Download S12 Pharmacology Adrenoceptor Blockers ANS 8

ADRENOCEPTOR BLOCKERS
Adrenoceptor antagonists
Alpha-blockers
Nonselective
Beta-blockers
Nonselective
Irreversible
Beta1-selective
Reversible
Beta2-selective
Alpha1-selective
Alpha2-selective
I. BASIC PHARMACOLOGY OF THE
ALPHA-RECEPTOR-ANTAGONIST
DRUGS
Mechanism of Action
 Reversible antagonists dissociate from
receptors: (phentolamine, tolazoline, prazosin
& labetalol, several ergot derivatives)

Irreversible drugs : phenoxybenzamine

The duration of action in both cases
Pharmacologic Effects
A.
Cardiovascular Effects:

↓PVR & ↓ BP


Alpha-receptor antagonists may cause postural
hypotension and reflex tachycardia.
Tachycardia may be more marked with agents
that block 2-presynaptic receptors in the heart
(e.g. yohimbine, tolazoline)
Pharmacologic Effects
(cont’d)
B. Other Effects:
 miosis
 nasal stuffiness.
 ↓resistance to the flow of urine (alpha
receptor blockade of bladder base &
prostate)
SPECIFIC AGENTS
Phentolamine (α1=α2)
1. competitive antagonist at both α1 and α2
receptors.
2. ↓PVR due to blockade of α1 receptors and
possibly α2 receptors in vessels.
3. cardiac stimulation is due to:
baroreflex
antagonism of presynaptic α2 receptors
→↑release of NA from sympathetic nerves.
Phentolamine

-
-
ADRs:
tachycardia, arrhythmias, & myocardial
ischemia.
diarrhea and ↑gastric acid production.
Headache, nasal congestion
Clinical Uses:
- treatment of pheochromocytoma
- male erectile dysfunction
Phentolamine Uses
Phenoxybenzamine

binds covalently to α receptors, causing irreversible
blockade of long duration (14-48 hours or longer).
Attenuates catecholamine-induced vasoconstriction
↓ BP when sympathetic tone is ↑, eg, as a result of upright
posture
Cardiac output may be increased (How? 1,2)
major use: orally in treatment of pheochromocytoma

ADRs:




1.
2.
3.
postural hypotension and tachycardia.
nasal stuffiness and inhibition of ejaculation
fatigue, sedation, and nausea (enters CNS).
Prazosin




Used in hypertension (HTN).
highly selective for α1 receptors → relative
absence of tachycardia
extensively metabolized (50% PO
bioavailability)
t1/2= 3 hrs
Terazosin



reversible α1-selective antagonist
Used in HTN
t1/2=9-12 hrs
Approved for use in men with benign prostatic
hyperplasia (BPH).
Doxazosin




used in HTN.
long half-life of about 22 hours.
also effective in the treatment of BPH.
t1/2= 22 hrs
Tamsulosin (Omnic®)



greater selectivity for α1A receptors
High efficacy in BPH
has relatively little effect on blood vessels
(and standing BP)
Other  adrenoceptor antagonists
Yohimbine
 α2-selective antagonist.
 Sometimes used to treat orthostatic
hypotenstion
 Veternary use: reverse xylazine anaethesia
 Previously: used to improve male sexual
function;
 can reverse the antihypertensive effects of
clonidine
Other  adrenoceptor antagonists




Alfuzosin: α1-selective antagonist,
BPH, F=60%, may cause QT
prolongation
Chlorpromazine and haloperidol:
DA antagonists α1-antagonist,
Trazodone: Antidepressant- α1antagonist
Ergotamine, dihydroergotamineα1-antagonist
CLINICAL PHARMACOLOGY OF THE
ALPHA-RECEPTOR-BLOCKING DRUGS
1. Pheochromocytoma
 phenoxybenzamine and phentolamine
 is a tumor usually found in the adrenal medulla
or sympathetic ganglion cells.
 ↑↑ epinephrine and norepinephrine.
 signs of catecholamine excess: HTN,
palpitations, headaches and increased sweating
1. Pheochromocytoma (cont’d)



Beta-blocking drugs may be required
after α-receptor blockers to reverse the
cardiac effects of excessive CAs.
Rarely: Metyrosine, a competitive
inhibitor of tyrosine hydroxylase  - rate
limiting step→↓the amounts of DA, NE & E
secreted by the tumor.
May cause extrapyramidal symptoms as a
side effect
2. Hypertensive Emergencies




have limited application, though labetalol
has been used
α antagonists are most useful when HTN is
due to excess α agonists (OD of
sympathomimetic, pheochromocytoma or
clonidine withdrawal)
Phentolamine
Considerable experience necessary
3. Chronic Hypertension

prazosin & other α1-selective
antagonists are used in mild to
moderate HTN.
major ADR: postural hypotension, may
be severe after the first dose (“firstdose hypotension”)
Nonselecetive α antagonists= NOT used!

↑ HDL (unknown mechanism)


4. Peripheral Vascular Disease (eg, Raynaud's
phenomenon)
 patients occasionally benefit from phentolamine, prazosin,
or phenoxybenzamine,
 calcium channel blockers are preferable (nefidipine)

Raynaud's phenomenon
(Maurice Raynaud, French physician, 1834-1881)
intermittent bilateral attacks of ischaemia of the fingers or
toes and sometimes of the ears or nose, marked by severe
pallor and often accompanied by paraesthesia and pain, it
is brought on characteristically by cold or emotional stimuli
and relieved by heat and is due to an underlying disease or
anatomical abnormality. When the condition is idiopathic or
primary it is termed Raynaud's disease.
5. Local Vasoconstrictor Excess

Phentolamine is used to treat the dermal
necrosis after extravasation of drugs with α
adrenergic effects (norepinephrine,
dopamine, epinephrine)

The α antagonist is administered by local
infiltration into the ischemic tissue
6. Urinary Obstruction


Relieving urinary symptoms of BPH
Mechanism involves partial reversal of
smooth muscle contraction in the
enlarged prostate and in the bladder
base


prazosin, doxazocin, and terazosin
tamsulosin is efficacious in BPH and has
little if any effect on BP
-RECEPTOR-ANTAGONIST
DRUGS
BASIC PHARMACOLOGY OF THE
-
RECEPTOR-ANTAGONIST DRUGS




-
-
The mostly used clinically are pure antagonists
a few are partial agonists
some have a higher affinity for β1 than for β2
receptors (cardioselective)
other major differences:
pharmacokinetic characteristics
local anesthetic membrane-stabilizing effects.
Table 10-2 Properties of several beta-receptor-blocking drugs.
Selectivity
Partial
agonist
Activity
Lipid
Solubility
Elimination
t1/2 (hrs)
Acebutolol
β1
Yes
Low
3-4
Atenolol
β1
No
Low
6-9
Bisoprolol
β1
No
Low
9-12
Carvedilol1
None
No
No data
6-8
Esmolol
β1
No
Low
10 min.
Labetalol1
None
Yes1
Moderate
5
Metoprolol
β1
No
Moderate
3-4
Nadolol
None
No
Low
14-24
Pindolol
None
Yes
Moderate
3-4
Propranolol
None
No
High
3.5-6
Timolol
None
No
Moderate
4-5
1Carvedilol
and labetalol also cause α1 adrenoceptor blockade.
3Bioavailability
is dose-dependent.
Pharmacokinetics





most are well absorbed after oral
administration
SR preparations of propranolol and
metoprolol are available.
propranolol: extensive (first-pass)
metabolism; F is relatively low
esmolol is short-acting, used
parenterally
nadolol: longest t1/2 (up to 24 hrs)
Pharmacodynamics of the βReceptor-Antagonist Drugs
A. Effects on the Cardiovascular System:
 on chronic use ↓ BP in pts. with HTN.
 factors involve effect on:
- heart
- blood vessels,
- renin-angiotensin system,
- perhaps CNS.
 do not usually cause hypotension in healthy
individuals with normal BP
Pharmacodynamics of the β-ReceptorAntagonist Drugs (cont’d)
B. Effects on the Respiratory Tract:
 blockade of the β2 receptors in bronchial
smooth muscle →↑in airway resistance,
particularly in pts with airway disease.
 Beta1-receptor antagonists may have some
advantage over nonselective agents.
 no currently available β1-selective
antagonist completely avoids interactions
with β2 adrenoceptors → these drugs
should generally be avoided in pts with
asthma
Pharmacodynamics of the β-ReceptorAntagonist Drugs (cont’d)
C. Effects on the Eye:

↓ IOP, especially in glaucomatous eyes (↓
aqueous humor production)
D. Metabolic and Endocrine Effects:
1.
↓sympathetic nervous system stimulation of
lipolysis.
2.
glycogenolysis in the human liver is at least
partially inhibited after β2-receptor blockade.

β antagonists should be used with great
caution in insulin-dependent diabetic patients
(impair recovery from hypoglycemia).
Pharmacodynamics of the β-ReceptorAntagonist Drugs (cont’d)
3.


↑VLDL & ↓HDL cholesterol (both changes are
unfavorable in terms of risk of cardiovascular
disease)
lipid changes are less likely to occur with βblockers with intrinsic sympathomimetic
activity (ISA) (partial agonists).
α-adrenoceptor antagonists, eg, prazosin
produce either no changes in plasma lipids or
↑HDL, which could be a favorable alteration
Pharmacodynamics of the β-ReceptorAntagonist Drugs (cont’d)
E. Effects Not Related to Beta Blockade:
1.
pindolol and other partial agonists may
be useful in patients who develop
symptomatic bradycardia or
bronchoconstriction in response to pure
antagonist.
2.
agents with local anesthetic (LA) action
are not used clinically
3.
sotalol is a nonselective β-receptor
antagonist with marked class III
antiarrhythmic effects, reflecting
potassium channel blockade
CLINICAL PHARMACOLOGY OF THE
BETA-RECEPTOR-BLOCKING
DRUGS
1. Hypertension
 many HTN patients will respond to a
β-blocker used alone, also often used
with either a diuretic or a vasodilator.
 may be administered once or twice
daily
 Some evidence: may be less effective
in blacks and the elderly
CLINICAL PHARMACOLOGY OF THE
BETA-RECEPTOR-BLOCKING
DRUGS
2. Ischemic Heart Disease (IHD)
 ↓frequency of anginal episodes and improve
exercise tolerance in pts with angina
 blockade of cardiac β1 receptors, →↓cardiac
work & ↓ in oxygen demand.
 Evidence: the long-term use of timolol,
propranolol, or metoprolol in pts who have
had a myocardial infarction (MI) prolongs
survival
CLINICAL PHARMACOLOGY OF THE
BETA-RECEPTOR-BLOCKING DRUGS
3. Cardiac Arrhythmias
 effective in the treatment of both
supraventricular and ventricular arrhythmias
 sotalol has antiarrhythmic effects in addition
to its β-blocking action
4. CHF
 metoprolol, bisoprolol, and carvedilol are
effective beneficial effects on myocardial
remodeling and ↓the risk of sudden death.
 should be used by skilled and experienced
physicians in carefully selected patients
CLINICAL PHARMACOLOGY OF THE
BETA-RECEPTOR-BLOCKING DRUGS
5. Glaucoma
 ↓production of aqueous humor by the ciliary
body.
 timolol has been favored because it lacks LA
properties and is a pure antagonist.
 sufficient timolol may be absorbed from the
eye to cause serious adverse effects on the
heart and airways in susceptible individuals
 may interact with orally administered
verapamil and ↑ the risk of heart block
 Betaxolol has the potential advantage of
being β1-selective
CLINICAL PHARMACOLOGY OF THE
BETA-RECEPTOR-BLOCKING DRUGS
6. Hyperthyroidism
1. Prevent excessive CA action on the heart &
CNS: tremors, nervousness, tachycardia,
arrhythmias
2. Prevent conversion of T4 to T3 in the
periphery
 Propranolol is particularly efficacious in
thyroid storm
7. Portal hypertension in pts with cirrhosis
 both propranolol and nadolol
CLINICAL PHARMACOLOGY OF THE
BETA-RECEPTOR-BLOCKING DRUGS
8. Neurologic Diseases
1. propranolol, metoprolol, atenolol, timolol and
nadolol ↓ frequency and intensity of migraine
headache.
2. ↓ certain tremors
3. ↓anxiety (propranolol) particularly when taken
prophylactically “stage fright”.
4. Propranolol: symptomatic treatment in
alcohol withdrawal.
CLINICAL TOXICITY OF THE BETA
RECEPTOR ANTAGONIST DRUGS
1. minor toxic effects for propranolol:
- rash, fever - drug allergy are rare
2. CNS effects: sedation, sleep disturbances,
depression; rarely, psychotic reactions.
 It has been claimed that β-receptor
antagonist drugs with low lipid solubility will
be associated with ↓incidence of CNS ADRs
than compounds with higher lipid solubility
CLINICAL TOXICITY OF THE BETA
RECEPTOR ANTAGONIST DRUGS
3. worsening of preexisting asthma and
other forms of airway obstruction without
having these consequences in normal
individuals. However, because of their lifesaving possibilities in cardiovascular disease,
may be used with caution in COPD pts. who
have appropriate indications for β-blockers.
4. caution in patients with severe peripheral
vascular disease or vasospastic disorders.
CLINICAL TOXICITY OF THE BETA
RECEPTOR ANTAGONIST DRUGS
5. ↓myocardial contractility and excitability


→ cardiac decompensation may ensue in pts
with compensated CHF even though long-term
use of these drugs in these patients may prolong
life.
effect of a β antagonist may be overcome
directly with isoproterenol or glucagon
(stimulates the heart via glucagon receptors)
Beta-blockers may interact with the calcium
antagonist verapamil → severe hypotension,
bradycardia, CHF, and cardiac conduction
abnormalities
CLINICAL TOXICITY OF THE BETA
RECEPTOR ANTAGONIST DRUGS
6. abrupt discontinuing β antagonist
therapy after chronic use →↑ angina
attacks (up-regulation of the number of β
receptors) → gradual tapering rather than
abrupt cessation is recommended
7. hypoglycemic episodes in diabetics
are exacerbated by β-blocking agents