Principles: Pharmacology

Principles: Pharmacology

1. Action potentials

   • Depolarisation = the membrane potential becomes less negative (or even becomes positive)
   • Hyperpolarisation = the membrane potential becomes more negative
   • The direction of change in potential depends on the direction of movement of the ion and the charge carried by the ion
   • Sodium channels
     • Na flows inwardly
     • Concentration 140 mM outside cell, 10-15 mm inside
     • Driving force = Vm - ENa
     • Negative driving force = inward movement of sodium
   • Potassium channels
     • K flows outwardly
     • Driving force = Vm - Ek
     • When positive, K flows inwards
   • Ion channels
     • Protein complexes spanning lipid bilayer, form a central pathway to allow rapid flow of selected ions
     • Ion channels responsible for action potentials in neurons
       • Voltage activated Na channels = depolarising
       • Voltage activated K channels = hyperpolarising
   • Voltage activated Na / K channels
     • Both activated by membrane depolarisation - Na channels rapidly, K channels with a slight delay
     • Activation of Na channels self-reinforcing, opening of a few channels causes further depolarisation (positive feedback, upstroke of graph)
     • Activation of K channels is self-limiting, outward movement of K causes repolarisation which turns off the stimulus (negative feedback, downstroke of graph + there is an undershoot due to delayed closure of K channels)
   • Refractory period and Na channel inactivation
     • Closed state (depolarisation to open)
       • Activation gate closed, inactivation gate open
       • Non-conducting
     • Open state (maintained depolarisation to closed)
       • Activation gate open, inactivation gate open
       • Conducting
     • Inactivated state (repolarisation to closed)
       • Activation gate open, inactivation gate closed
       • Non-conducting
   • Absolute refractory period
     • No stimulus, however strong, can elicit a second action potential
     • All Na channels inactivated
   • Relative refractory period
     • Stronger than normal stimulus may elicit a second action potential
   • The nerve cell membrane is leaky so passive signals do not spread far from their site of origin due to current loss across the membrane
   • Passive conduction is a factor in the propagation of the action potential. The longer the length constant, the greater the local spread. This in turn increases AP conduction velocity.
   • Oligodendrocytes = produce myelinated cells in CNS (Schwann cells do it in PNS)
   • Astrocytes = star shaped, support homeostasis and maintain blood brain barrier
   • Microglia = immune surveillance, macrophages of CNS

2. Autonomic Pharmacology 1

   • Autonomic Nervous System
     • Carries output from the CNS to the whole of the body other than skeletal muscle
     • Regulates visceral functions that are largely involuntary
     • Divided into sympathetic and parasympathetic
     • Sympathetic
       • Coordinates the body's response to stress, associated with fight or flight
       • Preganglionic neurones always ACh
       • Post ganglionic neurone usually noradrenaline
       • Thoraco-lumbar outflow (T1-L2)
       • Increases heart rate and force of contraction
       • Relaxes bronchi, decreases mucous production
       • Reduces GI motility and constricts sphincters
       • Vasoconstriction but relaxation in skeletal muscle
       • Release of adrenalin from adrenal gland
       • Ejaculation
     • Parasympathetic
       • Coordinates the body's basic homeostatic functions
       • Pre and post ganglionic neurones = ACh
       • Cranial nerves 3/7/9/10
       • Decreases HR
       • Bronchocontriction, stimulates mucous production
       • Increases GI motility and relaxes sphincters
       • No effect on blood vessels or adrenal glands
       • Erection
   • Neurochemical Transmission
     • Precursor taken up
     • Transmitter synthesised and stored
     • Action potential depolarises
     • Calcium influx through voltage activated channels
     • Calcium induced release of transmitter
     • Receptor activation
     • Enzyme mediated inactivation of transmitter or reuptake of transmitter
   • Chemical transmission
     • Sympathetic
       • Action potential from CNS
       • Travels to presynaptic terminal of preganglionic neurone triggering calcium entry and release of ACh
       • ACh opens ligand gated ion channels in the postganglionic neurone
       • Causes depolarisation and generation of action potentials that travel to presynaptic terminal of the neurone, triggering calcium entry and release, usually of noradrenalin
       • Noradrenalin activates G protein coupled receptors - adrenoreceptors
     • Parasympathetic
       • Almost the same as sympathetic
       • ACh always the transmitter used by post ganglionic neurones
       • ACh activates G protein coupled muscarinic acetylcholine receptors in target cell membrane
   • Ligand gated ion channels
     • Consist of separate glycoprotein subunits forming a central, ion conducting channel
     • Allow rapid changes in the permeability of membrane to certain ions
     • Rapidly alter membrane potential
   • G protein coupled receptors - muscarinic ACh receptors
     • Receptor, G protein and effector are separate proteins
     • G protein couples receptor activation to effector modulation
     • Signalling slow in comparisom to transmitter gated ion channels
     • Receptor
       • Integral membrane protein
       • 7 transmembrane spans joined by 3 extracellular and 3 intracellular connecting loops
     • G protein
       • Peripheral membrane protein
       • 3 polypeptide subunits (alpha = binding site)
       • Contains guanine nucleotide binding site which can hold GTP
   • How do G protein coupled receptors work?
     • No signalling
       • Receptor unoccupied
       • G protein binds GDP
       • Effector not modulated
     • Turning on the signal
       • Agonist activates receptor
       • G protein couples with receptor
       • GDP dissociates from and GTP binds to alpha subunit
       • G protein dissociates
       • Alpha subunit combines with and modifies activity of effector
       • Agonist may dissociate from the receptor, but signalling persists
   • Turning off the signal
     • Alpha subunit acts as an enzyme to hydrolyse GTP to GDP
     • G protein alpha subunit recombines with the beta/gamma subunit completing G protein cycle

3. Autonomic Pharmacology 2

   • Nicotinic Acetylholine receptors (ligand gated)
     • Consist of 5 glycoprotein subunits forming a central, cation conduction channel
     • Diverse range of subunits
     • Alpha 1-10, beta 1-4, gamma, delta, epsilon
     • Binding of transmitter opens gate
   • Cholinergic Transmission
     • Uptake of choline
     • Synthesis of ACh
     • Storage of ACh
     • Depolarisation by action potential
     • Calcium influx through voltage activated calcium channels
     • Calcium induced release of ACh - exocytosis
     • Activation of ACh receptors causing cellular response
     • Degredation of ACh to choline and acetate by AChE which terminates transmissions
     • Reuptake and reuse of choline
     • Nicotine acts as an agonist - mimics the action of ACh
   • Cholinergic Transmission at Parasympathetic Neuroeffector Junctions
     • Synthesis and storage of ACh
     • Depolarisation by action potential
     • Calcium influx through voltage activated calcium channels
     • Calcium induced release of ACh
     • Activation of muscarinic ACh receptor subtypes (M1-M3) causing cellular response
     • Degredation of ACh to choline and acetate by AChE - terminates transmission
     • Reuptake and reuse of choline
   • G protein Coupled Muscarinic ACh receptor subtypes at parasympathetic Neuroeffector junctions
     • M1-Gq = stimulates phospholipase C
       • increased stomach acid secretion
     • M2-Gi = inhibition of adenylyl cyclase, opening of K+ channels
       • Decreased HR
     • M3-Gq = stimulates phospholipase C
       • Increased saliva secretion and bronchoconstriction
   • Noradrenergic Transmission at Sympathetic Neuroeffector Junctions
     • NA synthesis and storage
     • Depolarisation by action potential
     • Calcium influx through voltage activated calcium channels
     • Calcium induced release of NA
     • Activation of adrenoreceptor subtypes causing cellular response
     • Reuptake of NA by transporters U1/U2
     • Metabolism of NA by MAO and COMT
   • G protein coupled adrenoreceptor subtypes at sympathetic neuroeffector junctions
     • B1-Gs = stimulation of sdenyl cyclase
       • Increased HR and force
     • B2-Gs = stimulation of adenyl cyclase
       • Relaxation of bronchial and vascular smooth muscle
     • A1-Gq = stimulation of phospholipase C
       • Contraction of vascular smooth muscle
     • A2-Gi = inhibition of adenyl cyclase
       • Inhibition of NA release
   • Amphetamine
     • U1 substrate
     • Inhibits MAO
     • Displaces NA into cytoplasm
     • NA accumulates in synaptic cleft causing increased adrenoreceptor stimulation
   • Prazoin
     • Selective, competitive antagonist of a1
     • Vasodilator used as anti-hypertensive
   • Atenolol
     • Selective, competitive antagonist of B1
     • Used as an anti-angina and anti-hypertensive agent
   • Salbutamol
     • Selective agonist at B2
     • Used as a bronchodilator in asthma
   • Atropine
     • Competative antagonist of muscarinic ACh receptors, does not block nicotinic ACh receptors
     • Blocks parasympathetic division of ANS
     • Used in reverse bradycardia post MI and in AChE poisoning