hale exam 2 lecture 2 part 1 [end of hypertension drug deck]

alpha 1 receptor antagonists

- selective blockade of a1 inhibits vasoconstriction induced by endogenous catecholamines

- positive effect on serum lipids and glucose; from improved tissue perfusion and increased insulin sensitivity

- not first line treatments for HTN

- longer acting terazosin and doxazosin are used for treatment of BPH

short term effects of a1 block

- reduction arteriolar resistance and decrease in venous return

long term effects of a1 block

- vasodilation persists; heart rate, cardiac output and renin return to normal

why are a1 blockers not first line for HTN

- syncope [fainting] is common; follows from mechanism-based, acute orthostatic hypotension and impairment of vascular reflexes

- antihypertensive effects can demonstrate tachyphylaxis

- may have higher rate of development of heart failure

Prazosin (Minipress)

- highly selective a1 receptor blocker

- little/no affinity for either a2 or B receptors

- via titration dosing can lower SBP 10-20 mmHg and DBP 10-15 mmHg

- short half life with 2-3 x day dosing

terazosin

- great oral bioavailability and long half life of 12 hours

- comes in oral tablet and solution

doxazosin

- decent oral bioavailability but longest half life of the a1 blockers (t1/2 = 22)

mixed a1/B blockers

- carvedilol

- labetalol

carvedilol

- after metoprolol

- nonselective between B1 and B2; also has a1 activity

- a1 antagonism and CCB activities provide stronger BP lowering

- antioxidant properties [scavenges ROS]

labetalol

- after carvedilol

- nonselective between B1 and B2; also has a1 activity

- a1 antagonist properties adds BP lowering

- may be preferred when rapid BP reduction is needed

- diminished CNS adverse effects compared to propranolol and metoprolol

b-blockers class therapeutic uses

- lower SBP 5-20 mmHg and DBP 5-15 mmHg

- Patient-to-patient differences in pharmacokinetics and tolerability influences choice of agent

- B-Blockers provide effective therapy for all grades of hypertension

- Widely used for other indications -> angina, congestive heart failure, cardiac arrythmias

b-blockers class toxicity and adverse effects

- Contraindicated vs. asthma, some heart conduction disorders

- Sudden discontinuation can produce rebound hypertension

b-blockers class contraindications and DDI

- Hypotension when used in combination with other anti-hypertensive agents

- NSAIDs may reduce anti-hypertensive activity

- metoprolol: CYP2D6 polymorphism

- nebivolol: excessive NO mediated vasodilation

clonidine

- alpha 2 adrenergic receptor agonist

- imidazoline receptor agonist

- oral formulation used for treatment of HTN 2nd line

- effects come from central effects not peripheral

- used more in pediatric ADHD

- off label use also for narcotic, alcohol, and tobacco withdrawal

adverse effects and precautions with clonidine

- dry mouth, sedation, bradycardia

- withdrawal reaction with long term use

contraindications with clonidine

- can potentiate the actions of CNS-sedating actions of alcohol, barbiturates or other sedatives

- avoid use with CCBs and B-blockers

methyldopa

- oral formulation used only in pregnancy for HTN

- prodrug that is activated in the CNS

- a2 adrenergic receptor agonist [acts centrally and results in diminished vasoconstriction]

adverse effects of methyldopa

- hypotension with overdosage

- transient sedation, reduced libido, Parkinsonian symptoms

- positive Coombs test, hemolytic anemia, and liver disorders may occur

- established safety profile for mother and fetus

contraindications with methyldopa

- co-administration with monoamine oxidase inhibitors

- avoid use in patients with active liver disease

4 major classes of drugs for hypertension

- ACE-is

- ARBs

- Long acting DHP CCBs

- thiazide or thiazide-like diuretics