PHARM; Lecture 28, 29, 30 - General Anaesthesia, Local Anaesthesia and Antidepressant drugs Flashcards Preview

Y2 LCRS 1 - Pharm, Endo, Reproduction > PHARM; Lecture 28, 29, 30 - General Anaesthesia, Local Anaesthesia and Antidepressant drugs > Flashcards

Flashcards in PHARM; Lecture 28, 29, 30 - General Anaesthesia, Local Anaesthesia and Antidepressant drugs Deck (41)
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What are the clinically desirable features that GA cause?

  • **Loss of consciousness at low conc
  • **Suppression of reflex responses at high conc
  • Relief of pain (analgesia)
  • Muscle relaxation
  • Amnesia

**are general in all GAs


What are the types of GA and how can we admin them?

Have very different structures (unlike other drugs, NSAIDS) -> very powerful euphoric high just before you lose conciousness


What is the proposed mechanism of action of GAs?

Anaesthetic potency increases in direct proportion with oil/water partition coefficient -> so thought they crosses the P/LB/L and dissolve/change the lipid bilayer BUT change in BL is very small and how would changing the membrane proteins cause anaesthesia?.

OVERALL: EITHER Reduce neuronal excitability OR altered synaptic function


What is the MoA of IV GAs?

Slightly more selective, targeting GABAa (also important in causing euphoria which occurs before being knocked-out by propofol).

GABAa has 5 subunits, with a different combination in different parts of the brain, but IV agents seem to target specific subunits in the GABAa receptor = beta-3 (reflex responses) and alpha-5 (amnesia)


What is the MoA of inhalational GAs which act by altering synaptic function?

Target GABAa and glycine receptors -> far less selective for GABA-A than IV agents, but more selective for alpha 1 containing GABA, important in suppression of reflex responses. Reduction of nerve conduction occurs when increasing concentration of inhalational GAs; via effect on nAChR, which are important for amnesia and relief of pain


What is the general difference between MoA of inhalational vs IV GAs agents?

IV agents are relatively selective -> largely mediated by GABA with mild effects on other things Inhalational agents -> non-selective, various agents.

Larger dose of inhalational agent needed compared to IV


How do GAs cause loss of consciousness?

  • Unconcious = massive decrease in cortical activity;
  • thalamus is a relay station for information going between the cortex and the rest of the CNS ->
  • depressing the excitability of thalamocortical neurones will result in disconnection of the periphery from the brain ->
  • depression of thalamocortical neurones are mediated by: TREK (hyperpolarisation), enhanced GABA function;
  • RAS also affect consciousness, thalamocortical neurones respond to sensory information and they are also impacted by the RAS - the greater the firing of the RAS, the greater the level of arousal


How do GAs cause suppression of reflex responses?

High density of GABA receptors located in the dorsal horn of the spinal cord, causing depression of reflex pathways;

anaesthetic agents that enhances GABA and glycine function in the dorsal horn will decrease the activity of the dorsal pathways;

this is another method by which the brain can be disconnected from sensory information coming from periphery; suppresses the reflex responses


How do GAs cause amnesia?

GA tend to cause amnesia at a pretty low dose, with amnesia as the first effect -> a lot of GABA receptors in the Hippocampus have the alpha5 subunit; so leads to decrease in synaptic transmission in the hippocampus


What is the difference between high/low blood:gas partition coefficient in GAs (IV vs inhalational)?

IV is injected into blood and goes to the brain; inhalation is more complex.

On the left: lung to blood to brain, and how well anaesthetic distributes in the blood is assessed using blood:gas partition coefficient;

really well dissolved in blood = less speed to penetrate brain ->

only agent still in Gas phase diffuses easily into brain => need lots of GA if well dissolved in blood, to have significant portion still in gas phase, takes longer for such GA to have effect.


RIGHT: if it doesn't dissolve well in blood, then more of drug in gs phase that can enter the brain, whihc is useful for anaesthetists, because direct correlation between amount of anaesthetic gas in the lung and in the brain


What is a local anaesthetic?

Drugs which reversibly block neuronal conduction when applied locally


Summarise the generation of a neuronal action potential?

All-or-nothing response -> reach the potential and then occurs


What is the structure of local anaesthetics?

All have same middle region, with 3 different region -> aromatic (lipid soluble), amine side chain (3ry amines - hydrophilic), ester/amide bond.

NB: Benzocaine doesn't have the amine side chain, lipid soluble and has a weaker effect; is a surface LA


How do local anasthetics interact with Na channels?

    • Local anaesthetic is B (weak bases) in the diagram, which needs to be able to penetrate the neurone ->
    • non-ionised form enters the neurone, which once inside is reionised (cationic form).
    • Cationic form is active and binds to a site on VGSC, when it is open (as site is inside the channel) which stereochemically inhibits the passage of Na+.
    • Shows property of use dependency of LA action = more active the cell, more channel is open and more it will be blocked, giving a greater selectivity for nociceptive neurones
    • If pathway is closed it can still cross through as it is lipid soluble -> doesn't cause use dependency as channels don't need to be open


What are the effects of Local anaesthetics?


  • Neurones go through open, resting -> inactivated -> resting open with action potentials which we believe the LA maintains the inactivated part of the cycle.
  • Prefer small diameter fibres as there is more concentration of ions: nociceptors are small diameter fibres (c and delta fibres); non-myelinated as they don't want to cross various lipid barriers.
  • PH: local anaesthetics are pH selective and pH dependency, less effective in infected tissue as it is more acidic, so more is ionised, so cannot enter the neuronal cell


What are the 6 methods of administration of local anaesthesia?



What are the pharmacokinetic properties of lidocaine and cocaine?

Cocaine is metabolised by butyrylcholinesterases


What are the unwanted effects of lidocaine?

Confusion/increased activity due to bolus/OD -> GABA neurones in brain shut down first as they are very sensitive, which is why you get CNS stimulation. CVS: may be a sudden drop in BP


What are the unwanted effects of cocaine?

Sympathetic or sympathomimetic actions; slows down reuptake of NA, both centrally and peripherally


What are the symptoms of depression?



What is unipolar depression/depressive disorder?



What is bipolar depression/manic depression?

Oscillating depression/mania

Less common;

Early adult onset

Strong hereditary tendency

Drug treatment (Lithium)


What is the monoamine theory of depression?

Delayed onset of clinical effects of anti-depressants (4-5wks) which could be due to adaptive changes such as downregulation of receptors


What is the pharmacological evidence supporting the monoamine hypothesis of depression?



What is the MoA of TCAs and what is their structure?

EXAMPLE: Amitriptyline Structures Neuronal monoamine re-uptake inhibitors NA = 5-HT >> DA (inhibition of reuptake)

Other receptor actions? -

  • α2 -
  • mAchRs -
  • histamine -
  • 5-HT
  • Delayed down-regulation of β-adrenoceptors and 5-HT2 receptors -> time course of downregulation correlates with clinical effects


What are the pharmacokinetics of TCAs?

Rapid oral absorption Highly PPB (90 - 95%) Hepatic metabolism - active metabolites - renal excretion (glucuronide conjugates) Plasma t1/2 (10-20 hrs)


What are the unwanted effects of TCAs?

THERAPEUTIC DOSAGE Atropine-like effects (dry as a bone, blind as a bat, etc) (amitriptyline) Postural hypotension (vasomotor centre - rather than SNS) Sedation (H1 antagonism) ACUTE TOXICITY (OD) CNS: excitement, delirium, seizures -> coma, respiratory depression CVS: cardiac dysrhythmias -> ventricular fibrillation/sudden death Care - attempted suicide (!!!)


What are the drug interactions of TCAs?

PPB: increase TCA effects (aspirin, phenytoin) Hepatic microsomal enzymes: increase TCA effects (neuroleptics; oral contraceptives all metabolised in liver by the same enzyme system -> slows down TCA metabolism, getting relative OD) Potentiation of CNS depressants (alcohol) Antihypertensive drugs (monitor closely -> sometimes increase/decrease; can be variable)


What are MAO inhibitors and what is their MoA and structure?

EXAMPLE: Phenelzine

  • MAO-A : NA+5-HT
  • MAO-B : DA

Most are non-selective MAOIs Irreversible inhibition -> long d.o.a

Rapid effects : increases cytoplasmic NA + 5-HT

Delayed effects : clinical response (3-4wks); down-regulation of β-adrenoceptors + 5-HT2 receptors

Inhibition of other enzymes


What is the pharmacokinetics of MAOi?

Rapid oral absorption Short plasma t1/2 (few hrs) but longer d.o.a. as they irreversibly bind Metabolised in liver; excreted in urine

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