephrine
- clonidine + dexmeditomidine
- xamoterol
- D
- bromocriptine, cabergoline
- apomorphine
- (inotropes & vasopressors)
- intropes
- I
- increase intra-cellular Ca
- Ca
- 10% calcium gluconate
- 10% calcium chloride
- increase cAMP
- adrenoceptor agonists
- phosphodiesterase inhibitors
- III
- bipridine derivative
- milrinone
- T 1/2: 2.5hrs
- 80% exc. unchanged by kidneys
- precipitates with furosemide
- imidazolone derivatives
- non-selective
- aminophylline
- = theophylline + ethylenediamine (stabiliser)
- actions
- inotropic and chronotropic
- vasodilatory
- think sildenafil! (PGEI 5)
- so reduce afterload
- unchanged/reduced myocardial oxygen consumption
- glucagon
- Gs, increases activity of adenylyl cyclase
- inhibit Na/K pump
- II
- increase sensitivity of actomyosin to Ca by binding to troponin-C
- III
- act by metabolic or endocrine pathways
- vasopressors
- noradrenaline
- ephedrine
- metaraminal
- phenylephrine
- vasopressin
Autonomic NS contd..
adrenergic antagonists
- alpha
- 1
- non-selective
- antagonists
- phentolamine
- phenoxybenzamine
- irreversible binding
- T1/2 24hrs
- marked nasal congestion
- beta
- 1 (cardioselective ‘NAME’)
- nebivolol
- atenolol
- mostly exc. unchanged by kidneys
- metoprolol
- esmolol
- rapidly met. by red cell esterases
- T 1/2 10 mins
- sympathomimetics when catecholamines low (‘OAP Time’)
- oxprenolol
- acebutolol
- pindolol
- timolol
-
- non-selective beta
- sotalol
- also type III anti-arrythmic
- exc. by kidneys unchanged
- propranolol
- extensive 1st pass
- similar to propofol
- 95% PB
- Vd 3.6
- lipophillic
- T1/2: 4 hours
- alpha and beta
- labetolol
- 1:3 alpha:beta orally
- 1:7 alpha:beta IV
- 4 isomers
- 50% PB
- used in pre-eclampsia
- carvedilol
parasympathetic
- cranio-sacral
- III, VII, IX
- X
- supplies thoracic and abdominal viscera
- S2, 3, 4
- long pre-ganglionic myelinated B fibres act on nicotinic Ach receptors on post-ganglionic neurone
- post-ganglionic unmyelinated C fibres act on muscarinic Ach receptors
- acetylcholine receptors
- nicotinic
- All pre-synaptic autonomic
- ligand gated ion channels
- 5 subunits
- Adults
- 2 alpha, 1 beta, 1 delta, 1 epsilon
- Fetus
- gamma instead of epsilon
- abcdeFG (like with HbF)
- muscarinic
- All post-synaptic parasympathetic
- GPCR's