SYMPATHOLYTIC AGENTS

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SYMPATHOLYTIC AGENTS Beta Receptor Blockers
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BETA-ADRENERGIC RECEPTOR BLOCKERS

• Widely used clinically for a variety of
  conditions mainly CVS
• Dichloro-isoproterenol (DCI) 1st selective
  ?-blocker
• Propranolol 1st to come in wide use
  prototype agent

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• Subsequent agents differ in terms of
• Selectivity for ?1 or ?2
• Intrinsic sympathomimetic activity - partial
  agonist activity
• Membrane stabilising property - local
  anaesthetic property
• Additional actions
• - on ?-receptors, vasodilatation,
  free-radicals
• Lipid solubility and pharmacokinetics

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Compound Intrinsic activity Local Anaesthetic Additonal activity
Non Selective Propranolol Nadolol Timolol Pindolol Labetalol Carvedilol Sotalol Selective ?1 Metoprolol Atenolol Esmolol Acebutalol Celiprolol (ß1) Betaxolol (ß1) - - - - - - - - - ß2 - - - - - - - - - - - - - ?1- blocking a- blocking antioxidant Antiarrhythmic - - - - Vasodilator -
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GENERAL PHARMACOKINETIC PROPERTIES Mostly well
absorbed orally Most agents undergo first pass
effect variable bioavailability
(exceptionsbetaxolol, sotalol, pindolol) Most
agents rapidly distributed - with large
Vd Metabolized in liver (Cy P450) Exception
Nadolol (excreted unchanged) Propranolol is
highly lipophilic readily crosses BBB T ½
between 3 to 10 hrs for most agents Esmolol
10 minutes Nadolol 24 hours
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PHARMACOLOGICAL ACTIONS Can be explained on basis
of knowledge of ?-receptor actions in tissues

• EFFECTS ON CVS
• Antiarrhythmic
• Antianginal
• Antihypertensive

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CVS Effects on Heart ? HR and contractility
Marginal in resting state. Exercise induced
? minimized Initially ? CO, ? peripheral
resistance (reflex) Continued use symp. tone
returns to normal or ? Prevent exercise-induced
? in HR and contractility Tend to limit
work capacity ?2 block in arteries
limits ? in muscle bl. flow Blunt CA
induced ? in glucose metabolism
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Rhythm and Conductivity ? sinus rate ?
rate of spontaneous depolarization ? CV in
atria and AV node ? ERP of AV node ( Membrane
stabilizing effects may also contribute to
antiarrhythmic effect of some members like
propranolol)
ANTIARRHYTHMIC
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• Effect on coronary blood flow
• myocardial oxygen demand important
  for anti-anginal action
• ( improve relationship between
  oxygen demand and supply)

ANTI ANGINAL
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Anti-hypertensive effects No marked effect
in normal ? in hypertensives Sites/mechanisms
? HR and contractility ? renin release from
J-G cells (?1 receptors
promote) ? presynaptic ?2 receptors
Central actions Additional effects in some ?
blockers (? blockade, intrinsic activity)
ANTIHYPERTENSIVE
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Actions on Pulmonary System Non selective ?
blockers --- No marked effect in
normal Bronchospasm in asthmatics, COPD
?1-selective less likely to cause this effect
but to be used with caution
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EFFECTS ON EYE Several agents reduce intraocular
pressure Especially in Gluacoma Mechanism
Possibly decreased aqueous formation due to
decreased CyAMP in ciliary body Timolol,
Betaxolol, Carteolol
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Metabolic actions Carbohydrates ?
gluconeogenesis glycogenolysis
Non-selective ? blockers ? recovery from
hypoglycaemia in IDDM (?1-selective
agents preferable less likely to cause
this effect) Block the warning signals of
hypoglycaemia Not much effect on insulin
release
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Metabolic actions Fat Attenuate release of FFA
from adipose tissue (?3) Modest ? in plasma
triglycerides and ? in HDL (? Undesirable)
?1 selective lesser action on lipid
metabolism Agents with intrinsic activity
possibly better
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Other effects Block CA induced tremor
(Propranolol) Block inhibition of mast cell
degranulation by CAs
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Therapeutic Uses Hypertension Ischaemic Heart
Disease Angina Pectoris (not in vasospastic)
Myocardial Infarction Acute infarction ?
mortality (not if ?? HR or BP, CHF ) Long
term use ? recurrence Supraventricular and
Ventricular arrhythmias ? AV nodal refractory
period Suppress ventricular ectopics
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Other CVS disorders
CHF Recent evidence ? blockers may be
beneficial in long term management of CHF - ?
mortality only metoprolol, carvedilol,
bisoprolol only in selected cases ß blockers
are generally contraindicated in CHF ? stroke
volume in hypertrophic cardiomyopathy
decreased ventricular rate decreased outflow
resistance Dissecting aortic aneurysm
decreased rate of development of
systolic pressure
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Other uses Hyperthyroidism to control CVS
signs Propranolol also inhibits peripheral
conversion of T3 to T4 Migraine
prophylaxis -- Propranolol,
Timolol, Metoprolol Acute panic attacks and
acute anxiety states Glaucoma - ? rate of
aqueous secretion ( Timolol, Betaxolol)
Pheochromocytoma after ? blockade
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ADVERSE EFFECTS Mainly attributable to ?-receptor
blockade 1. CVS CHF in susceptible pts.
(compensated HF, post-MI, cardio-megaly) (prolonge
d low dose ?-blocker administration may be
beneficial in selected cases) Bradycardia Partial
or complete AV block --- serious
brady-arrhythmias Abrupt discontinuation
exacerbates angina, sudden death.
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ADVERSE EFFECTS..
2. Due to vascular ?-receptor blockade
Vasoconstriction cold extremities worsening
of peripheral vascular insufficiency
(eg. Raynauds ) 3. Bronchospasm In
susceptible, asthmatics Can occur even with
ß1 selective
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ADVERSE EFFECTS..
4. CNS Fatigue, sleep disturbances
(insomnia, nightmares) 5. Metabolic effects
? triglycerides,? HDL Prolong
hypoglycaemia (IDDM) Overdosage ?? in HR,
hypotension, prolonged AV conduction, widening of
QRS, depression. (Glucagon may be used as
antidote)
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Non-selective ? Blockers PROPRANOLOL ?1 ?2
membrane stabilizing action No intrinsic
activity no ? blocking action Pharmacokinetic
properties Completely absorbed from GIT but
extensive 1st pass (upto 75) Variable
presystemic clearance and dose
requirements Highly lipophilic 90 plasma
protein bound readily enters CNS
Short t ½ (4 hrs) but antihypertensive effects
fairly prolonged to enable BD dosage
Extensively metabolized and excreted in urine
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Propranolol. Therapeutic Uses
Hypertension, stable angina pectoris,
arrhythmias, Migraine prophylaxis,
Hyperthyroidism Interactions Phenytoin,
rifampin, phenobarb - ? conc. CCBs (verapamil
and diltiazem) additive effects on
conduction Nifedipine positive interaction
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TIMOLOL Non-selective, no intrinsic or
membrane stabilizing activity Used mainly
in Glaucoma by local instillation (significant
absorption may occur to cause systemic effects
adverse effects in susceptible LABETALOL Non
selective ? ?1 blocker partial agonist at ?2
4 isomers with relatively different proportion of
the above actions Complex actions Use
Pheochromocytoma Hypertensive
emergencies
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NADOLOL Long t ½ once daily dosage PINDOLOL
Intrinsic activity may be
preferable in Pts with diminished
cardiac reserve or propensity for
bradycardia SOTALOL
Antiarrhythmic activity
independent of ?-blocking action ( K Channel
blockade )
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?1 - selective blockers (Cardioselective) ATENOLO
L No intrinsic activity Limited CNS
penetration Pharmacokinetics Incomplete
oral absorption Insignificant presystemic
clearance Relatively little individual
variation Excreted unchanged in urine
(May accumulate in renal failure) Uses
Hypertension Stable angina pectoris Isolated
systolic hypertension in elderly
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METOPROLOL Completely absorbed High first
pass effect 40 bioavailability
Extensively metabolized 10 excreted
unchanged in urine Uses Hypertension
Stable angina IV for Ac. MI Selected
cases of CHF ACEBUTALOL ?1 selective with
some intrinsic activity Uses hypertension
ventricular arrhythmias
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ESMOLOL Very short duration of action Quick
onset and quick recovery from effect Administered
IV in severe acute conditions
where adverse effects may necessitate
quick withdrawal
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Newer Agents CARVEDILOL Non-selective ? ?1
blocker anti-oxidant action BETAXOLOL ?1
selective, used in glaucoma, Less chances of
bronchospasm as compared to
Timolol CELIPROLOL ?1 selective mild ?2
agonist weak vasodilator
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ß2 selective blocker Butoxamine ß2 selective
blockers do not have any potential use hence
not pursued for development