Lecture 4

Question 1

What are the resting conditions/state of calcium levels?

Answer 1

Intracellular Ca= low
Extracellular Ca= 10,000X higher
Due to pumps and active reuptake

Question 2

Mechanisms mediating increase in intracellular Ca levels

Answer 2

1. voltage-sensitive Ca channels= respond to depolarization
2. Agonist-mediated Ca release= respond to 2nd messengers (need some type of neurotransmitter to trigger activation)
3. Receptor-operated Ca channels= respond to ligand

Question 3

Different types of voltage-sensitive Ca channels

Answer 3

• L-type (main one)= found in vasculature and heart
• T-type= transient, tiny channels
• N-type= neuronal type

Question 4

Contraction of vascular smooth muscle cells

Answer 4

LOOK AT SLIDE ON PPT

Question 5

Contraction of cardiac myocytes

Answer 5

LOOK AT SLIDE ON PPT

Question 6

Calcium channel blockers (CCBs)

Answer 6

have 2 classes

1. Dihydropyridines (“-dipine”)
2. Non-dihydropyridines (diltiazem, verapamil)

Block the L-type Ca channel and prevent Ca entry

Question 7

MOA of DHP CCBs

Answer 7

access the closed channel and stabilize it –> mainly act on arterial muscle cells –> vasodilation
Most closed channels are found in the vasculature

Question 8

MOA of Non-DHP CCBs

Answer 8

bind to the open channel, inactivate it, and slow down the recovery –> more pronounced effects in the heart since majority of open channels are in the heart

Question 9

ADR’s for verapamil and diltiazem

Answer 9

Major= cardiodepression
Mod= hypotension, AV node blockade, peripheral edema, inc liver enzymes
Minor= HA, facial flushing, dizziness, constipation (pronounced for verapamil)
CAUTION: mod inhibition of CYP3A4!

Question 10

ADR’s for amlopdipine

Answer 10

edema, dizziness, flushing, palpitation, gingival hyperplasia
Long-term use: may increase breast cancer risk
CAUTION: combining with CYP3A4 inhibitors –> hypotension, kidney failure

Question 11

α1 adrenergic receptor blockers

Answer 11

“-zosin”

block α1 receptors in arteries and veins

Question 12

Main ADR’s of α1 adrenergic receptor blockers

Answer 12

Postural/ orthostatic hypotension (α1 receptors in veins)= when we change our posture/ stand up then we can experience huge drop in BP; In healthy individuals, we need these receptors to change from horizontal to vertical getting up in the morning (Contracts the veins so gravity doesn’t make all the blood accumulate to lower part of body when we stand up)

Question 13

MOA of central α2 adrenergic receptor agonists

Answer 13

• activation of central α2 receptors –> suppression of sympathetic outflow from the brain
• POSSIBLE stimulation of presynaptic α2 receptors –> decreased NE release
• Clonidine= POSSIBLE interaction w/ central imidazoline receptors

Question 14

Clonidine PK facts

Answer 14

50% is eliminated in the urine unchanged (caution in pts with renal failure)
Guanfacine (Tenex) does this as well

Question 15

Effects of clonidine

Answer 15

• decrease BP (central effect)
• decrease HR (from dec sympathetic drive and inc vagal tone)
• dec intraocular pressure (used in glaucoma)

Question 16

ADR’s of clonidine

Answer 16

• sedation and dry mouth
• sexual dysfunction
• bradycardia
• DO NOT ABRUPTLY D/C THIS DRUG

Question 17

Methyldopa

Answer 17

prodrug
Metabolized in same way that Tyr is being metabolized and stored in same vesicles that E and NE can be stored –> when there is signal, it gets released from vesicles as methyl-NE which then binds to α2
takes a long time to work (peak effect after 6-8 hours)

Question 18

Reserpine

Answer 18

sympatholytic drug
Blocks a transporter that is responsible to recycle E or NE
binds irreversibly and completely depletes NE levels (pretty powerful)
2nd class agent to manage HTN

Question 19

ADR’s of reserpine

Answer 19

• depression
• sedation & inability to concentrate
• inc retention of Na and water

Question 20

Hydralazine

Answer 20

direct vasodilators
MOA not clear
decreases peripheral resistance (with powerful stim of SNS –> usually combined w/ other drugs)
MINIMAL effect on veins –> no postural hypotension

Question 21

ADR’s of hydralazine

Answer 21

• drug-induced lupus
• inc retention of Na and water
• HA, flushing, hypotension, tachycardia
• CAUTION: aggravation of myocardial ischemia

Question 22

Minoxidil

Answer 22

direct vasodilator
MOA: prodrug; activates ATP-dependent K+ channels to cause hyperpolarization and relaxation of smooth muscle
dec in peripheral resistance (with powerful stimulation of SNS –> usually combo w/ other drugs)

Question 23

ADR’s of minoxidil

Answer 23

• inc retention of Na and water
• tachycardia, myocardial ischemia
• hypertrichosis (stimulated hair growth)