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Adrenoceptor Blocking Agents
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Adrenergic Blocking Agents
Alpha Adrenoceptor
Blocking Agents
Non-Selective
Phenoxybenzamine
Phentolamine
Alpha-one Selective
Prazosin
Terazosin
Beta Adrenoceptor
Blocking Agents
Non-Selective
Propranolol (Prototype)
Nadolol
Timolol
*Pindolol
*Carteolol
Ergotamine
Ergonovine
Cardioselective
Atenolol
*Acebutolol
Metoprolol
Betaxolol
Alpha-two Selective
Yohimbine
Very Short Acting
Esmolol
Tamsulosin (1A)
Doxazosin
Ergot Alkaloids
Alpha and Beta Blocker
Labetalol
 -Adrenergic Receptor
Antagonists

 Receptor Blockers
- irreversible 1 & 2 blocker
 Phentolamine - prototype reversible 1 & 2 blocker
 Prazosin - selective 1 blocker
 Tamsulosin – selective 1A blocker
 Yohimbine - selective 2 blocker
 Phenoxybenzamine
 -Adrenergic Receptor
Antagonists
Phenoxybenzamine = noncompetitve,
irreversible
 Phentolamine = competitive, reversible
Both bind both 1 &  receptors


very low potency at -receptors
Alpha Adrenergic Blockers
Non-selective blockers: Block both alpha-one and
alpha-two adrenergic receptors.
 Alpha blockers are antagonists (they have no
intrinsic activity but do produce pharmacological
changes).
 ’ cause they block the effects of endogenous
agonists (epinephrine; norepinephrine)

Phenoxybenzamine
(Dibenzyline)

Mechanism. Binds covalently to alpha-1 and
alpha-2 adrenergic receptors. i.e. non-selective,
irreversible, alpha blocker. Onset is slow requiring
10-20 minutes for formation of covalent
linkages. Offset is even slower with a t1/2 of 24
hours. Terminated by metabolism and new
receptor synthesis. Called non-equilibrium or noncompetitive blocker.
Phenoxybenzamine

New receptors must be synthesized to overcome
the blockade
 Several

(2-5) days to regenerate
“Dirty” drug - also blocks histamine,
acetylcholine, & serotonin receptors

Effect of NE to
contract vascular
smooth muscle
in the presence
of increasing
doses of
phenoxybenzamine.
Phenoxybenzamine:
Pharmacological Effects.
1. Vascular. Dependent on the degree of sympathetic
tone. i.e., blocks the effects of endogenous NE.
See reduced blood pressure. Orthostatic
hypotension.
Phenoxybenzamine:
Pharmacological Effects
2. Cardiac. Reflex tachycardia from reducing BP,
which enhances NE release. Because alpha-2
receptors on adrenergic nerves are also blocked,
this further increases NE release at the heart,
where it can act on beta-1 receptors.
Phenoxybenzamine: Effects
3. CNS. lipophilic agent which can cross the blood
brain barrier. Nausea, vomiting and weakness may
be signs of non-specific effects.
4. Others: miosis, inhibition of ejaculation, stuffy
nose (all alpha1 blockade).
Phenoxybenzamine: Clin. Uses
1. Pheochromocytoma: Pre-operative management
to treat vascular effects of high circulating
catecholamines.
2. Peripheral Vascular Disease. Raynaud’s syndrome
where sympathetic tone to peripheral
vasculature is high. Acrocyanosis from frost
bite.
Reversible Alpha Blockers
Competitive blockers. Rapid onset of blockade.
Surmountable by high concentrations of alpha-1
agonists
 Phentolamine and Tolazoline (Imidazoline
derivatives). Non-selective for alpha-1 and alpha2 receptors. Duration of several hours. They also
activate histamine receptors (adverse effect).

Phentolamine: Clinical Uses
1. Pheochromocytoma. Acute hypertensive
crisis.
2. Clonidine withdrawal
3. Treat necrosis due to vasoconstrictors such
as NE and phenylephrine.
4. For erectile dysfunction (ED) – has been
replaced by drugs with less severe sideeffects.
 Side effects: tachycardia, nausea, diarrhea,
orthostatic hypotension.
Alpha-1 Selective Blockers





Block alpha-1 but not alpha-2 adrenergic
receptors.
Generally reflex tachycardia is less prevalent than
with non-selective alpha blockers.
Syncope is noted when first administered in a
large group of patients. Caution patients to avoid
sudden postural changes.
Agents: PRAZOSIN, TERAZOSIN,
DOXAZOSIN
Uses: Hypertension, benign prostatic hypertrophy
Alpha-One Selective Blockers
Prazosin (Minipress) (prototype)
 Terazosin (Hytrin)
 Doxazosin (Cardura)
 Selective block for 1 receptor; 2 intact
 Clinical Uses:

 Hypertension
 Benign
prostatic hypertrophy - reverses smooth
muscle contraction
Other -Blockers

Yohimbine
 2
& 5-HT blocker
 aphrodisiac, improves erectile function


Viagra will replace
Ergot Alkaloids
 Ergotamine,
Ergonovine
 originally found in spoiled rye (fungus), caused
abortions, gangrene, convulsions
 used to treat migraine (also 5-HT agonists)
 Receptor Antagonists
 Blockers
Nonselective = both 1 and 2
 Propranolol (prototype)
 Timolol
 Pindolol

 partial

Nadolol
agonist, ISA
 Blockers
Cardioselective = 1-selective
 Atenolol (prototype)
 Others

 Acebutolol


partial agonist, ISA
Metoprolol
 Betaxolol
 Blockers
Very short acting - Esmolol
 Alpha and beta Blocker - Labetolol
- Carvedilol

Beta Adrenergic Receptor
Blockers.
A. Propranolol (Inderal) is the prototype
 mechanism. Non-selective competitive antagonist
at beta-1 and beta-2 receptors.
High therapeutic doses may also have a nonreceptor related quinidine-like or membranestabilizing effects.
Relatively high lipid solubility allows distribution to
the CNS (some drowsiness)
Propranolol: Pharmacological
Effects
The effect of antagonists is due to blocking
existing tone. Effects are greater if sympathetic
tone is high.
1. Heart. decreases HR, CO, and pacemaker activity.
2. Blood vessels. Slow developing decrease in
peripheral resistance. Possibly due to: central
reduction in sympathetic tone and reduction in
renin release (beta-1 effect)

Propranolol
Pharmacological Effects - depend on existing
sympathetic tone
 Heart:


heart rate and cardiac output
 exercise tolerance
 rate of depolarization of ectopic pacemakers
  O2 demand
  AV nodal conduction
  infarct size & re-infarction- prevent sudden death
Propranolol: Pharmacological
Effects.
3. Bronchial Smooth Muscle.
4. Metabolic. Blocks beta receptor effects on
lipolysis and glycogenolysis.
5. Quinidine-like effect.
Propranolol: Metabolism
Well absorbed following oral administration.
 Up to 2/3 may be inactivated by first pass
metabolism. There is large inter-individual
variation. Variation is relatively constant for a
given patient. Must titrate the dose upward for
each patient.

Propranolol: Clinical Uses
1. Angina pectoris. Reduces cardiac work and
O2 consumption.
2. Hypertension. Decreases CO and produces
slow decrease in peripheral resistance due
to blockade of renin release. May see Na+
and water retention with prolonged use
because of reduced CO.
3. Migraine headache (Prophylactic
treatment)
Propranolol: Clinical Uses
4. Arrhythmias: sinus tachycardia and
supraventricular ectopic beat
 Recurrent
VT, VF - especially when due to ischemia
5. Pheochromocytoma
Propranolol: Clinical Uses

Thyrotoxicosis:
 hyperthyroid

patients have receptor sensitivity
Adjuntive treatment for anxiety (panic) attacks
 reduces
peripheral sympathetic signs and symptoms,
e.g., palpitations

MI & Post-MI prophylaxis
 protects
against arrhythmias & limits infarct size
 Acute MI: assess LV function
 5-12 days after MI, reduces O2 demand & spread of
infarct zone
Congestive Heart Failure

Congestive Heart Failure






Dramatic results in recent clinical trials
Beta blockers prevent HF in >50%, strokes reduced by >38%,
occurrence of CAD and other CV events significantly decreased
Mortality rate reduced 65% by carvedilol, 34% by metoprolol,
33% by bisoprolol
Beta blockers increase LVEF, cause beneficial remodeling of
heart
Use only in stable CHF (class II &III), gradually titrate dose
Patients also treated with diuretic, ACE inhibitors, & digoxin
Propranolol: Side Effects

Common:
 dizziness,
fatique, diarrhea, constipation, nausea,
depression

Severe
 purpura,
rash, fever
Interferes with SGOT and BUN tests
 Chronic use (hypertension)  VLDL & HDL

Propranolol: Side Effects

Use with caution in diabetics
 inhibits
compensatory response to hypoglycemia
(glucagon release & glycogenolysis)
 masks signs of hypoglycemia (tachycardia) that are
important “clues” to diabetic patient
Contraindicated in most asthmatics and COPD
 Sudden withdrawal syndrome:

 rebound
hypertension, anginal attack & possibly MI if
drug suddenly withdrawn after chronic therapy
Propranolol:
Sudden Withdrawal. rebound
hypertension and possibly anginal attacks.
Beta receptor synthesis is increased by beta
blocker use. Example of receptor upregulation.
 Other Contraindications. Acute treatment
of heart failure; 2nd and 3rd degree heart
block, and cardiogenic shock.

Propranolol: Drug Interactions

Other hypotensive medications
 reserpine,

guanethidine, methyldopa
Other anti-arrhthymic agents
 calcium
channels blockers
 lidocaine

Insulin and oral hypoglycemic drugs
 prolongs

hypoglycemia and masks signs
Masks symptoms of hyperthyroidism
Other Nonselective  Blockers

Nonselective Blockers
 Nadolol (Corgard) -
longer acting; once-per-day dosing
 Timolol (Blocadren) - more potent than propranolol
 Timolol (Timoptic) lowers IOP in glaucoma
 reduces aqueous humor production

 Pindolol
(Visken) - partial agonist; partial blockade
less incidence of rebound hypertension
 less bradycardia

 Carteolol
- like pindolol
1-Selective Blockers
 All
are more potent at 1 than 2 receptors
at higher doses, block 2 as well
 lessen risk of bronchospasm -still contraindicated in asthmatic
 do not prolong hypoglycemia

 Atenolol (Tenormin) prototype
 Acebutolol (Sectral) - partial agonist, hypertension, dysrhythmias
 Metoprolol (Lopressor, Topral XL) – hypertension, CHF
 Betaxolol (Betoptic) – glaucoma
 Bisoprolol (Zebeta) - CHF
Labetolol (Trandate)
Selective 1 blocker
 Nonselective 1 & 2 blocker
 Clinical Uses:

 hypertension
 pheochromocytoma
Cardio- or Beta-1 Selective
Metoprolol-hypertension
 Atenolol-hypertension, stable angina
 Acebutolol-hypertension, dysrhythmias
 Betaxolol-glaucoma, hypertension

They must be used very cautiously if at all in
patients with reactive (asthma) airways.
Esmolol (Brevibloc)
Very rapid onset & short duration of action
 1-selective
 Used as IV infusion for peri-operative tachycardia
and hypertension, arrhthymias
 Used in electroconvulsive therapy

Beta-Blockers with Partial
Agonist Activity
Pindolol
 Acebutolol

No demonstrated therapeutic advantage over pure
antagonists. Lessened bradycardia, better lipid
profile ?
ISA (Intrinsic sympathomimetic activity)
Carvedilol (Coreg)
Nonselective -blocker + -blocker
 Very lipid soluble
 Also has antioxidant properties
 Very dramatic results in CHF clinical trials

 Decreased
mortality by 65%