Adrenergic antagonists

alpha receptors: CV systems

alpha 1 receptors are located on arterial and venous smooth muscle

endogenous NT is NE and Epi (SNS)

normally there is underlying sympathetic tone at arteries and veins that control BP

so blockade of alpha receptors in normal and hypertensive patients will cause vasodilation and decrease BP

alpha receptors: Urinary system

urination is controlled by a PSNS/SNS balance

M3 receptors cause contraction of detrusor and relaxation of the sphincters to cause micturition (PSNS)

beta 2 receptors cause relaxation of the detrusor and alpha 1 receptors cause contraction of the sphincters to prevent micturition (SNS)

Blockade of alpha 1 receptors reduces the constriction and sphincter tone allowing urine to flow more freely

BPH (Benign Prostatic hyperplasia)

a condition in which the prostate grows in size

this places pressure on the urethra and bladder neck making urination difficult and incomplete

non-selective alpha antagonists

Phentolamine and Phenoxybenzamine

both block alpha 1 and alpha 2 receptors

alpha 2 receptors are located presynaptically and their role when activated is to decrease the amount of NE release. Blockade of alpha 2 will cause an increase in NE release

Non-selective alpha antagonists: clinical limitations

vasodilation can cause activation of the baroreceptor reflex resulting in reflex tachycardia

phentolamine and phenoxybenzamine exaggerate the reflex tachycardia because they block alpha 2 receptors causing more NE to be released in the synaptic cleft

Prazosin: MOA/kinetics

selective alpha 1 antagonist (1000x more potent at alpha 1)

vasodilates venous blood vessels which decreases venous return to the heart to reduce CO

may have a CNS effect to inhibit SNS outflow and inhibit baroreceptor reflex

DOA = 10h (BID dosing)

Tx HTN (also effective in BPH)

Prazosin: counseling points

First dose phenomenon: up to 50% of patients experience syncope and/or orthostatic hypotension with the first dose

Take first dose at bedtime or remain recumbent for a few hours

dosing started low and is slowly titrated up

large dose changes/addition of antihypertensive agent can cause reoccurrence of syncope

nasal stuffiness is common

Terazosin/Doxazosin

selective alpha 1 antagonist

both have similar profiles as prazosin

BPH: may be an advantage, both appear to cause induction of apoptosis of prostate cells

Tx BPH

Alfuzosin

- selective alpha 1 antagonist (not approved for HTN Tx)

Tamsulosin/Silodosin

- alpha 1_A selective, which appears to be located on the smooth muscle of prostate cells and bladder neck and trigone sphincter

- effect on urine flow is seen within the first few doses

- minimal effects on BP and syncope

Yohimbine

alpha 2 antagonist

increases SNS outflow and potentiates the actions of NE by blocking negative feedback on release

Not really used clinically

Beta-blocker characteristics

Selectivity (can reduce side effects)

Intrinsic sympathomimetic activity (partial agonist)

Membrane stabilizing activity (local anesthetic-like effect, may be helpful in treating arrythmias)

alpha - blocking activity (another benefit to reducing BP)

lipid solubility (CNS penetration can be advantage or disadvantage)

isoproterenol

beta 1/beta 2 agonist

Propranolol

nonselective beta blocker

classic/standard beta blocker

Atenolol

beta blocker

beta 1 selective

Metoprolol

beta blocker

beta 1 selective

Pindolol

nonselective beta blocker

has ISA

beta 2 effects on the heart

Stimulation: increased chronotropy, ionotropy, and dromotropy (increased CO, HR/BP)

Blockade: decreased chronotropy, ionotropy, and dromotropy (decreased CO)

Beta 2 effects on the kidney

stimulation: increased renin secretion (increased fluid retention, BP)

blockade: decreased renin secretion (Decreased plasma volume and BP)

Beta 2 stimulation

vascular smooth muscle: vasodilation

bronchial smooth muscle: bronchodilation

liver: glycogenolysis

beta 2 blockade

vascular smooth muscle: small vasoconstriction

bronchial smooth muscle: bronchoconstriction

liver ???

not a big player in BP control

Effects of beta blockers: CV system

HR

- effect on resting HR is dependent on SNS tone

- typically have little effect on resting HR

- greatest effect seen during stress/exercise (less stamina, less endurance bc HR cannot rise)

BP

- initially rises then returns to baseline

Kidney

- tends to reduce renin secretion (beta 1 receptors)

beta blockers: metabolic effects

beta 2 receptors cause glycogenolysis and release of glucose

non-selective beta blockers can impair T1D patients’ ability to recover from hypoglycemia (can also mask the symptoms) - use with caution in patients with uncontrolled diabetes

nonselective beta blockers have an adverse effect on lipid profile

beta blockers: respiratory system effects

little effect on respiratory function on normal people

non selective beta blockers can produce life threatening bronchoconstriction in patients with asthma or COPD

beta 1 selective antagonists with ISA are safer but still carry risk

labetolol

nonselective beta blocker

alpha 1 antagonist

has additional CV effects

Carvedilol

nonselective beta blocker

alpha 1 antagonist

anti-inflammatory actions that may have cardioprotective actions