M&R session 11: the clinical significance of receptor regulation

Question 1

Components of ligand/receptor interaction

Answer 1

Ligand may be endogenous (naturally occurring) or exogenous (administered compound i.e. drug)

Binding–>affinity (measure of ability of ligand to form a drug-receptor complex)
Response–>efficacy (measure of ability of drug-receptor complex to produce a response)

Binding of ligand to receptor produces a conformational change in receptor protein structure, which leads to a response:

• change in membrane permeability to ions
• generation of second messengers

Question 2

Agonists and antagonists

Answer 2

Agonists: possess efficacy (i.e. activate a second messenger, leading to a response). Efficacy may vary. Can be full or partial agonist

Antagonists: possess no efficacy and impair the ability of the agonist to bind. May be competitive (competes with agonist for the same binding site) or non-competitive (binds to a different site, inducing conformational change which alters ability of receptor to bind agonist)

Question 3

Dose response curve

Answer 3

Learn graph from slide 9 and 11
More potent drugs give a greater response at a lower concentration. Some individuals need higher doses for same response

ADR: adverse drug reaction. More drug given, more likely to generate adverse effect (in general). In some individuals the risk of ADR is much higher and dose needed to be beneficial can give same amount of ADR

Question 4

What is tachyphylaxis?

Answer 4

Reduced sensitivity due to excessive exposure to an agonist

Term used interchangeably with “desensitisation”

Beneficial dose-response curve shifts right (towards the ADR curve)

Question 5

What is suprasensitivity caused by?

Answer 5

Agonist deprivation
or
Excessive exposure to an antagonist

Question 6

What can altered responsiveness to a drug result from?

Answer 6

Changes in:

• receptor number
• receptor coupling to second messengers
• availability of second messengers
• cell responsiveness

Question 7

What effect does activation of the mu-opioid receptor have?

Answer 7

Analgesia, sedation, euphoria

E.g. endogenous opioids including endorphins released by body to relieve pain and increase relaxation during periods of stress

Question 8

What happens in opiate dependence?

Answer 8

• Repeated use of opioid causes mu-receptors to become upregulated–>tachyphylaxis
• More opioid is needed to elicit the same response
• When opioid levels fall, the molecule leaves the receptor and is less likely to be replaced, so 2nd messenger activity falls, so patient perceives pain (withdrawal)

Question 9

What actions need to be taken if a patient on tramadol is getting worsening pain and other symptoms?

Answer 9

They are not getting full pain relief but are also experiencing ADRs (ADR curve has moved left towards beneficial curve), so would:

• reduce opioid (to get some benefit but fewer ADR)
• substitute with a different class of analgesia

Question 10

Why does the effectiveness of repeated opioid (morphine) pain relief diminish over a period of months and weeks, and how is this dealt with?

Answer 10

Tolerance mechanisms:

• not fully understood
• acutely, causes receptor desensitisation by down- regulation (internalisation) or receptor desensitisation at the cell surface
• long term more opioid needed for same pain relief. Not because of desensitisation. More mu opioid receptors needed, downstream elements of signalling pathway from mu receptors have become uncoupled, so harder for analgesic effects to occur

Dealt with by reducing opioid dose and replacing with a non-opioid analgesic, giving signalling system time to recover so opioid dose can be increased at a later date if necessary

Question 11

Describe the action of tamoxifen

Answer 11

Anti-oestrogen drug for oestrogen positive breast cancers-but is SELECTIVE:
-antagonist at breast
-agonist at bone and uterus
Therefore, shrinks tumour but doesn’t cause osteoporosis

Question 12

Phaeochromocytoma

Answer 12

Neuroendocrine tumour of adrenal medulla, causing increased intermittent secretion of catecholamines (noradrenaline and adrenaline), so high concentration of these in blood and urine

NA and A act at alpha/beta adrenoceptors:

• cause sweating, tremor, anxiety, hypertension
• INTERMITTENT release so tachyphylaxis DOES NOT develop
• use alpha and beta blockers to antagonise. Also need to remove tumour and other areas as necessary

Question 13

Beta antagonists are used to treat angina, how do they work and what are the complications?

Answer 13

Action: reduce adrenergic stimulation, heart rate and coronary vasoconstriction

SUPRASENSITIVITY leads to beta receptor UP-REGULATION, so with sudden cessation of treatment antagonist withdrawal can occur: receptor numbers are increased so increased SNS action so exacerbation of symptoms

Question 14

Age-dependent catecholamine sensitivity

Answer 14

Increasing age:

• decreased sensitivity to endogenous catecholamines
• reduced HR responsiveness to endogenously administered catecholamines
• potential excess pharmacological efficacy of administered drugs