Classification of Adrenoreceptor Antagonists

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Classification of Adrenoreceptor Antagonists

• a blockers
• Non selective
• Relatively selective
• Selective
• ß blockers
• Non selective
• Relatively selective
• Selective
• Both a and ß adrenergic antagonists

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a Adrenoceptor Antagonists (a blockers)
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selective Relatively selective Non selective
tamsolusin prazosin phenoxybenzamine
alfuzosin terazosin phentolamine
doxazosin tolazoline
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Non selective a blockers(act on a1 and a2
receptors)

• Phentolamine and Tolazoline (Reversible)
• Induce reversible competitive blockade for a1
  adrenoreceptors which can be overcome by increase
  of NE
• T1/2 3 5 hours
• Phenoxybenzamine (Irreversible)
• It alkylates the receptors binds by methyl
  covalent bond. Thus, it produces irreversible a
  blockade which cannot be overcome by increase of
  NE
• t1/2 14 48 hours

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Pharmacological effects of a blockers

• I. Effects Mediated by blocking a receptors
• A. Cardiovascular Effects
• 1) They block
• a1 causing VD. So, decrease TVR
• The pressor effect of a agonists
• So, they decrease BP (hypotension)
• But they are of limited clinical use in treating
  hypertension because they may cause
• Tachycardia (Reflex Type)
• Cardiac arrhythmia
• Angina pectoris
• Peptic ulcer
• Sexual dysfunction

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Cont.

• 2) They produce tachycardia more than the a1
  selective blockers by
• Producing reflex tachycardia.
• All a blocker (selective and non selective) block
  a1 to inhibit the effect of sympathetic tone on
  blood vessels. This leads to VD decrease BP
  (more obvious during standing ) leading to
  postural hypotension. This will stimulate the
  baroreceptors to send impulses to CNS to increase
  HR
• Increase HR by
• Block a2 cause increase NE in synapse. NE will
  bind to ß1 receptor leading to ?HR
• Phenoxy benzamine
• Block NE reuptake. This will increase NE in
  synapse leading to increase HR. So, more
  tachycardia with Phenoxybenzamine as compared to
  phentolamine.

So both drugs block a2 leading to ?NE but
pehnoxybenzamine block reuptake of NE leading to
more NE in synap
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• B. Non-cardiac Effects of a blockers
• A) Miosis
• b) Nasal stuffness
• c)decrease resistance to the flow of
  urine
• d) They decrease adrenergic sweating. So
  they
• produce dry skin
• e) Inhibit ejaculation
• II. Effects mediated by non- aadrenergic
  blocking effects
• They induce weak blockade for
• H 1 receptors (Histamine) (Sedation antinausea)
  
• Serotonin receptors
• Muscarinic receptors (dry mouth)

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Side effects of Phenoxybenzamine

• Fatigue
• Nausea (because it enters CNS)
• Diarrhea
• Postural hypotension.
• Tachycardia.

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a blockers Relatively selective

• Prazosin
• Terazosin
• Doxazosin

Please remember that they act on a1 only but in
case of higher doses they might act on a2
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1. PrazosinMechanism of action

• It is a relatively selective a1 adrenoceptor
  competitive antagonist
• Its action can be overcome by increasing agonist
  concentration(reversible)
• T1/2 3 hours

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PrazosinActions

• It produces arterial venous dilation. So it
  decreases BP, so it is used for the treatment of
  hypertension
• It causes less tachycardia than nonselective
  vasodilators (because it doesnt act on a2
  receptors)
• It precipitates less angina cardiac arrhythmia
• It may increase HDL / cholesterol ratio. HDL
  protects against ischemic heart disease
• There is tolerance to its action
• Dose 2 3 times daily for Hypertension and
  congestive heart failure (CHF).

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Heart failure

• In heart failure the following happens
• Decreased C.O leads to sympathetic stimulation.
• Sympathetic stimulation ? ?HR ?contractility
  (which increase the pressure on the heart thus,
  worsening the situation). Furthermore, NE will
  increase the release of renin and this leads to
  incerease preload and after load
• In this case we will use ß blockers to decrease
  HR and contractility and inhibit renin release.

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Side effect of prazosin

• 1st dose produce hypotension syncope, but this
  disappears after continuous treatment(we prevent
  this effect by decreasing the 1st dose and giving
  it at bedtime)
• Infrequent postural hypotension (rare and less
  than the non selective)
• Nasal stiffness due to VD congestion
• Dizziness, headache faintness . These are
  caused by hypotension
• Sexual dysfunction but less than the
  non-selective.

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a blockers Relatively selective2. Terazosin
Doxazosin

• They are relatively a1 selective blockers, with
  higher selectivity than prazosin
• T1/2 Terazosin 12 hours Doxazosin 22 hrs
• They produce VD with less tachycardia than
  prazosin
• Like prazosin they produce postural hypotension
• They produce relaxation of smooth muscle of the
  bladder neck and prostate capsule. So, they
  facilitate micturition. For this action, they can
  be used in case of urine retention associated
  with benign prostatic hyperplasia(BPH) in which
  prostate compresses the urethra prevent
  micturition.

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a blockers SelectiveTamsolusin Alfuzosine

• It is selective for a1A adrenoreceptors in the
  sphincter of urinary bladder
• a1A blockade leads to relaxation of the
  sphincter. So, it facilitates micturition
• Tamsolusin is used clinically in treating urine
  retention associated with BPH. It is better here
  than prazosin, Terazosin and Doxazosin
• It causes less hypotension than prazosin or
  terazosin. Because
• It has low potency in inhibiting receptors in
  vascular smooth muscle

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TamsolusinAdverse affects

• Retrograde ejaculation 15
• Hypersensitivity reaction skin rash urticaria
• Nausea and vomiting
• Nasal stiffness
• Over dose will cause hypotension, tachycardia
  and fatigue
• Note Similar to prazosin but with less
  magnitude.

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Tamsolusin Contraindications

• Renal impairment
• Tamsolusin is metabolized in the liver to an
  active metablite which is entirely excreted via
  the renal tubules, therefore,
• In case of renal impairment, Tamsolusin will
  accumulate in blood lead to toxicity

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Clinical Uses of adrenergic a-antagonists

• Pheochromocytoma (phenoxybenzamine,
• phentolamine) with ß blockers to reduce
• cardiac effect from increased catecholamines
• 2) Hypretensive Crisis (Labetalol)
• 3) Essential Hypertension (Prazosin, Terazosin)
• 4) Peripheral Vascular Occlusion Diseases
• (Raynauds phenomenon) e.g Prazosin (but
• Calcium Channel Blockers are better choice)
• 5) Urinary Obstruction associated with BPH
• (Tamsolusin)

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treatment T1/2 Act on Name of antagonist
Hypertension pheochromocytoma 3-5 hours Alpha 1 , 2 Phentolamine tolazoline
same 14-48 Alpha 1 , 2 phenoxybenzamine
Hypertension Congestive heart Failure Protect against ischemic disease Raynaud phenomenon 3 Alpha 1 prazosin
Hypertension Urinary retention 12 Alpha 1 terazosin
same 22 Alpha 1 doxazosin
Urinary retention Alpha 1A Tamsolusin Alfuzosin
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Adrenoreceptor Antagonists ß blockers
Alpha and beta blockers Relatively selective Non selective
Labetalol Atenolol Propranolol
carvedilol Esmolol Timolol
Metoprolol Nadolol
Practolol Labetalol
Acebutol pindolol
bisoprolol
More potent than atenolol
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How could you distinguish between b-adrenergic
Blockers?

• b-adrenergic antagonists (blockers) differ from
  each others in the following
• Selectivity for b1 as compared to b2. or by the
  following

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ß blockersPharmacological actions

• CVS
• BP CO TVR. Clinically ß blockers lower BP By
  these mechanisms
• Blockade of ß1 in the heart will cause decreased
  HR and CO
• Blockade ß1 in the kidney will cause decreased
  rennin leading to decreased angiotensin 2. this
  will lead to
• VD and ultimately decreased BP
• decrease aldosterone. This will lead to decerased
  salt and water retention and finally decreased BP
  
• decrease release of NE that will cause VD and
  decreased BP
• Blockade of central ß adrenergic in adrenergic
  nerve terminals. This will makes NE acts at
  a2-adrenergic agonist leading to a decrease in
  its own release and decrease sympathetic tone to
  blood vessels, leading to VD and decreased BP
• Which one of the above mechanism is more
  important for treating hypertension? Decreasing
  renin secretion

Angiotensin normally induces the release of NE
from postganglionic sympathetic fibers
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???? ?? a2
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Cont.

• The respiratory system
• Blockade of ß2 receptors in bronchi will cause
  bronchoconstriction
• Nonselective ß blocker (are contraindicated in
  the bronchial asthma (propranolol)
• The ß1 selective blockers (e.g Atenolol
  Bisoprolol) are also should be avoided in the
  acute bronchial asthma because their selectivity
  is relative and they may have antagonistic
  affects on the ß2 receptors at therapeutic doses.

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Cont.

• The eye
• ßblockers are used in treatment of glaucoma
  (Timolol). They act by
• Blocking ß2 in ciliary epithelium. This will
  decrease production of aqueous humor ??
  intraocular pressure (IOP)
• Block ß2 in ciliary muscle. This will cause of
  contraction of the ciliary muscle leading to
• Opening of the canal of Schlemm this Increases
  outflow of aqueous humor which leads to Decreased
  IOP

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Cont.

• Metabolic and endocrine effects
• ß blocker inhibit lipolysis
• In type 1 diabetes
• The patient depends on catecholamines to increase
  blood glucose if he took overdose of insulin.
• If he took ß blockers, they will impair the
  recovery from hypoglycemia
• ß1 blockers are advised in the case of diabetic
  patients
• ß blockers cause increase VLDL triglycerides
  (TG) and decrease HDL / Cholesterol ratio. So,
  they will
• Increase risk of coronary artery disease
• contraindicated in a patients with familial
  hypercholesterolemia because VLDL TGs are
  atherogenic may cause myocardial infarction

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Cont.

• Intrinsic sympathomimetic activity (ISA )
• Some of the ß antagonist produce some action of
  ß agonist e.g. Pindolol Labetalol, so, they
  are less dangerous when given to patients with
  bronchial asthma or excessive bradycardia
• Membrane Stabilizing Action (MSA)
• Some ß blockers stabilize the cell membrane by
  blocking Na channels. Therefore, produce local
  anesthetic action e.g. Propranolol Pindolol

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ß blockersSide effects of ß blockers

• Rash fever
• Worsening of asthma
• CNS include
• Sedation and Depression and sleep disturbances
• These are more sever in Lipid soluble ß
  blockers (e.g. Propranolol) than in water soluble
  ß blocker (e.g. Atenolol)
• Heart failure

Some ß blockers are effective in treating chronic
heart failure but not acute because you want to
decrease the see slide 11)) work load O2
consumption on the myocardium
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ß blockersContraindications of ß-blockers

• Bronchial asthma
• Peripheral vascular disease
• Heart failure (in severe cases only) (acute)

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ß blockersDrug interactions

• Verapamil (Ca ) channel blocker
• If it is combined with ß blockers, this can
  cause
• Congestive heart failure
• Severe bradycardia
• Severe hypotension

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ß blockersWithdrawal of ß blockers

• On chronic use, abrupt withdrawal of ß blockers
  causes the ß receptors to become supersensitive
  and even the circulating catecholamine can
  stimulate them cause severe arrhythmia. So,
  withdrawal should be very gradual over weeks

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ß blockers Propranolol

• It is non selective ß blocker
• T1/2 2 5 h
• It is Lipid soluble
• Can be given orally or I.V
• It undergoes extensive 1st pass metabolism (90
  of the drug)

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Cont.

• It is excreted in urine as Propranolol or as
  Glucouronide conjugate
• Its duration of action is increased in
• Hepatic disease
• Decreased hepatic BF
• Metabolic inhibition e.g. when giving Cimetidine,
  it inhibits the metabolism of propranolol, so,
  increase t1/2
• It has no ISA
• It has MSA . SO,
• It is used as antiarrhythmic drug but not in
  hypertension.
• It stabilize the cardiac cell membrane decrease
  the activity of ectopic foci

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Side effect of propranolol
Bradycardia Cold extremities Fatigue Sedation
Mental depression Sleep disturbances Heart
failure A V block Bronchospasm Impotence
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ß blockers Timolol

• It is a non selective ß blocker
• T1/2 4 5 h
• No ISA
• Low MSA so not good for arrethmia.
• Lipid soluble
• Pass via the cornea. So, it is used as eye
  drops to treat glaucoma

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ß blockers Labetalol

• It is a non-selective ß blocker selective a1
  blocker
• T1/2 4 6 h
• Weak lipid soluble
• It has ISA
• Has MSA
• It differs from other ß blockers in that it
  produce less bradycardia.
• It block a1 in blood vessels. So, causes VD and
  decrease BP (postural hypotension). This will
  stimulate baroreceptors to send impulses to CNS
  to increase HR (reflex tachycardia) but this
  tachycardia is less than seen with other a
  blockers
• It is used in Pheochromocytoma and hypertension
  of pregnancy

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Cont.

• Adverse effects include
• Nausea
• skin rash
• tiredness
• Aching limbs
• Bronchospasm
• Heart failure
• Sleep disturbance nightmares
• Sexual dysfunction (more than other ß blockers)
• Postural hypotension (because it is selective a1
  blocker)
• Raynaud syndrome (peripheral vasospasm)
• It is intermittent claudication or peripheral
  vascular disease
• It is due to decreased blood supply to the
  periphary by ß blockers due to
• Bradycardia
• Block ß 2 in blood vessels to skeletal muscle
  causing VC and decrease blood supply

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ß blockers Pindolol

• It is a non-selective ß blocker
• T1/2 3 4 h
• Has ISA (very important) lead to bradycardia.
• Weak lipid soluble
• Has MSA but less than Propranolol

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ß blockers Carvedilol like labitolol

• It is non selective ß blocker and non
  selective a blocker
• It can be used in patients with heart failure due
  to
• It is a peripheral vasodilator (unlike other ß
  blockers)
• It has antioxidant activity
• It can neutralize (scavenge) the free radicals
  which cause heart failure
• It used in renal impairment
• Because it improves kidney function. So, its
  used in patients with Renal impairment

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ß blockers Atenolol

• It is a relative ß1 selective blocker
• Hydrophilic so it has
• Longer t1/2 12 18 h because it stays in tissue
  for a long time
• For this reason, the dose is once daily
• Less severe side effects on CNS
• No ISA
• No MSA
• Adverse effects include
• CNS insomnia, headache dizziness
• Impairment of glucose tolerance
• Bradycardia
• Bronchospasm
• Sexual dysfunction
• Fatigue due to decreased blood supply to the
  periphery
• all ß blockers cause sexual dysfunction and
  fatigue.

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ß blockers Practolol

• It is a relatively ß1 selective blocker
• It is used in intensive care unit for severe
  ventricular arrhythmia
• It is not used to treat hypertension because of
  its side effect

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ß blockers Esmolol

• It is a selective ß1 blocker
• Has very short duration of action (t1/2 8min)
• Has low ISA
• Has MSA (good for arrhythmia )
• It is given I.V when short term ß blockade is
  required
• Safer to use than longer acting antagonists in
  critically ill patients.

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Name of Drug Selectivity ISA MSA T1/2 Lipid solubility
Atenolol Beta 1 No no 6-9 no
Carvedilol Beta 1,2 No No 7-10 yes
Esmolol Beta 1 No No 10 min no
Labetalol Beta 1,2 Yes Yes 5 yes
Pindolol Beta 1,2 Yes Yes 3-4 yes
Propranolol Beta 1,2 No Yes 3-6 yes
Timolol Beta 1,2 No No 4-5 yes
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• Migraine
• Propranolol

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Centrally acting sympatholytic drugs
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Centrally acting sympatholytic drugs

• These drugs have the opposite effect to those of
  the sympathomimetic drugs by acting on the CNS.
• Examples
• a-methyldopa
• Clonidine

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a methyldopa

• Mechanism of action
• amethyldopa is given orally then absorbed from
  GIT enters the circulation
• It freely passes BBB reaches CNS then it is
  converted to a methylenorepinephrine which acts
  as an agonist at central a2 adrenoreceptors
  then It will decrease the sympathetic tone to
  blood vessels (VD) ? ?BP
• These a2 adrenoreceptors are found in the
  medulla pons
• a methylenorepinephrine is called false
  neurotransmitter or (reactive metabolic of a
  methyldopa)
• Action of a methyldopa
• VD lead to decrease TVR without significant
  effects on CO or HR or renal blood flow

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Cont.

• Clinical uses
• Treat pregnancy associated hypertension
• Treat mild to moderate hypertension (not common
  used)
• Side effects include
• It may cause fluid retention
• Lead to increase ECF and increase in BP slightly
• This negates its therapeutic use
• It may produce postural hypotension when standing
  from the sleeping position
• This not severe like a blockers
• Sedation, insomnia, depression
• in the beginning of treatment disappears after
  continuous use
• Serious extrapyramidal signs
• It interferes with neurotransmitter of extra
  pyramidal tract
• May lead to muscle incoordination

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Cont.

• Lactation
• Even in male the breast may produce milk
• Hepatitis drug fever (can be serious)
• Impotence
• A lupus like reaction skin rash and pustules
• Hemolytic anemia
• Leukopenia sometimes

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Clonidine

• Already mentioned in a2 agonist.

Clonidine Alfa methydopa
I.V , orally, I.M I.V , orally Route of administration
5 7 h 2 4 h t1/2
125 250 ug/day 800 1200mg total / dose/day Dose
To give inactive form and secreted in the urine after conjugation To give alfa methyl NE, then conjugated in urine and some of it secrete in faeces Metabolism
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????? ??????

• All adrenergic blockers reduce BP
• But
• a blockers produce postural hypotension
• Any a2 agonist is considered an antagonist
  because it inhibits the release of NE.
• Relatively selective, means in high dose it may
  act on other receptors. (a1 blocker may act on a2
  in high doses).