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To describe the pharmacology of alpha receptor blocking agents and apply this to
their clinical use
Imidazoline derivatives
Competitive antagonist eg phentolamine and tolazine
Phentolamine - short acting duration of 10-15 minutes
3-5 x more potent in blocking 1 vs 2
10x more potent than tolazoline
These drugs cause a fall in MAP (block of mediated vasoconstriction) and postural
hypotension.
CO and HR increase
Reflex tachycardia in response to fall in MAP, if concomitant block of 2 then this
enhances the reflex tachycardia (increased nor-adrenaline release).
Use
Diagnosis and perioperative management of patients with phaeochromocytoma
Acute treatment of hypertension during anaesthesia
treatment of left ventricular failure complicating myocardial inharction
Previously used in pulmonary hypertension
Role in assessment of sympathetically mediated chronic pain
Injection into the corpus cavernosum has been used to treat impotence due to erectile
failure.
Presentation
Clear solution for injection of 10mg/mL of phentolamine mesilate.
Main Actions
Hypotension, positive inotropism, chronotropism
Mode of Action
Acts by transient competitive adrenergic blockade (1:2 3-5:1)
Also has some adrenergic agonist and anti 5-HT activity
Route of Administration/Doses
IMI 5-10mg
IV infusion (diluted in dextrose or saline) at 0.1-0.2mg/min
Onset of action in 1-2 minutes, duration of action 5-20 minutes
Pharmacokinetics
Absorption - given parenterally. Oral bioavailability 20%
Distribution
50% protein bound
Metabolism
Extensive metabolism
Excretion
10% excreted unchanged in the urine.
Plasma half life 10-15 minutes
Pharmacodynamics
CVS
1 blockade - vasodilatation and hypotension, reduced SVR
2 blockade - reflex tachycardia, increased CO. Indirect effect of inotropism
Coronary blood flow is increased
Drug also has class I antiarrhythmic effects.
In patients with heart failure, phentolamine causes an increase in the HR and CO,
with a concomitant decrease in PAP, SVR and LVEDP.
Resp
Increases vital capacity, FEV1, and maximum breathing capacity in normal subjects.
Prevents histamine induced bronchoconstriction
Respiratory secretions increased.
Pulmonary arterial vasodilator.
The presence of sulphites in phentolamine ampoules may lead to hypersensitivity
reactions, which are manifest as acute bronchospasm in susceptible asthmatics.
GIT
Increases salivation, gastric acid and pepsin secretion, and GIT motility
Metabolic/Other
May precipitate hypoglycemia secondary to increased insulin secretion
Toxicity/SEs
Generally well tolerated, may cause orthostatic hypotension, dizziness, abdominal
discomfort and diarrhoea.
Cardiovascular collapse and death have followed the administration of phentolamine
when it is used as a diagnostic test for phaeochromocytoma.
Special points
Phentolamine causes marked congestion of the nasal mucosa and this may make nasal
instrumentation more traumatic if topical vasoconstrictors are not used.
Pharmacokinetics
Absorption
Incompletely absorbed after oral administration - bioavailability 20-30%
Distribution
Highly lipophilic
Metabolism
Liver - deacetylation
Excretion
Urine and bile, half life 24 hrs. Effects may persist for 3 days while new -receptors
are synthesised.
Pharmacodynamics
CVS
Decrease in peripheral vascular resistance DBP, and pronounced orthostatic
hypotension.
Reflex tachycardia and CO
Inhibits catecholamine induced cardiac dysrhythmias
Fluid shift from interstitial to the vascular compartment due to vasodilation of pre and
post-capillary resistance vessels
CNS
CBF only if marked hypotension occurs
Usually causes sedation, although convulsions have been reported after rapid IV
infusion. Meiosis also seen.
GIT
Little change in GIT tone or splanchnic blood flow
GU
Little alteration in renal blood flow, decreases motility of non-pregnant uterus.
Toxicity/Side Effect
Overdose should be treated with noradrenaline
Dizziness, sedation, dry mouth, paralytic ileus and impotence can result
Contact dermatitis
Special points
Systemic administration of the drug may lead to an increase in the systemic absorption
of co-administered local anaesthetic agents.
Causes marked congestion of nasal mucosa and this may make nasal instrumentation
more traumatic if topical vasoconstrictors are not used.
Pharmacodynamics
CVS
Dilates coronary arteries, peripheral arterioles and veins, Pulmonary and
systemic vascular resistance and MAP.
Relatively little reflex tachycardia occurs
Drug may have direct negative chronotropic effect on the SA node.
CO may in patient with heart failure, due to reduced filling pressures
Resp
Atenolol
Tenormin
Metoprol
Propranolol
Labetalol Esmolol
ol
HCl
Minax
Inderal
Trandate
Ipran
Normodyn
Carvedil
ol
Brevibloc
Dilatrend
e
Relative sensitivity +
Intrinsic sympathetic 0
++
Low
Moderate
High
Low
Low
High
HM
HM
HM
Hydrolysis by
HM
activity
Membranestabilizing activity
Lipophilicity[]
unchanged)
RBC esterase
Drug accumulation
Yes
No
No
No
No
No
6 to 9
3 to 4
3 to 4
9 min
2 to 8
50-100mg qd
50-100m
60mg qid
100-600
N/A
25-50mg
in renal disease
Elimination half-life
(hr)
Usual oral
maintenance dose
Usual intravenous
dose (caution)
g qid
5mg
0.1mg/kg
mg bid
bid
15 mg
q5min 3 (maximum)
min infusion
HM, hepatic metabolism; N/A, not applicable; RBC, red blood cell; RE,
renal excretion; 0, no effect; +, mild effect; ++ moderate effect.
Propranolol
Non selective blocker without ISA.
Racemic mixture, the S-isomer conferring most of its effects, although the R-isomer is
responsible for preventing the peripheral conversion of T4 to T3
Use
HT
Angina
Essential tremor
Prophylaxis for migraine
blocker of choice for thyrotoxicosis, as it inhibits the effects of thyroid hormones, as
well as preventing the peripheral conversion of T4 to T3.
Dose
IV 0.5-10mg titrated to effect
Oral 160-320mg daily, but due to increased clearance in thyrotoxicosis even higher
doses may be required.
Kinetics
High lipid solubility it is well absorbed from the GIT.
High first pass metabolism reduces oral bioavailablility to 30%.
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To describe the clinical uses of beta receptor blocking agents and their potential
adverse effects
Clinical Uses
Treatment of Essential Hypertension
Chronic therapy results in a gradual reduction in systemic blood pressure
Antihypertensive effect is largely dependent on decreases in cardiac output due to
decreased heart rate.
Large doses of -blockers may decrease myocardial contractility as well
In many patients SVR remains unchanged.
Absence of orthostatic hypotension (cf prazosin)
Often -blocker used in combination with vasodilator to minimise reflex baroreceptor
mediated tachycardia and increased CO.
Release of renin from the juxtaglomerular apparatus that occurs in response to
stimulation of 2 receptors is prevented by nonselective beta blockers eg propranolol.
THis may account for a portion of the antihypertensive effect of propranolol especially in
patients with high circulating plasma concentrations of renin.
As drug induced decreases in secretion of renin, -blockers also will lead to a decrease
in release of aldosterone, and hence prevent the compensatory sodium and water
retention that accompanies treatment with a vasodilator.
Management of Angina Pectoris
Drug induced decreases in myocardial oxygen requirements secondary to reduced HR
and contractility.
Effective dose usually decreases resting HR <60
Treatment of Acute Coronary Syndrome
All patients who experience AMI receive IV -blocker as early as possible.
Contraindications to treatment are severe bradycardia, unstable left ventricular failure,
AV heart block.
Relative contraindications are asthma, reactive airway disease, mental depression,
peripheral vascular disease.
Diabetes is not a contraindication, there has to be recognition that the symptoms of
hypoglycemia may be masked.
The incidence of non fatal reinfarction and recurrent myocardial ischaemia was reduced
in patients who received oral metoprolol within 6 days following AMI.
Peri-operative beta-adrenergic blockade
Role is controversial at the moment
In the late 1990s, two important studies established the value of perioperative blockade in patients at risk for coronary ischemia who were undergoing noncardiac
operations.
Patients are labeled as at risk if they fit into one of two categories:
they are undergoing high-risk vascular surgery and have no evidence of inducible
coronary ischemia, or
they are undergoing a nonvascular procedure but have traditional risk factors for
coronary artery disease (elderly, high cholesterol, hypertension, cigarette
smoking, family history of coronary disease, or diabetes).
The Multicenter Study of Perioperative Ischemia Research Group[215] enrolled 200
patients about to undergo surgery who had risk factors for coronary artery disease
and randomized them to receive placebo or atenolol before and after surgery. Their
results demonstrated that although there was no improvement in in-hospital
outcomes (cardiac death or MI) in the atenolol-treated group, the treated group did
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have a lower incidence of cardiac events at the 6- to 8-month follow-up and a marked
decrease in all-cause mortality that persisted at 2-year follow-up (survival rate at 2
years: 68% in the placebo group and 83% in the atenolol-treated group).
The second study enrolled patients with known ischemic disease demonstrated on
preoperative stress echocardiography.
Treatment group in this study was given bisoprolol and the dose was titrated to
achieve a heart rate below the patients ischemic threshold.
The results of this study, whose participants were at much higher risk for ischemic
events than those of the previous study, demonstrated a 10-fold decrease in
perioperative cardiac death and MI (3.4% versus 34%).
These powerful demonstrations that -blockade could decrease perioperative cardiac
risk and improve survival out to 2 years led to tremendous political and administrative
pressure to increase the use of -blockers perioperatively.
Unfortunately, more recent research has brought the value of routine perioperative blockade into question.
POBBLE study results showed no reduction in 30-day cardiovascular morbidity in
patients undergoing vascular surgery (one of the at-risk groups from previous
studies). Similarly, the
DIPOM study showed no benefit of -blockade in diabetics (another at-risk group)
undergoing major noncardiac operations.
Finally, a large retrospective study looking at in-hospital mortality in more than
780,000 patients demonstrated a neutral or even negative effect of perioperative blockade in patients without clear-cut coronary artery disease. -Blockade was
associated with a reduced mortality rate in only the 3% of patients who had three or
more risk factors (based on the revised Cardiac Risk Index) for coronary ischemia.
Thus, until larger studies are completed, the only strong indication for initiating blockade preoperatively is for patients undergoing vascular surgery who are at high
cardiac risk as a result of the finding of ischemia on preoperative testing.
When perioperative -blocker therapy is initiated, it should be titrated to a nonischemiainducing heart rate (usually 60 to 70 beats per minute) and not given as a standard fixed
dose to all patients. -blockers should be continued in patients who are already taking
them as treatment of their angina, symptomatic arrhythmia, or hypertension.
The safety of continuing -blockade perioperatively is well established, and initial
concerns regarding interaction with general anesthesia have not been confirmed.
Attempts to discontinue -blockers increase the risk for rebound tachycardia (with or
without atrial fibrillation) and myocardial ischemia in patients with coronary disease.
These drugs should be given up to the time of surgery, and intravenous forms in
appropriate dosages should be used whenever gastrointestinal absorption may be in
question.
If -blockers have been omitted from the preoperative regimen, esmolol or labetalol may
be used acutely to blunt tachycardia and hypertension.
Cardioselective and nonselective -blockers appear to be effective in blocking the
chronotropic effects of endotracheal intubation and surgical stress.[231]
Esmolol, Metoprolol have been used for rapid AF and atrial flutter to control ventricular
response rate
Management of congestive cardiac failure
Metoprolol, carvedilol, bisoprolol improve ejection fraction and increase survival in
patients with chronic heart failure.
Sustained release metoprolol is associated with improved survival
Carvedilol a nonselective beta blocker with vasodilator and antioxidant properties has
been shown to decrease mortality associated with congestive heart failure.
Introduce slowly, and gradually increase dose.
Prevention of excessive sympathetic nervous system activity
-blockade is associated with attenuated HR and BP changes in response to direct
laryngoscopy and tracheal intubation.
Hypertophic obstructive cardiomyopathies are often treated with -adrenergic
antagonists
Tachycardia, and cardiac dysrhythmias associated with phaeochromocytoma and
hyperthyroidism are effectively suppressed with propranolol.
Likelihood of cyanotic episodes in patients with Tetralogy of Fallot is minimised by blockade.
Preoperative preparation of hyperthyroid patients
Thyrotoxic patients can be prepared for emergency surgery by IV administration of
propranolol or esmolol or electively by oral administration of propranolol.
Treatment of migraine headache
Treatment of glaucoma - timolol - reduces aqueous humour production, can have systemic
side effects.
Essential tremor
Panic disorder
Adverse effects
Cardiovascular
negative inotropic and chronotropic effect
can precipitate worsening of heart failure
av block in patients with pre-existing disease
bradycardia
hypotension
Excessive bradycardia and/or decreases in cardiac output due to drug induced blockade should be treated initially with atropine in incremental doses of 7g/kg IV.
Atropine is likely to be effective by blocking vagal effects on the heart and thus
unmasking any residual sympathetic nervous system stimulation.
If Atropine is ineffective, drugs which produce direct positive chronotropic and
inotropic effects are indicated eg isoproterenol (if non-selective blocker used) or
dobutamine (if selective -blocker was used).
Glucagon administered 1-10mg IV followed by 5mg/hr IV effectively reverses
myocardial depression produced by -adrenergic receptors at normal doses as it
does not exert its effect at receptors.
Calcium may also be effective
In the presence of bradycardia that is unresponsive to pharmacologic therapy
transvenous pacing or external pacing may be required
worsening of peripheral vascular disease
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patients with peripheral vascular disease do not tolerate well the peripheral
vasoconstriction associated with 2 blockade by non-selective blockers.
Vasospasm associated with Raynauds disease is accentuated by propranolol.
Respiratory
Nonselective blockers consistently increase airway resistance bronchoconstriction.
More common in those with pre-existing airway disease
Selective blockers are less likely to cause this.
GIT
Nausea, vomiting, diarrhoea
CNS
Lipid soluble -blockers (eg propranolol) can cross the BBB, and produce fatigue,
lethargy, vivd dreams.
Atenolol is less lipid soluble and may be associated with less CNS effects.
Metabolic
blockers alter carbohydrate and fat metabolism
Non selective blockers prevent glycogenolysis that usually occurs in response to the
release of adrenaline in response to hypoglycemia.
Mask the tachycardia associated with hypoglycemia in diabetics on treatment.
Other
Fever
Rash
Myopathy
Alopecia
Thrombocytopenia
Interaction with Anaesthetics
Generally well tolerated
Exception is timolol where profound bradycardia has been observed in the presence of
inhaled anaesthetics.
Acute Withdrawal
Acute discontinuation can result in excess nervous activity which manifests in 24-47
hrs.
Presumably, this enhanced activity reflects an increase in the number of receptors (upregulation) during chronic therapy with blockers.
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