- active efflux pumps - active reuptake into SR

L-type Ca channels-> decreased influx of Ca-> - vasodilation (blood flow) - - ionotropic effec-> - chronotropic effect-> < O2 demand

CCB lecture Flashcards by ashley hart

Ca key role in physiological processes

contractility of skeletal, cardiac & smooth muscles

- release of NT from vesicles by exocytosis

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at resting state, intracellular Ca is

low (<0.1micrometers)

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at resting state, extracellular Ca is

10,000 fold higher (~1mM)

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[Ca] achieved by

active efflux pumps

- active reuptake into SR

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mechanisms mediating increase in intracellular Ca

voltage sensitive Ca channels
agonist-mediated Ca release
receptor-operated Ca channels

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voltage-sensitive Ca channels

open in response to depolarization of the cell membrane (L-type, T-type, N-type)

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L-type

long-lasting large channels (cardiac & smooth muscle cell, SA & AV nodal cells)

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T-type

transient tiny channels

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N-type

neuronal tissue

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agonist mediated Ca release

results from activation of 2nd messengers (IP3) by agonist to release intracellular Ca from storage sites (SR)

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receptor-operated Ca channels

receptor forms a channel & the channel opens when the receptor is occupied by a ligand (NMDA receptor)

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what initiates contraction of vascular smooth muscle cells?

entry of Ca into SMC

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what initiate contraction of cardiac myocytes?

entry of Ca into myocardial cells

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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

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DHP access what channel?

CLOSED channel & stabilize it

- mainly act on arterial muscle cells-> VASODILATION

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non-DHP binds to the

OPEN channel & inactivate it & slow down the recovery

-more pronounced effects in the heart

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“cardio-selective” drugs

non-DHP

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“vascular-selective” drugs

DHP

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therapeutic uses for CCBs

HTN
Angina pectoris
superventricular arrhythmia
migraine

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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

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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)