CCB lecture Flashcards
Ca key role in physiological processes
contractility of skeletal, cardiac & smooth muscles
- release of NT from vesicles by exocytosis
at resting state, intracellular Ca is
low (<0.1micrometers)
at resting state, extracellular Ca is
10,000 fold higher (~1mM)
[Ca] achieved by
- active efflux pumps
- active reuptake into SR
mechanisms mediating increase in intracellular Ca
- voltage sensitive Ca channels
- agonist-mediated Ca release
- receptor-operated Ca channels
voltage-sensitive Ca channels
- open in response to depolarization of the cell membrane (L-type, T-type, N-type)
L-type
long-lasting large channels (cardiac & smooth muscle cell, SA & AV nodal cells)
T-type
transient tiny channels
N-type
neuronal tissue
agonist mediated Ca release
results from activation of 2nd messengers (IP3) by agonist to release intracellular Ca from storage sites (SR)
receptor-operated Ca channels
receptor forms a channel & the channel opens when the receptor is occupied by a ligand (NMDA receptor)
what initiates contraction of vascular smooth muscle cells?
entry of Ca into SMC
what initiate contraction of cardiac myocytes?
entry of Ca into myocardial cells
CCBs inhibit
L-type Ca channels-> decreased influx of Ca->
- < SMC contraction->vasodilation (blood flow)
- ionotropic effec-> < O2 demand
- < pacemaker rate of SA node & conduction velocity of AV node-> - chronotropic effect-> < O2 demand
DHP access what channel?
CLOSED channel & stabilize it
- mainly act on arterial muscle cells-> VASODILATION
non-DHP binds to the
OPEN channel & inactivate it & slow down the recovery
-more pronounced effects in the heart
“cardio-selective” drugs
non-DHP
“vascular-selective” drugs
DHP
therapeutic uses for CCBs
HTN
Angina pectoris
superventricular arrhythmia
migraine
main adverse effects of verapamil & diltiazem
(non-DHP: Cardio-selective)
- cardiodepression
- hypotension, AV node blackade, peripheral edema, elevation of liver enzymes’- HA, flushing, dizziness, constipation
- caution: inhibition oF CYP3a4
main adverse effects of amlodipine
(DHP: not cardio-selective)
- edema, dizziness, flushing, palpitation, gingival hyperplasia
- cardio, CNS, GI side effection
- long term use may > breast cancer risk
- caution combining w/ CYP3A4 inhibitors-> hypotenion, kidney failure
alpha 1 adrenergic receptor blocker MOA
blockage of alpha 1 adrenoreceptors in arteries & veins
- probably blockade of central alpha 1 receptors
main ADE of alpha 1 blockers
first-dose effect: postural/orthostatic hypotension (alpha 1 receptors in veins)
activation of alpha 1 receptors leads to
constriction
alpha 1 blocker drugs
doxazosin
terazosin
prazosin
central alpha 2 adrenoreceptor agonist MOA
- activation of central alpha 2 receptors(CV control centers)-> suppression of sympathetic outflow from the brain
- possible stimulation of presynaptic alpha2-> dec. NE release
- clonidine: possible interaction with central imidazoline receptors
central alpha 2 agonist drugs
clonidine
guanfacine
guanebenz
methyldopa
clonidine bioavailability
100%
- 50% is eliminated in urine unchanged- caution in renal failure
clonidine main therapeutic effects
- < BP (central effect)
- < HR (< sympathetic drive & > vagal tone)
- < intraocular pressure (used in glaucoma)
main adverse effect of clonidine
- sedation & dry mouth
- sexual dysfunction (due to hyperprolactinemia)
- bradycardia
- withdrawal rxn w/ abrupt DC
guanfacine (tenex) elimination
50% eliminated unchanged in urine
guanebenz (wytensin) metabolism
100% metabolized in liver
methyldopa is similar in structure to
tyrosine
tyrosine is a precursor for
epi & NE
what central alpha 2 agonist is a prodrug?
methyldopa
methyldopa can also be beneficial in
preeclampsia
peak effect of methyldopa
delayed 6-8 hours
duration ~24hrs
ADE of methyldopa
similar to clonidine + hepatotoxicity & hemolytic anemia
methyldopa MOA
- stored in secretory vesicles of adrenergic neurons, substituting NE
- released into synaptic cleft instead of NE
- effects similar to clonidine
methyldopa needs to be _____ to act
transported into CNS
what kind of drug is reserpine?
sympatholytic
what is the first drug that was found to interdere with the function of SNS in humans? (start of antihypertensive therapy)
reserpine
resperine MOA
- IRREVERSIBLY binds to the vesicular transporter
- BP lowering effects due to both central & peripheral actions
reserpine ADE
- > retention of Na & water
- sedation & inability to concentrate
- depression & suicidal thoughts
- caution: should be DC at first sign of depression
what kind of drug is hydralazine (apresoline)?
direct vasodilation
hydralazine MOA
direct vasodilation
main therapeutics effects of hydralazine
- effective decrease in peripheral resistance (powerful stimulation of SNS->usually combined w/ other drugs)
- minimal effect on veins-> no postural hypotension
Main ADE of hydralazine
- drug induced lupus
- > retension of Na & H2O
- HA, flushing, hypotension, tachycardia, angina pectoria
- caution: aggravation of myocardial ischemia
what kind of drug is minocidil (Loniten)?
direct vasodilator
MOA of minoxidil
- prodrug that needs to be converted to minoxidil sulfate
- activates ATP-dependent K+ channels in smooth muscles->efflux of K+ from cells-> hyperpolarization-> relaxation of smooth muscle
main therapeutic effects of minoxidil
dilation of arterioles similar to hydralazine-> decreased PR (powerful SNS stimulation- usually combined w/ other drugs)
main ADE of minoxidil
- > retention of Na and water
- tachycardia, angina pectoris, myocardial ischemia
- hypertrichosis (hair growth)
