What actions do muscarinic antagonists have on the peripheral NS?
5 actions
- Block of secretions: saliva, tears, bronchial secretion , sweating
- Tachycardia – by blocking the vagal inhibition of heart (no change in blood pressure because most of blood vessels have no parasympathetic innervation)
- Pupillary dilation (myadriasis) – blocks parasympathetic influence on sphincter pupillae. Myadriasis interferes with drainage via canal of Schlem → raises intraocular pressure. Cyclopegia – ciliary muscle paralysis → paralysis of accommodation
- Inhibition of motility and secretion of GI tract
- Other smooth muscle is also relaxed (bronchi, bladder)
What actions do muscarinic antagonists (atropine, hyoscine and atropine-like drugs) have on the central NS?
3 actions
Atropine – in high doeses causes stimulation, reustign in restlessness, disorientationand hallucinations
More subtle effects – attention and memory – can appear at low doses in the elderly
Hyoscine – powerful CNS depressant, sleep and amnesia
Anti – emetic action (anti-seasickness pills)
Atropine-like drugs – supress the tremor of Parkinson’s – probably by blocking cholinergic transmission in the basal ganglia
the mechanism for smooth muscle contraction?
- rise in intracellular calcium
- calcium bind to calmodulin
- ca-calmodulin activated Myosin light chain kinase
- MLCK phosphorylated MLC
- cross-bridge formation between myosin heads and actin filaments
how is smooth muscle contraction regulated?
intracellular calcium
increase in conc:
- calcium is released from SR storage sites
- calium enters the cell
decrease in calcium:
- calcium is taken back into the storage sites via ATP-calcium pump
- calcium leaves the cell via ATP-dependent ca pump or the Na/ca exchanger
What are the primary blood vessels for resistance?
how is the smooth muscle of these controlled?
arterioles
- control mean arterial blood pressure
- control blood flow to specific tissues
VSM controlled by sympathetic nervous system and local factors
what are the main capacitance vessels and how are they regulated?
- systemic veins and venules
- have 50% of total blood volume
- systemic and humoral regulation of these vessels -> changed venous return (preload) and fluid exchange in the capillary beds
What can intimate contraction of vascular smooth muscles
- passive stretching - originates from the smooth muscle = myogenic response
- electrical depolarisation - opening of voltage-gated calcium channels (L-type calcium) -> increased intracellular calcium concentration
- chemical stimuli
what chemical stimuli can contract VSM?
what are their receptors?
noradrenaline (alpha1 adrenoreceptor) angiotensin II endothelin (Eta, ETb2) vasopressin (V1 receptor) ergot alkaloids (ergotamine) 5-hydroxytryptamine (5-HT2) ACh (M3) prostaglandins (DP, EP, FP)
how does endothelin cause muscle contraction?
endothelia binds to GPCR Gq exchanges GTP forGDP PLC: PL - InsP3 activated calcium channel on SR increase in intracellular calcium calcium binds to calmodulin ca-calmodulin activates MLCK cross bridges - contraction
How does NA cause VSM contraction?
released from sympathetic nerves binds to alpha1-adrenoreceptors coupled to Gq PLC and InsP3 (inositol triphosphate) production IP3 causes release of Ca from SR contraction of smooth muscle
what are cotransmitters of NA in VSM contraction?
- ATP - activation of P2x, non selective cation channel
- Gq couples receptors to PLC (e.g. P2Y)
- neuropeptide Y - can potentiate action of NA
alpha1 - adrenoreceptor antagonists, action and examples
vasodilators -> cause falling blood pressure
prazosin
indoramine
how does cocaine affect VSM contraction?
blocks uptake of NA into nerve terminal -> vasocontriction
what are indirect vasoconstrictors that cause NA release from nerve terminals?
amphetamine
tyramine (the cheese reaction)
ephedrine
what does angiotensin II do?
how is it formed?
what inhibits it?
vasoconstrictor:
- AII activated AT1 receptors
- coupled to Gq to PLC
- IP3 production
angiotensin converting enzyme (ACE) expressed on nonvascular endothelial cells converts angiotensin I (inactive) to angiotensin II (active)
inhibited by captopril, an anti-hypertensic drug
Endothlin:
receptor and mechanism?
synthesis?
antagonists?
rececptor ETA-R, ETB2-R
-> coupled by Gq to PLC -> IP3 production -> ca released from SR
synthesised by endothelium
antagonists: BQ-123 (cyclic pentapeptide), BMS 182874 (sulphanomide derivative)
vascular actions of vasopressin (VP)?
analogue?
V1 receptors -> Gq -> PLC -> IP3
(also works on GI tract and uterine smooth muscle)
analogue: fleypressin (V1 receptor selective) -> used as vasoconstrictor with local anaesthetics
migraine treatments?
migraine = contraction/dilation of cerebral blood vessels
treated with:
1. ergotamine - causes vasoconstriction
- sumatriptan - HT1d-like receptor agonist
- > sumatriptan acts on nerves from trigeminal nucleus - nerves innervate cerebral blood vessels - methysergide - some selectivity as an antagonist for 5-HT2 receptors
mechanisms for VSM relaxation
G-PROTEIN:
- Gs coupled to adenylyl cyclase
- increased production of cAMP
- inhibition of MLCK
- decrease in MLC phosphorylation
- decrease interactions between myosin and actin
drugs that increase cAMP and therefore cause vasodilation:
beta2-adrenoreceptor agonists (e.g. epinephrine, isoproterenol)
phosphoidesterase inhibitors
NITRIC OXIDE - cGMP:
- increase in NO
- activation of guanylyl cyclase
- increased formation of cGMP
- cGMP activates cGMP-dependent protein kinase
- inhibits ca entry into VSM
- activated potassium channels
- decrease IP3
- vasodilation
how is action potential generated and conducted in excitable cell membranes?
- depolarisation: Na influx
- repolarisation: K+ efflux - Na channels inactivate, K channels activate
- voltage-dependent channels
- Na conc is low inside
- K conc is high inside
- depolarisation past threshold will cause AP:
threshold is when more sodium enters the cell than potassium is leaving the cell -> membrane potential becomes more positive
mechanism for local anaesthetic block of voltage-dependent sodium channels
- LA are weak bases
- after administration the base is liberated by relatively alkaline pH of tissue fluids
- they exist as equilibrium of charged and unchnarged form
- the uncharged form diffuses across the nerve sheath and neuronal membrane
- it partially ionises inside the axoplasm
- when the sodium channels opens, the ionised BH+ enters the Na+ channel
- BH+ combines with a specific channel subunit resulting in channel block
methods of LA administration
- administered as water soluble hydrochlorides (base HCl)
- surface anaesthesia
- applied directly to mucous membrane
- cornea, pharynx, bronchial tree, uretha, bladder
- lidocaine
- benzocaine - poorly soluble, sued as powder for prolonged burns
- EMLA = eutectci mixture of LA = lidocrain + prilocaine in crystalline mixture - applied directly to skin - infiltration anaestheisa
- injected directly into tissue to anaestheise nerve endings
- wound stitching, minor surgery, vasectomy
- need large amounts - danger of toxicity
- danger of intravascular injection
- lidocaine, prilocaine
- use with vasoconstrictors when not in extremities - nerve block anaesthesia
- drug injected close to nerve trunk
- anaesthetises whole area of distribution of nerve
- e.g. block of mandibular nerve in dentistry, block of brachial plexus for hand surgery - spinal anaesthesia
- injected into subarachnoid space of spine
- between 2nd and 5th lumbar vertebrae -> below conus modularise to avoid injury
- major surgery use - rectal surgery, caesarian
- procaine, tetracaine, cinchocaine
- combined with glucose, adjusts density - can control anaesthesia by titling the patient
- danger of reportery paralysis, paralysis vomitting, visceral pain because afferent not blocked - epidural anaesthesia
- injected into epidural space
- diffuses to block nerve roots
- cannot spread to brain as epidural spaces end at foreman magnum
- similar to spinal anaesthesia, sam drugs used but large amounts needed
- used in obstetrics - intravenous regional anaesthesia
- injected i.v. distal to cuff on the limb
- diffuses retrogradely into tissue
- danger of toxicity if cuff is prematurely released
three examples of LA and their uses
x
generation and conduction of cardiac action potential
phase 0 - rising phase: fast inward Na+ current
phase 1 - initial depolarisation: voltage gated- Na+ channel inactivation
phase 2 - slow inwards Ca2+ current
phase 3 - ca current inactivation, outwad K current
phase 4 - potassium channel closing
refractory period - Na channel inactivate, no cardiac AP can be elicited
