Mixed a1 & a2

Adrenergic receptor antagonists

Drugs

• Phenoxybenzamine
• Covalently binds a receptors
• Irreversible antagonist of a1 and a2 receptors

• Phentolamine
• Competetive, reversible antagonist of a1 and a2 receptors

Mixed a1 and a2

Adrenergic receptor antagonist

Physiological effects

(5)

• Vascular
• Blockade of a1 and a2 adrenergic receptors leads to; 
• vasodilation
•  decreased peripheral resistance
•  decrease BP

• Cardiac
• Can indirectly increase heart rate (reflex tachycardia)

Mixed a1 and a2

Adrenergic receptor antagonist

Therapeutic uses

(4)

• Pheochromocytoma
• Short-term pre- and- peri operative management (Phentolamine)
• Long-term management of pts who are not surgical candidates (Phenoxybenzamine)
• Manage local ischemic necrosis (Phentolamine)

Mixed a1 and a2

Adrenergic receptor Antagonist

Adverse Effects

(3)

• Orthostatic hypotension with reflex tachycardia and arrhythmias
• nasal stuffiness
• GI irritation, N/V

Mixed a1 and a2

Adrenergic receptor Antagonist

Contraindications/Precautions

(4)

• Patients with coronary artery disease (e.g. MI, atherosclerosis)
• Contraindication
• Administration of mixed sympathomimetic drugs (e.g. Epi)
• Precaution because B receptor activation will be unopposed (a receptors blocked), which can lead to profound hypotensive episode with reflex tachycardia

Selective a1

Adrenergic receptor Antagonists

The drugs

(5)

• Doxazosin
• Terazosin
• Prazosin
• Tamsulosin
• Selective a1a receptors
• Alfazosin, silodosin also selective for a1a receptors
• Hint, all end with "sin"

Selective a1

Adrenergic receptor Antagonists

Physiological Effects

(5)

NOTE: a1a selective antagonists have less effect on cardiovascular system and thus are not indicated for management of hypertension

• Vascular
• Vasodilation-due to a1 receptor blockade => dec. TPR => dec. BP
• Cardiac
• Less change than w/ non-selective a antagonists
• Genitourinary
• Relaxation of smooth muscle in bladder base and neck, as well as of prostate and its capsule
• Decreased resistance to urine outflow (Decreases "dynamic component" of bladder outflow obstruction)

Selective a1

Adrenergic receptor Antagonists

Therapeutic Uses

(6)

• Primary systemic hypertension
• Doxazosin, Terazosin, & Parazosin are the only a antagonists used to treat mild to moderate systemic hypertension
• That is Tamsulosin, alfazosin, & Silodosin are not used for HTN b/c are selective for a1a receptors in prostate/bladder
• Benign Prostatic Hypertrophy (BPH)
• AKA "Lower urinary tract symptoms" or LUTS
• All currently available a1 antagonists except for prazosin have this indication (prazosin is not indicated for BPH b/c it requires dosing of 2-3Xa day, others are all 1/day

Selective a1

Adrenergic receptor Antagonists

Adverse Effects

(6)

• Syncope & "1st dose phenomenon"
• Postural hypotension & dizziness or syncope may be experienced on 1st dose.
• Not as likely with a1a selective antagonists, but can still be seen
• Drowsiness &/or asthma (fatigue, weakness)
• Nasal congestion/rhinitis
• Retrograde ejaculation (Particularly for a1a selective antagonists)

Selective a1

Adrenergic receptor Antagonists

Contraindications/Precautions

(1)

• Warn patients about 1st dose phenomenon

B Receptor Antagonists

The drugs

(7)

• Non-selective B antagonists; Affinity for B1=B2
• Propranolol: increases survival in pts w/ MI
• Nadolol: t1/2 in plasma is 20 hrs. Unique in long duration of action
• Timolol: 1st FDA approved drug for topical treatment of glaucoma. Also shown to improve survival in pts with ischemic heart disorder
• B1 Selective antagonists
• Metoprolol: reduces mortality in MI and CHF
• Atenolol: Reduces vascular mortality rate in acute MI
• Esmolol: Unique in its short duration of action, t1/2=8 mins. For perioperative, itra operative, and emergency management of tachycardia &/or hypertension
• Betazolol: Only B1 slective antagonist available for treatment of glaucoma
• Hint; end in "olol"
  

B Receptor Antagonists

Physiological Effects

Heart

(4)

• Decrease HR & cardiac contractility (due to blockade of B1 receptors in the heart
• Normally, B blockade will impair exercise tolerance, b/c they will block the increase in cardiac output needed to exercise well
• However, in pts w/ angina pectoralis, exercise tolerance may be improved b/c the exercise tolerance in such pts is often limited by the development of anginal pain (due to cardiac workload exceeding available blood supply to the heart)
• By limiting exercise-induced increase in cardiac workload, B blockers may allow such pts to exercise longer

B Receptor Antagonists

Physiological Effects

Vascular, Renal, Respiratory

(3)

• Vascular
• There is a central effect of B adrenergic receptor blockade that leads to decreased sympathetic outflow, & therefore, decreased peripheral resistance.
• Renal
• Decreased renin release from juxtaglomerular cells (B1 receptor)
• Respiratory
• Life-threatening bronchial constriction in pts w/ asthma or other forms of COPD (B2 receptor)

B Receptor Antagonists

Physiological Effects

Metabolic, Aqueous Humor, Other

(5)

• Metabolic
• Decrease glycogenolysis and glucose mobilization in response to hypoglycemia (B2 receptors)
• Aqueous humor
• Decreased production of aqueous humor by ciliary body (B1 & 2 receptor)
• Other
• Note that propranolol and to a lesser extent, betaxolol & alebutolol have membrane-stabilizing activity independent of B receptor blockade
• This property likely underlies/contributes to some of the therapeutic benefit of these agents

B Receptor Antagonists

Therapeutic Uses

(9)

• Primary systemic hypertension (all except esmolol, sotalol)
• Congestive heart failure (Metoprolol)
• Acute MI/Prevention of recurrent MI (Propranolol, Timolol, Metoprolol, Atenolol)
• Angina pectoralis (Nadolol, Propranolol, Atenolol, Metoprolol)
• Cardiac arrhythmias (Propranolol, Esmolol, Sotalol, Acebutolol)
• Open-angle glaucoma (Timolol, Betaxolol, Cartelol, Levobunolol, Metipranolol)
• Pheochromocytoma (Propranolol after a blockade is in place)
• Migrane prophylaxis (Propranolol, Timolol)
• Essential Tremor (Propranolol)

B Receptor Antagonists

Adverse Effects

(6)

• Bradycardia
• Bronchial constriction
• Disrupted glucose balance
• Black box warning
• Atenolol, metoprolol, nadolol, propranolol, timolol
• Exacerbation of angina, MI, & ventricular arrhythmias if discontinued abruptly
• Need to taper down

B Receptor Antagonists

Contraindications/Precautions

(6)

• Pts w/ greater than 1st degree AV block
• Pts w/ sinus bradycardia
• Pts w/ cardiogenic shock/overt cardiac failure
• Use in caution in pts w/
• Diabetes (particularly non-selective B receptor antagonists)
• Compensated congestive heart failure
• Thyrotoxicosis (may mask signs of developing of progressing hyperthyroidism)
• Bronchospastic disorders (non-selective B receptor antagonists are contraindicated in such pts)

Mixed a1-B antagonists

Drugs

• Carvedilol
• Labetalol

Mixed a1-B antagonists

Pharmacology and Physiological Effect

• Pharmacology
• Non-selective is blockade
• a1 blockade
• anti-oxidant effects (preclinical models)
• nitric oxide production (Carvedilol)
• Physiological Effects
• as listed previously for a and B receptor antagonists

Mixed a1-B antagonists

Therapeutic Uses

• Treatment of hypertension (as for B blockers)
• Treatment of congestive heart failure
• B-block:
• Decreases HR & contractility, thereby decreasing cardiac workload.
• Decreases likelihood of fetal arrhythmia
• Decreases detrimental effects of excessive catecholamines on myocardial cells
• a1-Block/Possible NO production
• Decrease TPR, leading to decreased afterload & preload

Mixed a1-B antagonists

Adverse Effects

Contraindications/Precautions

• Adverse effects
• Bradycardia
• hypotension
• dizziness
• Contraindication/Precautions
• As for B blockers above

a2 Agonists

Drugs

(5)

• Clonidine
• Guanfacine (used in mngmt of ADHD as well)
• Guanabenz
• Methyldopa
• Produces a-methyl norepinephrine, which then acts on a2 receptors in the brain to decrease sympathetic outflow

a2 Agonists

Physiological Effects

(3)

• Initial hypertensive response (due to direct stimulation of a2 receptors on VSM) followed shortly thereafter by prolonged hypotensive response due to decreased Norepinephrine
• Stimulation of a2 receptors in the brainstem decreases sympathetic outflow and increases vagal tone (parasympathetic)
• Stimulation of a2 receptors on terminals of nerves decreasaes norepinephrine release, thereby also decreasing sympathetic tone.

a2 Agonists

Therapeutic Uses, Adverse Effects,

Contraindications/Precautions

(6)

• Therapeutic uses
• Treatment of hypertension
• Adverse effects
• Dry mouth
• Drowsiness/sedation
• Hypotension/dizziness
• Contraindications/precautions
• Withdrawal slowly to prevent severe rebound HTN
• Use w/ caution in pts taking other drugs that affect sinus node funtion or AV nodal conduction and in pts w/ coronary insufficiancy or cerebral vascular disease

Drugs that Deplete Norepinephrine Stores

(1)

• Reserpine

Reserpine

Pharmacological Effects

(7)

• Pharmacological effects
• Binds to transporter on storage vesicles
• Prevents the storage of catecholamines
• Decreased;
• Cardiac output
• Peripheral resistance
• Renin release
• Na+ and H2O retention

Reserpine

Therapeutic Uses

• Treatment of hypertension
• Relief of symptoms in agitated psychotic states

Reserpine

Adverse Effects

(2)

• Sedation and inability to concentrate are most common
• Depression- uncommon but serious

Reserpine

Contraindications/Precautions

(5)

• Contraindicated in pts with; 
• depression or a history of depression 
• Or receiving electroconvulsive therapy
• Contraindicated in pts with active peptic ulcer or ulcerative colitis. 
• Use with caution in pts with a history of diseases (Resperine increases gastric acid secretion and GI motility)
• Receptor supersensitivity (Patient will experience exaggerated response to direct-acting sympathomimetic drugs)