Hypertension Comprehensive

P-type calcium channels are sensitive to

funnel web spider toxin

N-Type calcium channels are sensitive to

omega (w) contotoxin

T-type calcium channels are sensitive to

octanol

L-type calcium channels are sensitive to

dihydropyridine, phenylalkylamine, or benzothiazepine

Dihydropyridine

amlodipine

nifedipine

felodipine

Phenyalkylamine

Verapamil

Benzothiazepine

Diltiazem

Dihydropyridine notable features

carbon ring with a N-H

Phenylalkylamine notable features

Long chains with a N and a ch3 branch

Benzothiazepine notable features

benzing ring with S and N connections

Increase in cytosolic Ca2+ in Vascular

results in enhanced binding of CA2+ to calmodulin and leads to sustained contraction of smooth muscles

Increased CA in cardiac

Ca2+ binds to troponin C reliving the inhibitory effect of the troponin complex leading to contraction

CCB general MOA

Volatge dependent Ca2+ channels are responsible for contraction of skeletal, smooth, and cardia muscles and for regulating aldosterone and cortisol secretion in endocrine cells. Involed in packmaker signals

CCB primary effects

1. Reduce contraction of the arteries and cause vasodilation
2. reduce force contraction of the heart
3. slow down heart beat
4. reduce aldosterone production, which correlates to lower blood pressure

Dihydropyridine effected tissues

vascular

Phenylalkylamine effected tissues

heart

Benzothiazepine effected tissues

heart and vascular

CCB adverse effects

1. baroreceptor reflux (medicated sympatheic discharge
2. tacycardia
3. bradycardia
4. sinoatrial node arrect
5. peripheral edma
6. gastroesophageal refluc
7. contispation

Hydralazine MOA

directly relaxes arterial smooth muscles

involes a reduction in intracellular Ca2+

Hydralazine was initially associated with

tachycardia and tachphylaxis due to compensatory cardio responses

Hydralazine pharmacological effects

selective decrease in vascular resistance in arterioles of coronary, cerebral, and renal circulations

does not relax venous smooth

lowers blood pressure

low bioavalibility

Hydralazine bio avaliability

16% in fast

35% in slow acetylators

in N acetylated in the bowl and the liver

Hydralazine acetylated compound

in inactive

the dose necessary to produce a systemic effect is larger in fast acetylators

Hydralazine use

hypertension emergencies in pregnant women for preeclampsia and in combination for resistance

hydralazine adverse effects

Headache, nausea, palpitation, tachycardia, agnia, flushing, coronary artery diease, ect

Drug induced lupus syndrom related to dose, gender, acetylator, and reace (white woman)

Minoxidil

Prodrug metabolized by hepatic sulfotransferase

Minodxidil NO is active

Minoxidil MOA

Activates ATP modulated K+ channel permitting K+ efflux and causes hyperpolarization and relaxation of vascular smooth muscles

Minoxidil Pharmacological effects

Arteriolar vasodilation

increase in myocardial contractility and in cardiac output

vasodilate renal artery

Minoxidil use

best served for severe hypertension especially with renal insufficiency

used for both adults and children

Minoxidil Adverse effects

1. retention of salt and water (swelling)


1. can be managed with thiazides or Loops
2. Cardiovascular effects like myocardial ichemia with paitnets with CAD


1. concurrent administartion of BBlocker
3. hypertrichosis


1. topical minoxidil (rogaine)

Minoxidil Rare effects

Rashes

Stenvens-Johnson Syndrome

African Patients

Increased need for combo treatment due to lower renin

Start with two meds if >20

If mono, Thiazide +/- CCB recommened as first med

Geriatric Patients

often isolated SBP

Use safest option

may need to be more conservative with goals

start low, go slow

Young Paitnets

>95% for gender, age, and height on 3 or more occasions

Start with lifestyle

Goal: reduce to

Orthostatic hypotension

Laying or sitting to standing

BP drop >10

Avoid by titrating slowly and avioding volume depletion

Ask if meds causing it (timing and dosing)

Pregancy Chronic Hypertension

Present before pregnancy or within 20 weeks

Gestational hypertension or Pregnancy induced hypertension

hypertension once (>140/90) present 20weeks or later

not present before pregnancy

goes away after delivery

Preeclampsia

BP>140/80 appearing after 20weks

Bed rest and monitoring intil delivery is safe

Can use hydralazine or labetolol if diastolic >105

may use low dose ASA in high risk

Eclampsia

Onset of convulsions

medical emergency

delivery is indicated

Hypertension in pregnancy

Methyldopa or labetolol are prefered agents

Metroprolol and carvediol are also used

B Blockers are generally safe

Few studies for Clonidine or CCB

Diuretics are not first line but safe at low doses, not added unless paitent already one them

Resistant hypertension

Failure to acheive Goal despite adherence to full doseage of 3 drug regiment that includes thiazide

Common cause = fluid overload

Treatment: evaulate adherence, add aldosterone

Resistance hypertension

1. ACE/ARB (prils/statins), CCB, Diuretic
2. subsitute diuretic for thiazide like (chlorthailidone)
3. Add spironolactone
4. Check heart rate and add a BBlocker (olols)
5. Add hydralazine
6. subsitue for minoxidil

blood pressure =

cardiac output (L/min) x Peripheral resistance (mmHg min/L)

Alpha 1

GPCR - Gq

Tissues - Blood vessels, cardiac muscles

Effects: vasoconstriction, inotropic

Alpha 2

GPCR - Gi

Tissues - Nevere terminal, blood vessels

Effects - decrease NE relases, vasoconstriction

B1

GPCR - Gs

Tissues - Heart, cerebral cortex

Effects - chrono, inotropic

B2

GCPR - Gs

Tissues - Blood vessels

Effects - vasodiliation

symatholytic agents for hypertension

B-adrenergic receptor antagonist (olol)

B-adrenergic receptor antagonist MOA

Reduction in myocardial contractility and heart rate. Reduces renin secreation and RAS activity

Efficacy of BBlockers depend on

lipid solubility

slectivity for the B1 adrenergic receptor subtype

presence of partial agonist

B adrenoceptor blockers

B Blockers use

prefered drug for patients with myocardial infarction, ischemic heart disease, or congestive heart failure

B Blocker combo therapy

a BB and a diuretic or vasodilator

B Blocker adverse effects

Asthma

SA or Av nodal dysfunction

insulin dependent diabetes

rebound hypertension

alpha 1 receptor antagonist

initially reduce ateriolar resistance and increase venous capacitance, but durring long term, vasodilation persists but cardiac output, heartrate and plasma renin activity returns to normal

A1 place in therapry

not mono

only used with diuretics, b blockers, or antihypertension agents

bb enhance the efficacy of alpha 1

A1 paitent population

attractive for paitents with benign prostatic hyperplasia

not for pheochromocytoma

A adrenergic major advere effects

first dose phenonmenon (orthostatic hypo)

Doxazosin as a monotherapy increases the risk for CHF (retention of salt and water)

1 gen nonselective

nadolol

propranolol

pinodolol

2nd gen b1 selective

acebutolol

atenolol

esmolol

bisoprolol

metoprolol

3rd gen non selective (combindined)

carvedilol

labatalol

Labetalol

equimolar mixture of four steroisomers:

alpha 1 antagonist

nonselective B antagonist with partial agonist activity

two other inactive isomers

Labetotal is approved for

eclampsia, preeclampsia, hypertension, and hypertensive emergancies

Carvediolol

bb with a alpha one receptor antagonist activity

ration of 1:10 for alpha 1 to B

Carvedilol is used for

hypertension and symptomactic heart failure

Clonidine MOA

stimulates the alpha2A receptor in the brainstem, reduction in sympathetic outflow form the CNS, and decrease in plasma concetrations of NE

Clonidine notes

leads to a a reduction in myocardial contractility and heart rate could promote congestive heart failure in susceptible patients

rebound hypertension → treat with sodium nitroprusside or a combination of a alpha2 and bb

Clonidine side effects

1. symptomatic bradycardia and sinus arrest
2. promote CHF
3. dry nasal muscosa, dry eyes
4. postural hypotension and ED
5. vivid dreams/nightmares

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Methyldopa

Centrally acting antihypertensive agent

methyldopa moa

prodrug that exerts its antihypertensive action via an active metabolite

Methyldopa in the CNS

agonist at presynaptic alph2 adrenergic receptors attenuating NE release

Methyldopa in PNS

reducing the output of vasocontriction

methyldopa use

hypertension in pregnancy (record of safety)

Methyldopa notes

less common orthostatic hypotension

pseudo tolerance with prolonged use

salt and water retained after NE plasma concentration fall → treat with diuretics

Can cause a positive antiglobulin coombs test

Methyldopa Adverse effects

sedation, diminution in psychic energy, depression, dry mouth, hepatotoxicity

1,4 DHP structure notes

1. the 1,4 DHP is essential for activity and subsitution at n1, oxidation, or reduction greatly decreases activity
2. a subsituted phenyl ring at c4 optimizes activity
3. ortho/meta position is important
4. ester groups at C3/C5 positions optimize activity
5. methyl groups at C2 and C6 for optimal accommodation in the 1,4 receptor

Nifedipine Lock

the ortho nitro group provides the bulk needed to lock in the structure

Verapamil and diltiazemn contain

tertiary amines resulting in more basic properties than most 1,4 DHP

At physiologic ph verapamil and diltiazem are

primarilty unionized

Calcium channel blockers have

goos lipid solubility and excellent oral absorption

Nisoldipin is __ __ lipid soluble than nifedipine

more

due to larger ester group

metabolism of 1,4 DHP

oxidation of the 1,4 - dihydropyridine ring through Cyp3A4 to the inactive form

Clevidipine has a

ultra-short duration of action (2-4 minutes)

Rapid hydrolysis inactivates the drug

Diester side chain at position 3 enhances lipophilic character

Hydralozine

highly specific for arterial vessels

Hydralozine metabolism

well absorbed from the GI tract and is metabolized in the GI mucosa and in the liver by acetylation, hydroxylation, and conjugation

hydralozine MOA

Causes smooth muscle hyperpolarization through the opening of K+ channels

inhibits the second messenger, IP3 induduces relase of calcium from the smooth muscle SR

stimulates the formation of NO by cascular endothelium leading to cGMP mediated vasodiliation

Diazoxide

hyperglycemic agent that works by preventing the release of insulin form the pancrease

approx 20-50 is eliminated unchanged in urine

Minoxidil

not an active hypotensive drug until metabolized

Alpha and Beta Blockers are substances that

competes with NE and EPI at the adrenergic receptors

A1 selective blockers structure (prazosin,ect)

look for quinazlone ring, piperazine ring, and acyl moeity

Labetalol structure

Carvediolol

Esmolol is excerted as a

zwitterion and has a half life of 8 minutes (used durring surgery)

Proprananolol

is the most lipophilic of availble BB

Lisinopril

ACE

SD: 5-10

MD: 10-40mg

Monitor: SCR and K+ 7-10 days after initiation

Enalapril

ACE

SD: 5-10mg

MD: 5-40 1-2 times

Monitor: SCR and K+ 7-10 days after initiation

Ramipril

ACE

SD: 2.5-5mg

MD: 2.5-20mg

Monitor: SCR and K+ 7-10 days after initiation

Losartan

ARB

SD: 25mg

MD: 25-100mg

Monitor: SCR and K+ 7-10 days after initiation

Valsartan

ARB

SD: 80mg

MD: 80-320mg

Monitor: SCR and K+ 7-10 days after initiation

Amlodipine

DHP CCB

SD: 5-10mg daily

Monitor: Edemda