Cardiovascular and renal pharma

Question 1

tetracaine

Answer 1

-local anaesthetic
-pKa of 8.5
(at this pH half of it is uncharged and at lower pH fewer are uncharged)

Question 2

benzocaine

Answer 2

• local anaesthetic
• pKa of 2.6
• therefore, most of it is in uncharged form at physiological ranges of pH

Question 3

for both tetracaine and benzocaine, there’s more effect when they are in uncharged form. what’s the explanation?

Answer 3

initially, two possible explanations thought of:

• either the uncharged form is the active form
• or uncharged form is required to get access to the site of action, and then either uncharged or charged form of the drug can act

experiment done– a permanently charged form of a local anaesthetic applied externally and injected. there was no effect in the former but there was effect in the latter

conclusion:

• uncharged drug needed as they need to cross PM
• charged drug is the one that interacts with the channel (on the intracellular side) to produce the anaesthetic effect

Question 4

Explain “use-dependance”

Answer 4

• in context of Na+ channels it is the phenomenon where more often the channel opens, more likely it is to be blocked by anaesthetic
• some degree of anaesthetic action is seen which does not show use dependance (through the hydrophobic pathway of action)

Question 5

Mechanism of action of local anaesthetics

Answer 5

Hydrophilic pathway (main)

• diffuse across cell membrane in relatively hydrophobic, uncharged form
• once inside the cell, a proportion of drug becomes charged (thus hydrophilic)
• the charged drug interacts with the intracellular portion of the channel —the channel must be open to allow this interaction

Hydrophobic pathway (to a less extent)

• when the hydrophobic form is passing through the membrane it lodges into the channel
• the channel does not need to be open

Question 6

effects of local anesthetics at a molecular level

Answer 6

• block the Na+ channel and hence stop influx of ions– they inhibit propagation of APs
• enhance inactivation of Na+ channels

Question 7

where do the local anaesthetics act on the Na+ channels? (according to site-directed mutagenesis)

Answer 7

a sequence of amino acids at the cytoplasmic end of S6 of domain IV confers anaesthetic sensitivity on channels

Question 8

toxins acting on Nav channels

Answer 8

• tetrodotoxin
• batrachotoxin
• scorpion toxins

Question 9

tetrodotoxin (and saxitoxin)

Answer 9

• guanidium derivatives
• highly selective and reversible blockers of neuronal Nav channels
• don’t affect voltage-dependance or inactivation
• considerably less effective on cardiac channels

Question 10

batrachotoxin

Answer 10

• alkaloid and membrane permeable
• acts on intracellular portion of Nav
• prevents inactivation and makes threshold potential more negative—> therefore opening of channels is increased greatly
• they can provoke cardiac dysrhythmias

Question 11

scorpion toxins

Answer 11

• a variable mixture of several toxins acting on ion channels
• alpha-scorpion toxin acts on the outside of the Nav channel – inhibits inactivation and acts cooperatively with batrachotoxin to open channel almost permanently
• binds in a voltage-dependant manner which is enhanced by batrachotoxin

Question 12

drugs principally acting on Cav channels

Answer 12

dihydropyridines- e.g. nifedipine
phenylalkylamines- e.g. verapamil
benzothiazepines- e.g. diltiazem