2. Prevent interaction of endogenous neurotransmitter NE or
sympathomimetics with corresponding adrenergic receptors
attenuation of sympathetic nervous system homeostatic
mechanisms
Presynaptic agonism of alpha 2 receptors results in similar
attenuation of sympathetic outflow
3.
4. Bind specifically to alpha receptors and interfere with
catecholamine and sympathomimetic action
Drug induced alpha blockade heart and peripheral
vasculature
Inhibitory action of Epinephrine on insulin secretion is
prevented
Orthostatic hypotension, baroreceptor mediated reflex -
tachycardia and impotence are invariable S/E
There is absence of beta blockade maximum expression of
cardiac stimulation tachycardia
5. Mechanism of action:
PHENTOLAMINE , PRAZOSIN, YOHIMBINE are competitive alpha receptor
antagonist reversible binding
PHENOXYBENZAMINE binds covalently to alpha receptors irreversible and
insurmountable type of blockade even massive doses of
sympathomimetics are ineffective until its effect terminates
PHENTOLAMINE & PHENOXYBENZAMINE nonselective
postsynaptic alpha 1
presynaptic alpha2
PRAZOSIN selective alpha1
YOHIMBINE selective alpha2
6. Substituted imidazoline derivative
Transient nonselective alpha blockade
IV administration alpha 1 blockade on vascular smooth ms. VD
decrease SVR manifests 2 minutes, lasts 10-15 minutes
Decrease BP reflex baroreceptor mediated increase in sympathetiv
nervous system cardiac stimulation
Reflex stimulation + alpha 2 blockade enhanced NE release
increase HR & CO cardiac arrhythmias and angina
Predominance of parasympathetic activity hyperperistalsis,
abdominal pain, diarrhea
Principally hepatic metabolism and only 10% excreted unchanged in
urine
7. CLINICAL USES
Hypertensive emergencies (intraop manipulation of phaeochromocytoma
or ANS hyperreflexia)
30-70mcg/kg IV prompt but transient decrease in systemic BP
A continuous infusion (0.1 to 2mg/min) may be used to maintain normal
BP during intaop resection of phaeochromocytoma
Local infilteration (5-10mg in 50ml NS) is appropriate when a
sympathomimetic is accidently administered extravascularly
9. CVS EFFECTS:
In supine, normotensive patient,no sympathetic stimulation minimal
changes in systemic BP
Preexisting hypertension or hypovolemia orthostatic hypotension
If impairment of compensatory VC exaggerated BP decrease in
response to blood loss or vasodilatating drugs (volatile agents)
Despite decrease in BP no decrease in CO or renal blood flow
No change is cerebral or coronary vascular resistance
Treatment in pregnancy may cause neonatal hypotension and
respiratory depression in first 72 hours of life
10. NONCARDIAC EFFECTS:
Prevents inhibitory action of NE on insulin secretion
Catecholamines induced glycogenolysis and lipolysis is not altered
Miosis as stimulation of radial fibres is prevented
Sedation in chronic therapy
Nasal stuffiness due to unopposed VD in mucous membranes
CLINICAL USES:
0.5-1.0 mg/kg orally preop. to control HTN in phaeochromocytoma
Relieves Intense peripheral VC expansion of IV volume (decrease in
hematocrit)
Haemorrhagic shock intense VC tissue ischemia
Raynauds disease
Not favourable in intermittent claudication related peripheral vascular disease
11. Selective antagonist
Presynaptic alpha 2 blockade increased release of NE
USED in orthostatic hypotension,impotence in male patients with
vascular, diabetic and vascular origin
Readily crosses BBB
Increased skeletal muscle activity and tremor
Excessive doses: tachycardia, HTN, rhinorrhea, paresthesias and
dissociative states
Alpha2 agonist stimulation decreases anesthetic requirement therefore
there is possible interaction of Yohimbine with volatile agents
12. DOXAZOCIN:
selective postsynaptic alpha1 receptor antagonist
Treatment of essential HTN & BPH
PRAZOSIN:
Selective post-synaptic alpha1 receptor antagonist
Dilates both arteries and veins
Causes reflex tachycardia as alpha2 action is uninhibited
TERAZOSIN:
Alpha1 antagonist
BPH
TAMSULOSIN:
Alpha1a antagonist
BPH
Side effects- orthostatic hypotension, vertigo and syncope
13.
14. Bind selectively to presynaptic alpha2 receptors negative
feedback decrease NE release reduced sympathetic
outflow decrease in BP similar to alpha1 antagonists
Alpha2 receptors mostly in CNS hypotension, analgesia ,
decrease secretions, sedation, anxiolysis
Peripheral inhibition decrease insulin release and increased
Glucagon release from pancreas.
Selective for alpha2 receptors ,act competitively
Withdrawl can lead to rebound effect elevation in HR & HTN
even to dangerous levels
15. Dose dependent decrease in HR & BP
Used to treat drug resistant HTN and tremors
Partial agonist of alpha2
Alpha1:alpha2 preference= 400:1
Routes: oral, IV, transdermal
Metabolised in liver
T ½= 12-16 hours (extremely variable with any liver or kidney
dysfunction)
16. Alpha2:Alpha1 = 1600:1
Most commonly used in ICU & intraoperatively as sedative and
analgesic due to Central sympatholytic activity
IV infusion 0.1-1.5 mcg/kg/min with terminal T ½ =2 hours
Undergoes excessive biotransformation in liver and excreted
mostly in urine
Protein binding + short T ½ physiological dependence
withdrawal phenomenon after only days of administration
tachycardia, HTN, anxiety
Large bolus iv doses paradoxical HTN with decrease HR
(0.125-1 mcg/kg over 3-5 minutes)
17.
18. Bind selectively to beta receptors
Interfere with ability of catecholamines or sympathomimetics to
provoke beta receptors (heart, smooth ms. Of airway and blood vs. )
For patients on beta antagonist therapy ,it should be continued
throughout periop period
Propranolol is standard beta antagonist drug to which all beta
antagonists are compared.
19. MECHANISM OF ACTION:
Competitive inhibition
Reversible binding
Causes rightward displacement of DRC for the agonist but slope remains
unchanged
Chronic administration is associated with increase in number of brta
adrenergic receptors
Beta receptors G protein coupled receptors+ +adenyl cyclase
cAMP+PK phosphorylates L-type voltage gated Ca++ & Troponin C
adrenergic stimulation
In myocardium 80% beta 1 receptors 20% beta 2 receptors
Beta1 blockade slows sinus rate, AV node conduction, decrease
inotropy activity> rest decrease myocardial oxygen demand decrease
in ischemia during exercise decrease in HR increases diastolic perfusion
time may enhance myocardial perfusion
Beta2 blockade enhances bronchospasm in patients with reactive airway
diseases
20. CLASSIFICATION:
Nonselective beta action: propranolol, nadolol, timolol, pindolol
Cardioselective: metoprolol, atenolol, acebutolol, betaxolol, esmolol,
bisoprolol
suited in essential HTN,
in asthma and patients with reactive airway disease,
Less interference with carbohydrate matabolism
Less chances of precipitating Raynaud’s phenomenon
21. PARTIAL ANTAGONIST: gave intrinsic sympathomimetic
activity (+beta ,beta2 submaximally)
Bradycardia and depression of contractility at rest are less
prominent
Withdrawl is less likely to exaccerbate HTN / angina
Plasma lipid profile is not/less worsoned
Not effective in migraine prophylaxis
Not suitable for secondary prophylaxis of MI
PURE antagonist
22. CVS EFFECTS:
Negative chronotropic and inotropic effects
Conduction speed is decreased and rate of spontaneous phase 4
depolarization is decreased preexisting blocks can be
accentuated
May impede left ventricular ejection due to unopposed alpha
mediated VC
prevent chronotropic and inotropic effect of isoproterenol and
increase in HR caused by vasodilator drugs
No detectable influence on cardiac stimulant effect of calcium,
glucagon and digitalis
Enhance pressor effect of epinephrine
23. Patients with peripheral vascular disease do not tolerate well the
peripheral vasoconstriction caused by beta2 blockade
Development of cold hands and feet is common side effect of non
selective beta blockade
Vasospasm associated with Raynaud’s disease is accentuated by
propranolol
The principal anti dysryhthmic effect is to prevent dysrythmogenic effect
of endogenous catecholamines or sympathomimetics
This is mainly due to decrease in sympathetic activity and little to do
with membrane stabilization
24. TREATMENT OF EXCESS MYOCARDIAL DEPRESSION CAUSED BY
BETA BLOCKADE:
Initially: Atropine in incremental doses of 7 mcg /kg IV (blocks
vagal effects on heart )
If atropine ineffective positive inotropic agents are to be used
eg isoproterenol (2-25 mcg/kg/min IV )
Glucagon 1-10 mg IV followed by 5mg/hour
Calcium chloride 250-1000 mg IV bradycardia unresponsive to
pharmacological therapy transvenous artificial cardiac
pacemaker is necessary
Hemodylasis should be reserved to remove minimally protein
bound renally excreted beta adrenergic antagonists in patients
refractory to pharmacological therapy
25. AIRWAY RESISTANCE:
Beta2 blockade increases airway resistance Bronchoconstriction
Exaggerated in patients with COPD
METABOLISM:
Alter carbohydrate and fat metabolism
Tachycardia which is important warning sign of hypoglycemia is
blunted by beta blockade so non selective beta blockers are not
recommended in patients of DM on insulin or OHA
DISTRIBUTION OF EXTRACELLULAR POTASSIUM:
Normally influenced by sympathetic system activity and insulin
Specific beta2 + intracellular movt. Of K+
So beta blockade increases S.K +
26. INTERACTION WITH ANESTHETICS:
Myocardial depression produced by inhaled or injected
anesthetics could be additive with depression produced by beta
antagonists but not as excessive to be unsafe can be used
perioperatively except in patients with TIMOLOL (extreme
bradycardia with inhaled anesthetics)
Additive cardiovascular effects with beta antagonists:
Greatest with Enflurane
Least with Isoflurane
Sevoflurane and desflurane also do not cause any additive effects
C.O. and systemic blood pressure are similar with isoflurane with
or without beta antagonism
Cardiovascular responses to high doses of opioids not altered
In presence of excessive sympathetic system activity acute
administration of beta antagonist decreases BP and C.O.
27. NERVOUS SYSTEM
May cross BBB to produce side effects
Fatigue and lethargy
Vivid dreams are frequent
Peripheral paresthesias
FETUS:
Can cross placenta
Can cause bradycardia, hypotension, hypoglycemia
Breast milk is also likely to contain beta antagonists administered
to mother
WITHDRAWL HYPERSENSITIVITY:
Acute discontinuation excess sympathetic stimulation that
manifests in 24-48 hours
This is due to upregulation of receptorsduring chronic therapy
28. CLINICAL USES:
Treatment of essential HTN (HR,CO,RENIN)
Management of angina pectoris(HR, oxygen demand)
Treatment of acute coronary syndrome (if not C/I)
Perioperative beta adrenergic blockade (in risk group)
Treatment of intraoperative MI ( esmolol, metoprolol, propranolol)
Suppression of cardiac dysarryhthmias (esmolol, propranolol)
Management of congestive heart failure (metoprolol,
carvedilol,bisoprolol)
Prevention of excessive sympathetic nervous system activity(HOCM,
Phaeochromocytoma)
Preoperative preparation of hyperthyroid patients
29. CONTRAINDICATIONS OF BETA ANTAGONIST:
ABSOLUTE: severe bradycardia, unstable left ventricular failure,
AV heart block
RELATIVE: asthma or reactive airway disease, mental
depression, peripheral vascular disease
Diabetes is not a contraindication (recognizing that signs of
hypoglycemia may be masked)
30. Nonselective
Lacks intrinsic sympathomimetic activity (pure antagonist)
Equal beta1 and beta2 antagonism
Standard drug to woth beta antagonists are compared
Administered in stepwise increment until p[hysiological plasma conc.
Have been attained ( indicated by HR 55-60/min)
CARDIAC EFFECTS:
Most important pharmacological effect is on heart
Beta 1 blockade decrease in HR and myocardial contractility
decreased C.O.
Effects on HR and C.O. prominent during exercise or in presence of
sympathetic nervous system activity
HR slowing lasts longer than negative inotropic effect
Concominant beta2 blockade decrease peripheral vascular resistance
Can relieve myocardial ischemia
Sodium retention may be associated due to intrarenal hemodynamic
changes (decrease C.O.)
31. PK:
Rapidly and completely absorbed in GIT
Systemic availability limited by extensive hepatic first pass metabolism
Oral dose (40-800mg/day) is greater than IV dose( 0.5-1.0mg every 5
minutes)
PROTEIN BINDING:
Extensively bound to plasma proteins (90-95%)
Heparin + lipoprotein lipaseincrease in plasma FFA decrease
plasma protein binding of propranolol
METABOLISM
Hepatic
Active metabolite: 4 hydroxypropranolol, produced after oral
administration
T ½ = 2-3 hours
Elimination decreases in hepatic dysfunction further propanlol
decreases C.O. nad hepatic blood flow so further decrease in clearance
No effect of renal dysfunction.
32. CLEARANCE OF LOCAL ANAESTHETICS:
Propranolol decreases clearance of amide LA by decreasing
hepatic blood flow and inhibiting metabolism in the liver
Bupivacaine clearance is relatively insensitive to changes in
hepatic blood flow (low drug extraction ratio)
Clearance of drugs with low extraction ratio is inversely
proportional to plasma protein binding
Bupivacaine binding to alpha1 glycoprotein is increased by
propranolol (without altering conc of alpha1 glycoprotein) , thus
its decreased clearance systemic toxicity can be increased
33. CLEARANCE OF OPIOIDS:
Pulmonary first pass uptake of fentanyl is substantially decreased in
patients being treated chronically with propranolol
2-4 times more fentanyl enters circulation
Reflecting one basic lipophilic amine( propranolol) inhibiting
pulmonary uptake od second lipophilic basic amine(fentanyl)
34. Selective beta 1 adrenergic receptor
Prevents inotropic and chronotropic responses to beta +
BD, VD, metabolic effects of beta2 + remain intact less likely to cause
adverse effects in pts. With COPD or PVD or pts vulnerable to
hypoglycemia
Selectivity is dose related:
Large doses: may become non-selective ( beta 2 antagonism less than
propranolol, reversed by terbutaline)
PK:
Readily absorbed from GIT, offset by substantial first pass metabolism
Low protein binding
No active metabolite
Two ral formulations: metoprolol tartarate, metoprolol succinate
Elimination T ½ =2-3 hours
35. METOPROLOL TARTARATE METOPROLOL SUCCINATE
T ½ = 2-3 hours T ½ = 5-7 hours
Twice or thrice daily dosing Once or twice daily dosing
Extended time to peak
concentrations with equal daily
dose
Decreased plasma concentration
with equal dose of tartarate
36. MOST SELECTIVE beta1 antagonist
Desirable in patients who need sustained beta2 activity
In patients at risk for CAD who must undergo non cardiac surgery, IV
atenolol treatment before and immediately after surgery f/b oral
therapy during remainder of hospitalization decreases mortality and
incidence of cardiovascular complications for as long as 2 years
Periop atenolol in patients at high risk of CAD there is decrease in
myocardial ischemia
Prolonged effect OD dose
Does not enter CNS but fatigue and mental depression still occur
Does not potentiate insulin induced hypoglycemia can be used with
caution in DM pts with HTN not controlled by other antihypertensives
37. Rapid onset
Short acting
Selective beta1 adrenergic receptor antagonist
Only IV
0.5mg/kg initial dose over 60 seconds full therapeutic effect evident
in 5 minutes action cease within 10-30 minutes after administration is
discontinued intraoperative useful
150mg IV administered 2minutes before DL and ETT protection
against increase in HR & BP ( compared to fentanyl & lidocaine which do
not affect HR)
Useful in phaeochromocytoma and perioperative management of
thyrotoxicosis, pregnancy induced HTN, epinephrine or cocaine induced
cardiotoxicity)
38. Conversely, treatment of excessive sympathetic activity produced by
cocaine or systemic absorption of topical or subcutaneous epinephrine by
beta adrenergic blockade has been associated with fulminant pulmonary
edema and irreversible cardiovascular collapse
So these conditions are more safely treated with vasodilator drug like
sodium nitroprusside or nitroglycerine
Esmolol can blunt detrimental effects of catecholamine release during
anesthesia in patients with HOCM and in patients undergoing
hypercyanotic spells associated with TOF
Esmolol is beta 1 selective can unmask beta2 mediated VD of
epinephrine secreting tumors
Patients chronically treated with beta blockers administration of
esmolol additional negative inotropic effects
1mg/kg IV Esmolol f/b 250mcg/kg/minute significantly decreases
plasma conc. Of PROPOFOL required to prevent patient movt. In response
to surgical skin incision.
39. PK:
available for IV administration
PH 4.5-5.5 (commercial preparation) pain on injection
compatible with commonly used IVF and NMBD
Elimination T ½ = 9 minutes
Rapid hydrolysis in plasma by esterases
Independent of hepatic and renal clearance
Evidence of short duration of action is return of HR to predrug
levels after 15 minutes of discontinuing the drug
Poorly lipid soluble
41. Unique
Selective alpha1 and nonselective beta1 & beta2 adrenergic antagonist
effect
Presynaptic alpha2 receptors are spared
1/5th to 1/10th as potent as phentolamine to block alpha receptors
1/3rd as potent as propranolol to block beta receptors
Beta : alpha potency oral labetalol 3:1
IV labetalol7:1
PK : Conjugation with glucuronic acid
5% drug recovered unchanged in urine
elimination T ½ =5-8 hours (prolonged in liver disease,unchanged in
renal dysfunction)
42. CVS EFFECTS:
alpha blockade decreases systemic vascular resistance decrease BP
Beta blockade attenuates reflex tachycardia
C.O. unchanged
Vasodilatation is caused by alpha 1 blockade and beta2 agonist activity
0.1-0.5 mg.kg IV labetolol effect in 5-10 minutes
CLINICAL USES
Hypertensive emergencies
HTN associated with epinephrine overdose (submucosal injection during
surgical hemostasis)
Excessive doses 2mg/kg iv excessive decrease in BP
Small doses 20-80mg undesirable decrease in BP repeated doses can
be given every 10mins
rebound HTN
HTN in phaeochromocytoma
Angina pectoris
0.1-0.5mg/kg to attenuate increase HR and BP due to surgical stimulus
in anesthetised patient
43. SIDE-EFFECTS:
Most common: orthostatic hypotension
Bronchospasm in suspected patients
In case of prolonged therapy fluid retention therefore combined
with diuretics
44. Nonselective
No intrinsic beta agonist effect
Oral administration extensively metabolized products with weak
vasodilator activity
Elimination T ½ 7-10 hours
Extensive protein binding
Use: mild to moderate congestive heart failure
Essential HTN