chronic therapy Flashcards
what are some examples of drugs where long term therapeutic use adaptations are present
reductions in response (airway conductance) for b2 adrenoceptor agonists like salbutamol
what is the mechanism of adaptation to B2 adrenoceptor agonists
Receptor numbers and function are plastic - allowing different response to the same amount of agonist applied.
Initially, desensitisation and tachyphylaxis occurs (within minutes), where the response to repeated administration of agonist diminishes. Tolerance is a slower (days-weeks) decline in responsiveness to application.
mechanism of B2-AR uncoupling that causes desensitisation
Following binding of the ligand at the receptor, the G-protein is uncoupled, which leads to a reduction in cAMP generation, and loss in the GTP-sensitive high affinity binding of agonists. This occurs due to the phosphorylation of the B2-AR by B-AR kinase, which conversely increases B-arrestin binding to the B2-AR. The binding of B-arrestin prevents the coupling of the receptor with its complementary G-protein.
Phosphorylation occurs at serine residues. Targets the IC C-terminus.
This desensitises the receptor, as it decreases both agonist affinity, and the G-protein mediated signalling processes.
mechanism for the Internalisation of B2-AR
The receptors can be internalised into endosomes. This is done by the interaction of B-arrestin with clathrin-coated vesicles, which transport the receptor to the endoscope.
The mechanism of externalisation of the receptors is unknown, but first the receptor much be dephosphorylated (by PP2A).
mechanism of Down-regulation of B2-ARs
When agonists are administered repeatedly over a long period of time, receptor degradation increases, while synthesis decreases.
The receptors are degraded when they are moved from the endosome to lysosomes.
Long-term elevation of cAMP (B2-AR agonism-mediated) leads to the down regulation of the receptor, while upregulating PDE (which metabolises it). Opposite happens following long-term B2-blockade (which decreases [cAMP]).
what is the mechanism of adaptation to B2 adrenoceptor antagonists
Following abrupt cessation to treatment with beta blockers, there is a period of rebound myocardial ischaemia.
Cessation of propranolol has been associated with increased tachycardia and angina for 3-4 days, as well as hypersensitivity to catecholamines.
These occur due to receptor up-regulation to account for the deficits in adrenergic signalling.
CREB (primarily phosphorylated by PKA) dimerises and binds to CRE in the B1-AR gene, to increase transcription of the B1-AR.
what are some examples for adaptations to chronic drugs that are undesiarable
reductions in response (airway conductance) for b2 adrenoceptor agonists like salbutamol.
opioid tolerance
In cancer, increase DNA repair (such as the conversion O6-methylguanine back into guanine by unregulated meghylguanine methyltransferase) and the formation of trapping agents and chelators (such as increased GST levels, which negates actions of oxidisers and radials) reduce treatment efficacy.
Enzyme and transporter regulation may also occur in cancer. Downregulation of certain enzymes to decrease prodrug production, or upregulation to increase metabolism of drugs.
Upregulation of transporters (such as ABC) can reduce IC [cancer drug]. Similar mechanism for antibiotic resistance.
what are the adaptations to chronic drugs that are desirable
Topical capsaicin used to treat back pain, as it desensitises the TRPV1 channels that innervate nerves that conduct pain signalls.
GnRH1 agonists to desensitise the GnRH1-mediated production of testosterone - prostate cancer
Antagonist (degarelix) can be used to treat the prostate cancer top^
