Adrenoceptor Antagonists a-Adrenoceptor Antagonists

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Adrenoceptor Antagonists a-Adrenoceptor
Antagonists

• Non-selective
• Irreversible antagonist phenoxybenzamine, that
  binds covalently to receptor, long duration of
  action of 14-48 hours
• Reversible competitive antagonist phentolamine
  tolazoline

• Selective
• a1-adrenergic antagonists prazosin, doxazocin
  tamsulosin (a1A-blocker)
• a2-adrenergic antagonists yohimbine rauwolscine

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Nonselective a-receptor antagonists

• Vascular Blood Pressure Effects
• By blocking postsynaptic a1-adrenoceptors, they
  produce vasodilation, decreased total
  peripheral resistance and a fall in blood
  pressure opposed by stimulation of peripheral
  sympathetic activity via blockade of the
  presynaptic a2-adrenoceptors
• Postural hypotension via blockade of reflex
  sympathetic control of capacitance vessels upon
  standing

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Cardiac Effects

• Reflex tachycardia mainly via a2-receptor
  blockade because the inhibitory effect on NE
  release is blocked and peripheral NE release is
  increased stimulating ß1 cardiac receptors

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Therapeutic Uses Nonselective a-Receptor
Antagonists

• Treatment of pheochromocytoma which is a tumor of
  adrenal gland which secretes NE EP leading to
  signs of excessive catecholamine including
  hypertension, tachycardia arrhythmias
• Preoperative control of severe hypertension
  resulting from tissue manipulation in patient
  undergoing pheochromocytoma surgery
• Treatment of Raynauds disease

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Major Side Effects a-Receptor Antagonists

• Postural hypotension
  
• Reflex tachycardia
• Inhibition of ejaculation
  
• Nasal stuffiness

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Selective a1-receptor antagonists

• Vascular Blood Pressure Effects
• Blocking the vascular postsynaptic
  a1-adrenoceptors, produce vasodilation,
  decrease total peripheral resistance and a
  powerful fall in blood pressure
• Unopposed by blockade of the presynaptic
  a2-adrenoceptors that doesnt occur and hence the
  blood pressure lowering efficacy is high

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CVS Effects

• Postural hypotension is much less pronounced than
  the non-selective a-blockers possibly because of
  lower effect on veins
• Cardiac effects
• They may cause reflex tachycardia mediated via
  baroreceptors

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Therapeutic Uses

• Treatment of mild hypertension alone or in
  combination with other antihypertensives such as
  thiazide diuretics or ß-blockers in moderate or
  severe hypertension
• Treatment of benign prostatic hypertrophy.
  Blockade of a1-adrenoceptors at the base of the
  bladder and the prostate possibly reduces the
  symptoms of obstruction and the urinary urgency
• Tamsulosin has antagonistic affinity to a1A
  receptors (in vas deferens) more than to a1B in
  vascular smooth muscles

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Beta (ß)-Adrenergic Antagonists (ß-blockers)

• Non-selective ß-adrenergic antagonists
• blocking the effects of sympathetic stimulation
  upon all subtypes ß-receptors
• propranolol, pindolol, nadolol, and timolol

• Cardioselective ß1-adrenoceptor Antagonists
• preferentially block the cardiac ß1 adrenergic
  receptors with little effect on ß2-receptors
• metoprolol, atenolol, acebutalol esmolol

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ß-Adrenergic Antagonists with Intrinsic
Sympathomimetic Activity (ISA)

• Pindolol and acebutolol are ?-adrenergic
  antagonists in presence of catecholamines
• In addition, they possess a partial AGONISTIC
  activity on ?-adrenergic receptors
• Hence, they cause less bradycardia than
  propranolol, and can be preferred in patients
  with bradycardia
• Acebutolol is a selective ?-adrenergic
  antagonist, but metabolised into a non-selective
  antagonist

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Pharmacological Actions of ß-Blockers

• Cardiac effects
• Negative chronotropic effects especially at high
  sympathetic discharge as during exercise
• Decreased cardiac force of contraction. Peak
  cardiac tension rate of cardiac tension rise
  (contraction velocity) are reduced leading to
  lowered stroke volume, and increased end-systolic
  (residual) cardiac volume
• As a result, the cardiac output decreases

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Cardiac Effects of ß-Blockers

• Decreased cardiac oxygen consumption as a result
  of reduced cardiac work (decreased heart rate,
  ventricular systolic pressure contractility)
• Blocked sympathetic tone to A-V node hence
  vagal action predominates and atrioventricular
  conduction velocity decreases
• Depression of pacemaker activity (automaticity)

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Vascular Effects of ß-blockers

• Acute administration
• vasoconstriction (increased peripheral
  resistance)
• Unopposed a-mediated vasoconstriction in vascular
  beds containing both the a- ß-adrenoceptors
• Reflex increase in sympathetic tone as a result
  of reduced cardiac output

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Vascular Effects of ß-blockers

• Chronic administration
• Decreased blood pressure possibly
• decreased cardiac output
• antagonism of ß-receptors in the CNS
• blocking the facilitator presynaptic
  ß-adrenoceptors on sympathetic nerves
• reduction of renin release from juxtaglomerular
  apparatus and hence reduced angiotensin II and
  aldosterone levels
• Peripheral vasoconstriction through
• Unopposed a-mediated vasoconstriction in vascular
  beds containing both the a- ß-adrenoceptors
• Reflex increase in sympathetic tone as a result
  of reduced cardiac output

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Bronchiolar Smooth Muscle

• Propranolol antagonizes the ß-adrenoceptor
  mediated bronchodilation
• Augmenting ACh- histamine-induced bronchospasm
  airway resistance is increased
• ß-blocker bronchospasm is seriously dangerous in
  asthmatics

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Metabolic Effects

• Fat metabolism
• ß-blockers inhibit catecholamine-induced increase
  in lipolysis and the increase of plasma free
  fatty acids

• Carbohydrate metabolism
• ß-blockers enhance hypoglycemia by inhibiting
  catecholamine-stimulated hepatic glycogenolysis
  (important for diabetic patients)
• After insulin injection or exercise, ß-blockers
  delay the recovery of blood glucose (hypoglycemia)

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Therapeutic Uses of ß-blockers

• Treatment of hypertension Selective ß1-blockers
  are preferable in asthmatic diabetic patients
  and in patients with Raynauds disease
• Myocardial Infarction (MI)
• ß-blockers administered 1-4weeks after MI reduce
  much the probability of myocardial re-ifarction
  possibly by reducing cardiac work.
• ß-blockers given immediately (few hours) after MI
  reduces the infarct size and enhance cardiac
  reperfusion and recovery timolol, propranolol,
  and metoprolol are used

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Therapeutic Uses of ß-blockers

• Chronic Treatment of Glaucoma (Mainly
  Propranolol, timolol are used)
• They decrease the formation of aqueous humor by
  ciliary body reducing the IOP
• They dont affect accommodation for near vision
  nor affect pupil size as cholinergic agonists do
• Pilocarpine is of choice in acute attacks
• Chronic Migraine Propranolol is used in
  treatment of migraine where it reduces the
  severity of attacks and lowers their frequency
• Possibly via inhibition of catecholamine-induced
  cerebral vasodilation

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Therapeutic Uses of ß-blockers

• Treatment of effort angina but not variant angina
• Hyperthyroidism ß-blockers control the symptoms
  of excessive sympathetic stimulation (adjuvant
  therapy)
• Cardiac supraventricular arrhythmias to stop
  conversion of atrial to ventricular arrhythmia.
  ß1-receptor blockade results in the following
• decreased firing rate of SA node
• decreased AV conduction prolongation of
  AV-nodal refractory period
• decreased ventricular response to atrial flutter
• Esmolol is a cardio-selective ß1-blocker that is
  used only by IV route for emergency treatment of
  supraventricular arrhythmias arising during
  surgery

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Side Effects of ß-blockers

• Hypoglycemia that is much pronounced in patients
  with diabetes especially after insulin injection
  or oral hypoglycemic
• Severe cardiac slowing lowered cardiac
  contractility make the use of ß-blockers cautious
  in cases of sinus bradycardia, partial heart
  block severe congestive heart failure

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Side Effects of ß-blockers

• Dysrhythmias or anginal attacks may develop after
  withdrawal of ß-blockers from long term patients
• This may be due to adrenergic receptor
  super-sensitivity mediated by receptor
  up-regulation or re-enhancement of sympathetic
  cardiac drive
• Dosage of ß-blockers should be tapered off
  gradually over 1-2 weeks

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Side Effects of ß-blockers

• Bronchoconstriction ß2-receptor blockade can
  produce an increase airway resistance in patients
  with asthma selective ß1-blockers should be used
  in asthmatics
• Peripheral vascular disease vasoconstriction is
  aggravated in presence of ß-blockers because of
  uncovering the a1-adrenoceptor-mediated
  vasoconstriction in response to endogenous
  catecholamines
• Sexual dysfunction via undetermined mechanism,
  apparently ß-adrenoceptors-independent

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Combined a- ß-adrenoceptor Antagonists

• Labetalol and carvedilol are competitive
  antagonists for catecholamines at a1-, ß1- and
  ß2-adrenergic receptors
• They dont cause peripheral vasoconstriction
• Carvedilol, has additive antioxidant activity and
  protect against vascular thickening (remodeling)
• These two extra properties made it of value in
  treatment of some cases of heart failure
• Labetalol is preferable in treatment of
  hypertension of elderly black patients to avoid
  peripheral vasoconstriction
• Black hypertensive patients are usually resistant
  to ß-blockers
• IV labetalol is used in hypertensive emergencies
  preoperative pheochromocytma management

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Indirectly Acting Adrenergic Blockers

• Reserpine
• Mechanism of Action
• Potent inhibition of transporters responsible for
  neuronal vesicular NE uptake from neuronal
  cytoplasm (as well as other biogenic amines)
• Inhibition of vesicular storage capacity
• Hence, NE leaks into cytoplasm to mitochondria
  where it is catabolizstores are depleteded by MAO
• Ultimately peripheral central NE (together with
  DA 5-HT)

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Reserpine

• Actions Uses
• Reduction of vascular tone at small arteries
  veins as a result of peripheral adrenergic
  neurotransmitter depletion
• Bradycardia reduced cardiac output a s a result
  of decreased ?1-mediated actions
• It mayy be used in hypertension resistant to
  other agents
• Centrally, it may cause depression, nightmares
  and parkinsonism
• It increases tone motility of GIT as well as
  gastric HCl secretion

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Guanethidine

• It inhibits neuronal release of NE
• It is actively taken by adrenergic nerve
  terminals competing with NE for the same
  transporter proteins
• Therefore, intra-neuronal NE concentration
  decreases and its release is diminished
• It is rarely used in hypertension

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Effects of ?-Adrenergic Receptor Antagonists

• ?1-Adrenergic Receptor
• Bradycardia
• Decreased AV nodal conduction velocity
• Decreased pacemaker cells activity
• Decreased forve of contraction (reduced stroke
  volume, increased end-systolic volume decreased
  cardiac output)
• Decreased O2 consumption
• Reduced renin release (decreased ang II)
• Edema formation (decrased cardiac output

• ?2 -Adrenergic Receptor
• Peripheral vasoconstriction in some areas
• Decreased glcogenolysis insulin release
• Decreased adrenergic mediated tremors