We're Getting Mutants in the MCU - The Loop


Lecture Details

Richard Loiacono; Week 2 MED1022; Pharmacology

Lecture Content

Pain is sensed in small fibres of peripheral nerves, sensory nerve endings can be set off by touch/pressure/heat/pain. Cell bodies are found in the dorsal root ganglion. Fibres end in the dorsal horn of the spinal cord. Resting cells aren't resting, have cell membrane permeability to different ions. Membrane potential can be -90mV. The 'up phase' of the AP is voltage gated Na channels which depolarises the cell membrane. Down phase is slower sustained increase of K permeability, hyperpolarises the cell.

Tetrodotoxin is an Na channel blocker found in fugu fish. Poisoning is associated with weakness, paralysis and death. Can produce reversible blockade of nerve conduction. It is poorly lipid soluble and acts exclusively from the outside of the channel, the charged part permeates the Na channel and lodges. Is non specific to whether the channel is open or closed.

Local anaesthetics block in both open and inactive state (use dependent). They block both high and low frequency firing neurons. The greater the proportion of channels open/inactive the more they are blocked. Antiepileptics include carbamezapine, antidysrhythmics such as lignocaine preferentially block channels in inactivated state. They are use dependent- only block high frequency neurons and do not interfere with normal state.

Local anaesthetics bind directly to intracellular part of Na channel, plug the inner part of the channel and prevents influx of Na into the cytoplasm. It reversibly inhibits depolarisation of the nerve. The drug has to be non-ionised to cross membranes but ionised to block Na channels.

A delta and C transfer pain signals. Order of block is pain, cold, warm, touch, deep pressure and motor. Drugs must be lipid soluble (un-ionised) to enter the cell; weak bases are ionised/charged at physiological pH. Anaesthetics can be esters (inactivated by tissue/bound esterases) or amides (longer half life, metabolised in the liver).

Lignocaine is an amide, widely used, long duration of action. Amethocaine used mainly for spinal and corneal anaesthesia, is an ester, and has a slow onset/long duration of action. Bupivicaine is widely used (epidural anaesthesia), amide, long duration of action.

Absorption is dependent on dosage, site of injection and drug-tissue binding as well as vasoconstrictor presence. Toxic reactions are associated with overdosage leading to escape in systemic circulation, can cause restlessness, shivering, tongue numbness or a metallic taste, resp depression in the CNS. CVS effects cause myocardial depression, conduction block, vasodilation (direct effect on vascular smooth muscle). Combined effects cause a fall in blood pressure and death. Administration can be by surface (nose, mouth, cornea, not skin), infiltration (direct injection into tissues to reach nerve branches), intravenous regional (limb surgery, limb can be isolated by pressure cuff), nerve block (injected close to nerve trunks/plexus).

Local infiltration affects nerve endings in the skin and subcut tissue which are blocked by direct contact with a local anaesthetic which is injected into the tissue. Topical block is applied to mucous membrane surfaces blocking nerve terminals in the mucosa (anaesthatises the cornea and oral mucosa). Surface anaesthesia is applied to skin to relieve itching, burning and surface pain. Nerve block is where anaesthesia is injected around a nerve/nerve trunks that lead to the operative site (local surgery and dentistry). Epidural is injected into epidural space surrounding nerve roots, used for spinal anaesthesia/childbirth. Spinal anaesthesia is injected into subarachnoid space surrounding spinal roots, is used for abdominal surgery.

Adrenaline and felypressin are potent vasoconstrictors often used with local anaesthetics, local anaesthetics are removed by absorption into blood, addition of vasoconstrictors reduces absorption of anaesthetics (prolonging anaesthetic effect, reducing systemic toxicity, limiting spread of local anaesthetic into systemic circulation).

Increasing probability of Na channel opening are batrachotoxin, scorpion toxin or DDT. Batrachotoxin prevents closing of Na channels, membrane is hyperexcitable, death via cardiac fibrillations/convulsions.


Rang and Dale (6th); 44

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