Pharmacodynamics, pharmacokinetics, and drug adaptations

Difference between drug desensitisation and drug tolerance

desensitisation - Repeated and continuous administration over a short time (minutes) period lowers effectiveness

tolerance - continuous administration over days/weeks lowering drug effectiveness

Define refractoriness

Complete loss of drug effect due to prolonged/excessive use

Define drug resistance

When the loss of drug effectiveness is due to an organism developing resistance (e.g. antimicrobials/anti tumour drugs)

Main mechanisms that cause adaptations - Change in receptors

can be cause by

• Phosphorylation of receptor - changes its function

• Translocation - location of receptor changes (e.g. from inside to outside of cell)

• Heterologous/homologous desensitisation

Difference between heterologous/homologous desensitisation

Source of inhibition - if the receptor itself inhibits β-arrestin, (e.g. phosphorylates it) then it is homo, if a different part of the body causes the β-arrestin to stop functioning, then it is hetero.

Main mechanisms that cause adaptations - Exhaustion of mediators

If a mediator is needed for a drug to be a effective, and those mediators run out, the drug will no longer be effective

Main mechanisms that cause adaptations - Induced metabolic degradation of a drug

Overactive enzymes in (e.g.)liver cause excessive metabolism of drug, so less active form reaches active site

What is the function of β-arrestin, and how does it work

Controls G-protein coupled receptor (GPCR) signalling. Does this by binding to phosphorylated GPCRs, and preventing them from interacting with G-proteins, terminating signalling

How does GABA make GABA_A receptors less sensitive?

GABA binding means the channel opens, and Cl- flows in, hyperpolarising the cell, and means more stimulus is required to generate an action potential, desensitising the neuron

How do benzodiazepines exacerbate the inhibitory effect of GABA?

Benzos have their own binding site of GABA receptors, and have a high affinity with them. This allows more Cl- to flow in neuron, and further hyperpolarises the neuronal cell, desensitising it

How does long-term benzodiazepine therapy affect the effect of GABA?

Makes it harder for the GABA to bind to receptor, and uncoupling is more likely. This leads to decreased expression of GABA_A receptors