Drug Interactions with Receptors and Ion Channels

Question 1

Acetyl-β-Methylcholine

Answer 1

AChR Agonist. Its isomer is inactive and has no affinity.

Question 2

Isoprenaline

Answer 2

β-adrenoreceptor agonist. The D-isomer is inactive but has affinity so acts as a competitive antagonist with the L-isomer.

Question 3

Muscarine

Answer 3

MAChR Agonist

Question 4

Nicotine

Answer 4

NAChR Agonist

Question 5

Atropine

Answer 5

MAChR Antagonist

Question 6

D-Tubocurarine

Answer 6

NAChR Antagonist

Question 7

Benzilylcholine

Answer 7

Irreversible MAChR antagonist. Causes alkylation of the receptor. Demonstrates the spare receptor principle, as maximal responses can still be achieved in the initial period after application.

Question 8

Cholera Toxin

Answer 8

Causes ADP ribosylation of αs subunit, which inhibits it’s intrinsic GTPase activity. Results in sustained activation of adenylyl cyclase.

Question 9

Pertussis Toxin

Answer 9

ADP ribosolation of αi prevents activation of Gi in response to receptor stimulation, therefore preventing inhibition of adenylyl cyclase activity.

Question 10

Lithium

Answer 10

Uncompetitive inhibitor of phosphatase that converts IP1 to inositol. Blocks IP3 recycling pathway, affects the brain particularly since blood cannot provide an alternative source of IP3 as it does not cross the BBB. Used to treat manic depression.

Question 11

Tyrphostins

Answer 11

Inhibitors of tyrosine kinases. Have potential uses if the treatment of neoplastic growth.

Question 12

Prednisolone

Answer 12

Glucocorticoid Receptor Agonist. May have anti-inflammatory or immunosuppressive effects.

Question 13

Mifepristone

Answer 13

Glucocorticoid R Antagonist. Also a partial progestagen R agonist. It has abortifacients effects.

Question 14

Fludrocortisone

Answer 14

Mineralocorticoid R agonist. Used in replacement therapy to treat Addison’s disease.

Question 15

Spironolactone

Answer 15

Mineralocorticoid R antagonist. Diuretic effects

Question 16

Ethinylestradiol

Answer 16

Estrogen receptor agonist, used in HRT and for contraceptive purposes.

Question 17

Tamoxifen

Answer 17

Estrogen R antagonist used in the treatment of breast cancer

Question 18

Norethisterone

Answer 18

Progestagen receptor agonist used in contraception

Question 19

Danazol

Answer 19

Progestagen R antagonist. Used in the treatment of endometriosis and menorrhagia. In men, it can be used to treat gynomastia

Question 20

Lidocaine

Answer 20

V-gated Na+ channel blocker. LA. Use-dependent, so has a mild selectivity for rapidly firing pain fibres. Shifts the inactivation curve of the channel to the left, such that at any given membrane potential, a greater proportion of the channels are inactivated. It is a weak base (pKa 8-9) so exists in both forms at the physiological pH. It needs to cross the CSM in the unprotonated form, but is a more potent blocker in its charged, protonated form. It binds preferentially to the I form of the channel, so is most effects in ischaemic tissue. Used to treat ventricular dysthymia, and has fast association/dissociation properties.

Question 21

Procaine

Answer 21

V-gated Na* channel blocker. LA. A weak base (pKa 8-9) so exists in both forms at physiological pH. Most potent in the protonated form, but needs to cross CSM unprotonated.

Question 22

QX314

Answer 22

A quaternary LA which is a permanently charged form of lidocaine. It is inactive when applied externally, but potent when infused.

Question 23

Benzocaine

Answer 23

V-gated Na+ channel blocker that acts as a LA. It is always uncharged (pKa 2.6) so it only enters via the hydrophobic pathway, showing no use dependence. It is not affected by pH changes in the physiological range, as shown in the Hille experiments.

Question 24

Quinidine

Answer 24

V-gated Na+ channel blocker, LA. Slow association/dissociation properties means it shows use dependence at low rates of stimulation only. It is used to treat supraventricular tachycardia.

Question 25

Tetradotoxin

Answer 25

Na* channel blocker. Possesses a guanidinium. Blocks the channels from the outside, showing no use dependence.

Question 26

Bay K 1844

Answer 26

L-Type Ca2+ channel agonist

Question 27

Nifedipine

Answer 27

L-type Ca2+ antagonist. It is a dihydropyridine, which preferentially binds to the inactivated form of the channel, so has a selectivity for vascular tissue (which undergoes prolonged periods of depolarization.) Used to treat hypertension and angina pectoralis as it can cause both coronary and peripheral vasodilation.

Question 28

Verapamil

Answer 28

L-type Ca2+ channel antagonist. It is a phenylalkamine that binds to a different site from the DHP, but decreases the affinity of DHP binding. It shows greater use dependence and a more prolonged block than produced by the DHPs. Anti-dysrhythmic uses.

Question 29

Diltiazem

Answer 29

L-type Ca2+ antagonist. A benzothiazepine that binds to a site different to the DHP, but increases the affinity of DHP binding. Produces a more use dependent and prolonged block than the DHP.

Question 30

Diazoxide, Minoxidil, Nicorandil.

Answer 30

K+ channel openers that acts on K+ATP channels. The increased K* efflux leads to hyperpolarisation which results in smooth muscle relaxation. Potential clinical applications in the treatment of IBS, asthma and male alopecia. They are useful in the treatment of hypertension, however their action on insulin release leads to decreased glucose tolerance and hyperglycemia.

Question 31

Tolbutamide and Glibenclamide

Answer 31

Orally acting anti-hyperglycemic agents. Sulphonylureas bind to sulphonylurea Rs on sites associated with the K+ATP channel. This results in β islet cell depolarization, Ca2+ influx and insulin release . Used in the treatment of NIDDM.