Cardiovascular Drugs 2

Question 1

calcium ion channel

Answer 1

control passage of calcium ions into cells, and respond to changes in membrane potential rather than to the presence of an external ligand

Question 2

most important channel in terms of cardiovascular medicine

Answer 2

voltage gated L-type calcium ion channels

Question 3

function of calcium ion channels

Answer 3

• when open calcium floods into cell and produces effect based on what type of cell it is
• in vascular smooth muscle this corresponds to muscle contractions
• in heart muscle, causes an increase in heart rate and force of contraction

Question 4

calcium channel blockers

Answer 4

used for treatment of hypertension and angina pectoris

Question 5

how calcium channel blockers work

Answer 5

they bind to distinct binding sites on the alpha-1 subunit, all of the binding sites are very close together

Question 6

three main structural classes of calcium channel blockers

Answer 6

dihydropyridines
- phenylalkylamines
- benzothiazepines

Question 7

phenylalkylamine

Answer 7

inhibits dihydropyridines and benzothiazepines from binding

Question 8

benzothiazepine and dihydropyridine

Answer 8

inhibits binding of phenylalkylamines

Question 9

benzothiazepines

Answer 9

promote binding of dihydropyridines

Question 10

how dihydropyridines work

Answer 10

they approach their binding site from the extracellular side of the ion channel and show selectivity for ion channels in vascular smooth muscle

Question 11

what are dihydropyridines used for

Answer 11

treatment of hypertension

Question 12

dihydropyridine effectiveness depends on

Answer 12

structural factors

Question 13

SAR of dihydropyridines

Answer 13

• N in dihydropyridine ring must be unsubstituted
• small hydrophobic alkyl groups preferred at positions 2 and 6
• ester groups preferred at positions 3 and 5
• aryl substituent must be present at position 4
• aryl ring usually has a substituent at ortho or meta position, para substitution is detrimental

Question 14

preferred conformation for dihydropyridines

Answer 14

• lightly fattened boat structure with the aromatic ring perpendicular to the dihydropyridine ring
• unsymmetrical dihydropyridines contain asymmetric centre at position 4, with one enantiomer being more active than the other

Question 15

how phenylalkylamines work

Answer 15

block calcium ion channel by binding to an intracellular binding site, and it is believed that the structures have to cross the cell membrane in order to reach that binding site

Question 16

structure of phenylalkylamines

Answer 16

• contain hydrophobic aromatic rings
• contain aliphatic tertiary amine which is mostly protonated at physiological pH
• small % of drug can exist as free base and can therefore cross cell membranes

Question 17

what happens if the tertiary amine is methylated

Answer 17

• the formation of the quaternary ammonium salt results in loss of activity, however if the salt is injected directly into the cell the activity is observed
• the positive charge is therefore important for binding
• thought that ionic interactions are formed with negatively charged glutamate residues involved in calcium ion transport

Question 18

what about the rest of the phenylalkylamine structure

Answer 18

the rest of the molecule is hydrophobic and is likely to form van der Waals interactions with hydrophobic regions of the channel

Question 19

clinical applications of phenylalkylamines

Answer 19

• only one used is Verapamil
• used to treat hypertension by blocking calcium channels in vascular smooth muscle
• also useful in treating arrhythmias by blocking calcium channels in cardiac muscle

Question 20

how benzothiazepines work

Answer 20

they access the calcium ion channel from the extracellular side of the membrane

Question 21

clinical uses of benzothiazepines

Answer 21

• only example of an approved benzothiazepine in NI is Dialtiazem
• prescribed to treat angina in patients that are unable to tolerate beta-blockers

Question 22

SAR of dialtiazem

Answer 22

• basic tertiary amine crucial for activity and is likely to be protonated when binding to binding site, allows for ionic and h-bonds
• ortho and meta substituents on phenyl group not well tolerated, suggesting that aromatic ring is in a confined pocket
• methoxy substituent at para position of phenyl group increases activity, suggests oxygen acts as H-bond acceptor
• activity lost with larger alkoxy groups
• activity lost with alcohol group instead of methoxy group

Question 23

SAR of dialtiazem continued

Answer 23

• presence of hydrophobic methyl or chloro substituents at position 8 beneficial, suggesting substituent occupies small hydrophobic pocket
• S atom not essential for activity, but binding affinity drops if replaced by CH2
• thought that the electro density of S atom contributes to binding

Question 24

minor effects of calcium channel blockers

Answer 24

constipation, dizziness, fast heartbeat, fatigue, flushing, headache, nausea, rash

Question 25

common effect of calcium channel blockers

Answer 25

peripheral oedema

Question 26

peripheral oedema

Answer 26

• occurs in 70% of patients
• lymphatic drainage relies on contraction of smooth muscle inside lymphatic vessel supported by voltage-gated calcium channels
• inhibition of channels poses threat towards lymphatic removal of interstitial fluid essential for normal lymphatic functioning