Adrenergic Antagonists (Sympatholytics)

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Adrenergic Antagonists (Sympatholytics)
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Adrenergic Antagonist

• Inhibition of sympathetic system by blocking
• Adrenergic receptors (reversible or irreversible
  blocking of a or/and ß receptors)
• Adrenergic neurons (blocking uptake or release)

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Adrenergic Blocking Drugs

• These drugs competitively inhibit a and ß
  receptor sites.
• a receptors, a1, a2.
• One group of drugs is specific for both ß1 and ß2
  receptors.
• One group is specific for ß2 receptors.
• One group is specific for both a and ß receptors.

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Adrenergic Receptor Antagonist

• a-Blockers
• Non selective Phenoxybenzamine Phentolamine
• a1-Blocker Prazosin, Terazosin, Doxazosin
  Tamsulosin
• a2-Blocker Yohimbine (Sympatholytic ?)
• ß-Blockers
• Non selective Propranolol, Timolol Nadolol
• ß1-Blocker Atenolol, Metoprolol Esmolol
• ß1-Blocker with partial ß2 agonist activity
  Acebutolol Pindolol
• a ß Blocker Labetalol carvidilol

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Effects of a-adrenoceptor Antagonists

• The most important effect is CVS effect
• They block a1 receptors causing decrease in
  peripheral resistance and consequently BP
• The resultant hypotension provokes reflex
  tachycardia

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• For non selective a-antagonists, the main
  differences between phenoxybenzamine and
  phentolamine are
• Phenoxybenzamine is a prodrug that takes few hrs
  for biotransformation while phentolamine is not a
  prodrug
• Phenoxybenzamine bind covalently (irreversible
  binding) to a receptors and so the activity last
  for about 28 hrs. On the other hand, phentolamine
  is competitive blocker (reversible binding), so
  the activity last for 4hr.

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• For selective a1 blockers like prazosin
  (Minipress) and terazosin, they are competitive
  blocker of a1 receptors causing profound
  vasodilation and decrease in arterial BP. The
  hypotensive effect is more dramatic than non
  selective.
• Yohimbine blocks a2 causing increase in
  sympathetic flow and so BP. is sometimes used as
  a sexual stimulant.

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Clinical uses of a-adrenoceptor antagonists

• Hypertension a1 selective blockers are more
  preferred e.g. prazosin. They are used alone or
  in combination with other antihypertensive drugs
• Phaeochromocytoma A combination of a- and ß-
  receptor antagonists is the most effective way of
  controlling the BP
• e.g. phenoxybenzamine and atenolol

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• Flomax (tamsulosin). Used in BPH. Produces smooth
  muscle relaxation of prostate gland and bladder
  neck. Minimal orthostatic hypotension.
• Priscoline (tolaxoline) used for Pulmonary
  hypertension in newborn.

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Adverse effects of a-adrenoceptor antagonists

• 1st dose effect syncope. With alpha 1 blockers,
  first dose syncope may occur from hypotension.
  Give low starting dose and at hs.
• Postural hypotension
• Tachycardia (a1-selective produce less
  tachycardia because they do not increase NA
  release from sympathetic nerve terminal)
• Prazosin may cause sodium water retention,
  therefore it is frequently used with a diuretic

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Orthostatic hypotension dentistry

• Orthostatic hypotension is a problem with
  prazosin analogs and to a lesser extent
  tamsulosin. Significantly, orthostatsis is a
  problem that can be seen with any vasodilator
  that affects the tone on venous smooth muscle.
• This would include, organic nitrates,
  hydralazine, clonidine, minixodil and the many
  drugs.
• Orthostatic hypotension or postural hypotension
  occurs when systemic arterial blood pressure
  falls by more than 20 mmHg upon standing.

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• In this situation, cerebral perfusion falls and
  an individual may become light headed, dizzy or
  fatality may occur.
• In changing from the supine to the standing
  position, gravity tends to cause blood to pool in
  the lower extremities. However, several reflexes,
  including sympathetically mediated
  venoconstriction minimize this pooling and
  maintain cerebral perfusion. If these reflex
  actions do not occur, then orthostatic
  hypotension could result.

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• By blocking the alpha1-receptors associated with
  venous smooth muscle, prazosin-like drugs,
  inhibit the sympathetically mediated
  vasoconstriction associated with postural
  changes. Hence, orthostatic hypotension can
  occur.
• Drugs like clonidine cause orthostasis due to its
  CNS actions that block the sympathetic reflexes.
• Vasodilators such as nitrates, minoxidil,
  hydralazine or impotence medications cause
  orthostasis because of their actions directly on
  the vasculature.

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ß-adrenoceptor antagonists

• They are all competitive blocker, most of them
  are nonselective or ß1 blocking activity
  (cardioselective)
• ß-Blockers
• Non selective Propranolol, Timolol Nadolol
• ß1-Blocker Acebutolol, Atenolol, Metoprolol
  Esmolol
• ß1-Blocker with partial ß2 agonist activity
  Acebutolol Pindolol

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ß-adrenoceptor antagonists

• Beside ß blocking activity, some blockers may
  possess one or more of the following properties
• Intrinsic Sympathetic Activity (ISA) i.e. they
  have the ability to stimulate the occupied
  receptors, hence known as partial agonist e.g.
  pindolol
• Membrane stabilizing activity i.e. inhibit
  depolarization of excitable membrane (by blocking
  Na channels) and so they have antiarrhythmic and
  local anaesthetic action e.g. propranolol

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They have ISA Intrinsic Sympathomimetic Activity
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Effects of ß-adrenoceptor antagonists

• Cardiovascular
• Heart
• -ve chronotropic inotropic (?CO, O2 consumption
  HR)
• ?excitability (antiarrhythmic effect)
• ?Conductivity (heart block in large dose)
• BV
• Block ß2 mediated VD
• No postural hypotension (No a effect)
• Reflex VC due to ?CO BP and so ? blood flow to
  the periphery
• BP ? with no reflex tachycardia
• Reduction in CO
• Reduction in renin release

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Effects of ß-adrenoceptor antagonists

• Bronchial smooth muscles
• In asthma obstructive pulmonary disease, they
  can cause severe bronchoconstriction. This danger
  is less with ß1 selective blocker
• Metabolism
• Inhibition of glycogenolysis (Caution with
  insulin treatment?)
• Inhibition of glucagon release
• Hypertriglyceridemia hypercholesterolemia

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• Decreased production of aqueous humor in eye
• May increase VLDL and decrease HDL
• Diminished portal pressure in clients with
  cirrhosis
• Decreased renin production.

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Receptor selectivity

• Acetutolol, atenolol, betaxolol, esmolol, and
  metoprolol are relatively cardioselective
• These agents lose cardioselection at higher doses
  as most organs have both beta 1 and beta 2
  receptors.
• esmolol is the most rapidly acting, short t ½ (8
  minutes), given only IV for management of
  arrhythmia.

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Non-Receptor selectivity

• Carteolol, levobunolol, metipranolol, nadolol,
  propranolol, sotalol and timolol are all
  non-selective
• Can cause bronchoconstriction, peripheral
  vasoconstriction and interference with
  glycogenolysis

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Combination selectivity

• Labetalol and carvedilol (Coreg) block alpha 1
  receptors to cause vasodilation and beta 1 and
  beta 2 receptors which affect heart and lungs
• Both alpha and beta properties contribute to
  antihypertensive effects
• May cause less bradycardia but more postural
  hypotension
• Less reflex tachycardia

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Intrinsic sympathomimetic activity

• Have chemical structure similar to that of
  catecholamines
• Block some beta receptors and stimulate others
• Cause less bradycardia
• Agents include acebutolol, penbutolol and
  pindolol

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Clinical Uses of ß-adrenoceptor antagonists

• Cardiovascular
• Hypertension
• They are used alone or in combination.
• Mixed a ß blocker, labetalol, is often used in
  preeclamptic toxaemia (a form of hypertension
  occurring late in pregnancy)
• Angina pectoris
• ? Cardiac work O2 consumption by decreasing
  rate, BP and contractility
• Chronic management of stable angina (not acute
  treatment)
• Cardiac arrhythmias
• Following myocardial infarction
• It is preferred to give ß-blocker immediately
  following a myocardial infarction to reduce
  infarct size by blocking the action of
  circulating catecholamines

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• Useful in pheochromocytoma in conjunction with
  alpha blockers (counter catecholamine release)

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Clinical Uses of ß-adrenoceptor antagonists
(cont.)

• Glaucoma Open angel
• Particularly timolol, used as eye drops
• ? secretion of aqueous humor by the ciliary body
• They do not affect the ability of eye to focus
  for near vision or pupil size
• Hyperthyroidism
• Preoperatively in thyrotoxicosis by blocking
  sympathetic stimulation that occurs in
  hyperthyroidism, particularly cardiac arrhythmia
• Migraine
• as prophylaxis by blocking catecholamine-induced
  VD in the brain vasculature

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Specific condtions-beta blockers

• With significant bradycardia, may need medication
  with ISA such as pindolol and penbutolol
• Patient with asthma, cardioselectivity is
  preferred
• For MI, start as soon as patient is
  hemodynamically stable

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Special conditionsbeta blocers

• Should be discontinued gradually. Long term
  blockade results in increase receptor sensitivity
  to epinephrine and norepinephrine. Can result in
  severe hypertension. Taper 1-2 weeks.

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Adverse effects of ß-adrenoceptor antagonists

• Bronchoconstriction
• Cardiac failure (large dose), May worsen
  condition of heart failure as are negative
  inotropes
• Hypoglycemia (with reduced awareness of
  hypoglycemia in patients receiving insulin)
• Physical fatigue (due to reduced cardiac output
  and reduced muscle perfusion in exercise)
• Cold extremities

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Adrenergic Neuron Antagonists

• They act by
• ?NA Synthesis
• e.g. a-methyltyrosine, carbidopa
• a-methyldopa
• ?NA Storage
• e.g. Resepine
• ?NA Release
• e.g.Guanthidine

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Inhibitors of NA Synthesis

• a-methyltyrosine
• It inhibits tyrosine hydroxylase
• Not used clinically
• Carbidopa
• It inhibits dopa decarboxylase
• Its main use is an adjunct to treatment of
  Parkinsonism with L-dopa

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Inhibitors of NA Synthesis

• a-methyldopa
• It is taken up by noradrenergic neurons, where it
  is decarboxylated and hydroxylated to form the
  false transmitter, a-methyl-nor-adrenaline
• The false transmitter is released in the same way
  as NA but differ in two points
• - It is less active than NA on a1 receptors and
  thus it is less effective in causing
  vasoconstriction
• - It is more active on presynaptic a2 receptors
  and so stimulates autoinhibitory feedback
  mechanism
• It is used in treatment of hypertension

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Inhibitors of NA Storage

• Reserpine
• a plant alkaloid
• It acts by blocking ATP-dependent transport of NA
  and other amines (e.g. 5-HT dopamine) into
  synaptic vesicles, apparently by binding to the
  transport protein ? depletion of NA from the
  adrenergic neurons
• It induces a gradual decrease in BP with
  concomitant slowing of heart rate. It has slow
  onset and longer duration of action (persist for
  many days after stopping)
• Used for hypertension resistant to other treatment

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Inhibitors of NA Release

• Guanthidine
• Overall, the principle action of guanthidine
  involves its accumulation by the synaptic
  vesicles, which are then unable to fuse with the
  cell membrane in the normal way, so the
  exocytosis is prevented i.e. Stop the release
• It induce transient increase in BP because
  guanthidine displace NA in its storage sites
• At large doses, it causes structural damage of
  noradrenergic neurons
• It is no longer used clinically