What are the resting conditions/state of calcium levels?
Intracellular Ca= low
Extracellular Ca= 10,000X higher
Due to pumps and active reuptake
Mechanisms mediating increase in intracellular Ca levels
- voltage-sensitive Ca channels= respond to depolarization
- Agonist-mediated Ca release= respond to 2nd messengers (need some type of neurotransmitter to trigger activation)
- Receptor-operated Ca channels= respond to ligand
Different types of voltage-sensitive Ca channels
- L-type (main one)= found in vasculature and heart
- T-type= transient, tiny channels
- N-type= neuronal type
Contraction of vascular smooth muscle cells
LOOK AT SLIDE ON PPT
Contraction of cardiac myocytes
LOOK AT SLIDE ON PPT
Calcium channel blockers (CCBs)
have 2 classes
- Dihydropyridines (“-dipine”)
- Non-dihydropyridines (diltiazem, verapamil)
Block the L-type Ca channel and prevent Ca entry
MOA of DHP CCBs
access the closed channel and stabilize it –> mainly act on arterial muscle cells –> vasodilation
Most closed channels are found in the vasculature
MOA of Non-DHP CCBs
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
ADR’s for verapamil and diltiazem
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!
ADR’s for amlopdipine
edema, dizziness, flushing, palpitation, gingival hyperplasia
Long-term use: may increase breast cancer risk
CAUTION: combining with CYP3A4 inhibitors –> hypotension, kidney failure
α1 adrenergic receptor blockers
“-zosin”
block α1 receptors in arteries and veins
Main ADR’s of α1 adrenergic receptor blockers
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)
MOA of central α2 adrenergic receptor agonists
- 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
Clonidine PK facts
50% is eliminated in the urine unchanged (caution in pts with renal failure)
Guanfacine (Tenex) does this as well
Effects of clonidine
- decrease BP (central effect)
- decrease HR (from dec sympathetic drive and inc vagal tone)
- dec intraocular pressure (used in glaucoma)
ADR’s of clonidine
- sedation and dry mouth
- sexual dysfunction
- bradycardia
- DO NOT ABRUPTLY D/C THIS DRUG
Methyldopa
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)
Reserpine
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
ADR’s of reserpine
- depression
- sedation & inability to concentrate
- inc retention of Na and water
Hydralazine
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
ADR’s of hydralazine
- drug-induced lupus
- inc retention of Na and water
- HA, flushing, hypotension, tachycardia
- CAUTION: aggravation of myocardial ischemia
Minoxidil
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)
ADR’s of minoxidil
- inc retention of Na and water
- tachycardia, myocardial ischemia
- hypertrichosis (stimulated hair growth)
