classification of adrenoreceptor antagonists
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Adrenergics & Antiadrenergic drugs 1
Classification of Adrenoreceptor Antagonists α– blockers
Non selective Relatively selective Selective
β– blockers Non selective Relatively selective Selective
Both α and β adrenergic antagonists
Adrenergics & Antiadrenergic drugs 2
α– Adrenoceptor Antagonists (α– blockers)
Non selective Relatively selective
selective
phenoxybenzamine
prazosin tamsolusin
phentolamine terazosin alfuzosintolazoline doxazosin
واحدة على يؤثرالج2رعة زدنا واذاعلى يؤثر فانه
األخرى
Adrenergics & Antiadrenergic drugs 3
Non selective α– blockers(act on α1 and α2 receptors)
Phentolamine and Tolazoline (Reversible)
Induce reversible competitive blockade for α1 – adrenoreceptors which can be overcome by increase of NE
T1/2 = 3 – 5 hours
Phenoxybenzamine (Irreversible)
it produces irreversible α– blockade. t1/2 = 14 – 48 hours
4
Pharmacological effects of α– blockers
I. Effects Mediated by blocking α– receptors A. Cardiovascular Effects: 1) They block
α1 causing VD. So, decrease TVR The pressor effect of α– 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
B. Non-cardiac Effects of α– 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- α–adrenergic blocking effects: They induce weak blockade for:
• H 1 receptors (Histamine) (Sedation; antinausea) • Serotonin receptors • Muscarinic receptors (dry mouth)
Adrenergics & Antiadrenergic drugs 6
Side effects of Phenoxybenzamine Fatigue Nausea (because it enters CNS) Diarrhea Postural hypotension. Tachycardia.
Adrenergics & Antiadrenergic drugs 7
α– blockers Relatively selective Prazosin Terazosin Doxazosin
Adrenergics & Antiadrenergic drugs 8
1. PrazosinMechanism of action It is a relatively selective α1 –
adrenoceptor competitive antagonist
reversible T1/2 = 3 hours
Adrenergics & Antiadrenergic drugs 9
PrazosinActions: It produces arterial & venous dilation. So it
decreases BP, so it is used for the treatment of hypertension
It causes less tachycardia than non–selective vasodilators (because it doesn’t act on α2 receptors)
It precipitates less angina & cardiac arrhythmia It may increase HDL / cholesterol ratio. HDL
protects against ischemic heart disease There is tolerance to it’s action Dose 2 – 3 times daily for Hypertension and
congestive heart failure (CHF).
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.
Side effect of prazosin
Adrenergics & Antiadrenergic drugs 11
α– blockers Relatively selective2. Terazosin & Doxazosin: They are relatively α1 – 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).
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α– blockers SelectiveTamsolusin & Alfuzosine
It is selective for α1A – adrenoreceptors in the sphincter of urinary bladder
α1A 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
Adrenergics & Antiadrenergic drugs 13
TamsolusinAdverse affects: Retrograde ejaculation 15% Hypersensitivity reaction: skin rash &
urticaria Nausea and vomiting Nasal stiffness Over dose will cause hypotension,
tachycardia and fatigueNote: Similar to prazosin but with less
magnitude.
Adrenergics & Antiadrenergic drugs 14
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
Clinical Uses of adrenergic -antagonists:
1) Pheochromocytoma (phenoxybenzamine, phentolamine) with β blockers to reduce cardiac effect from increased catecholamines2) Hypretensive Crisis (Labetalol)3) Essential Hypertension (Prazosin, Terazosin)4) Peripheral Vascular Occlusion Diseases (Raynaud’s phenomenon) e.g: Prazosin (but
Calcium Channel Blockers are better choice) 5) Urinary Obstruction associated with BPH (Tamsolusin)
Adrenergics & Antiadrenergic drugs 16
Name of antagonist
Act on T1/2 treatment
Phentolamine & tolazoline
Alpha 1 , 2 3-5 hours Hypertensionpheochromocyto
maphenoxybenzami
neAlpha 1 , 2 14-48 same
prazosin Alpha 1 3 HypertensionCongestive heart
FailureProtect against
ischemic diseaseRaynaud
phenomenonterazosin Alpha 1 12 Hypertension
Urinary retentiondoxazosin Alpha 1 22 same
Tamsolusin & Alfuzosin
Alpha 1A Urinary retention
Adrenergics & Antiadrenergic drugs 17
Adrenoreceptor Antagonists β– blockers:
Non selective Relatively selective
Alpha and beta blockers
Propranolol Atenolol LabetalolTimolol Esmolol carvedilolNadolol Metoprolol
Labetalol Practololpindolol Acebutol
bisoprololMore potent than atenolol
How could you distinguish between -adrenergic
Blockers ? -adrenergic antagonists (blockers)
differ from each others in the following: Selectivity for 1 as compared to 2. or by the following:
β– blockersPharmacological actions: CVS
BP = CO * TVR. Clinically β blockers lower BP By these mechanisms:
Blockade of β1 in the heart will cause decreased HR and CO Blockade β1 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 β adrenergic in adrenergic nerve terminals. This will makes NE acts at2-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
يطلع بالعربيNE يلقى
الريسيبتور يضطر مقفلةل2 يروح انه
α2
Adrenergics & Antiadrenergic drugs 20
Cont…. The respiratory system
Blockade of β2 receptors in bronchi will cause bronchoconstriction
Non–selective β blocker (are contraindicated in the bronchial asthma (propranolol)
The β1 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 β2 receptors at therapeutic doses.
Adrenergics & Antiadrenergic drugs 21
Cont…. The eye
β–blockers are used in treatment of glaucoma (Timolol). They act by:
Blocking β2 in ciliary epithelium. This will decrease production of aqueous humor.
Block β2 in ciliary muscle. This will cause of contraction of the ciliary muscle leading to
Decreased IOP
Adrenergics & Antiadrenergic drugs 22
Cont…. Metabolic and endocrine effects
β 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 β blockers, they will impair the recovery
from hypoglycemia β1 blockers are advised in the case of diabetic
patients β – blockers cause increase VLDL & triglycerides
(TG) and decrease HDL / Cholesterol ratio.
Adrenergics & Antiadrenergic drugs 23
Cont…. Intrinsic sympathomimetic activity (ISA )
Some of the β antagonist produce some action of β 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 β blockers stabilize the cell membrane
by blocking Na+ channels. Therefore, produce “local anesthetic action” e.g. Propranolol & Pindolol …
Adrenergics & Antiadrenergic drugs 24
β– blockersSide effects of β blockers Rash & fever Worsening of asthma CNS include
Sedation and Depression and sleep disturbances
These are more sever in Lipid – soluble β blockers (e.g. Propranolol) than in water soluble β blocker (e.g. Atenolol)
Heart failure
Adrenergics & Antiadrenergic drugs 25
β– blockersContraindications of β-blockers: Bronchial asthma Peripheral vascular disease Heart failure (in severe cases only)
(acute)
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β– blockersDrug interactions: Verapamil (Ca++ ) channel blocker If it is combined with β – blockers,
this can cause : Congestive heart failure Severe bradycardia Severe hypotension
Adrenergics & Antiadrenergic drugs 27
β– blockersWithdrawal of β blockers:On chronic use, abrupt withdrawal of
β – blockers causes the β receptors to become supersensitive and even the circulating catecholamine can stimulate them & cause severe arrhythmia. So, withdrawal should be very gradual over weeks
Adrenergics & Antiadrenergic drugs 28
β– blockers Propranolol It is non – selective β 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)
Adrenergics & Antiadrenergic drugs 29
Cont…. It’s duration of action is increased in
Hepatic disease Decreased hepatic BF Metabolic inhibition e.g. when giving Cimetidine
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
Side effect of propranolol
30
BradycardiaCold extremities Fatigue Sedation Mental depression Sleep disturbances Heart failureA – V block Bronchospasm Impotence
Adrenergics & Antiadrenergic drugs 31
β– blockers Timolol: It is a non – selective β 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
Adrenergics & Antiadrenergic drugs 32
β– blockers Labetalol: It is a non-selective β blocker & selective α1
blocker T1/2 = 4 – 6 h Weak lipid – soluble It has ISA Has MSA It differs from other β blockers in that it
produce less bradycardia. It is used in Pheochromocytoma and
hypertension of pregnancy
Adrenergics & Antiadrenergic drugs 33
Cont…. Adverse effects include:
Nausea skin rash tiredness Aching limbs Bronchospasm Heart failure Sleep disturbance & nightmares Sexual dysfunction (more than other β blockers) Postural hypotension (because it is selective α1 blocker) Raynaud syndrome (peripheral vasospasm)
Adrenergics & Antiadrenergic drugs 34
β– blockers Pindolol: It is a non-selective β blocker T1/2 = 3 – 4 h Has ISA (very important) lead to
bradycardia. Weak lipid soluble Has MSA but less than Propranolol
Adrenergics & Antiadrenergic drugs 35
β– blockers Carvedilol : like labitolol It is non – selective β blocker and non –
selective α blocker It can be used in patients with heart
failure due to: It is a peripheral vasodilator (unlike other β
blockers) It has antioxidant activity It used in renal impairment .
Adrenergics & Antiadrenergic drugs 36
β– blockers Atenolol: It is a relative β1 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 β blockers cause sexual dysfunction and fatigue.
Adrenergics & Antiadrenergic drugs 37
β– blockers Practolol: It is a relatively β1 selective
blocker It is used in intensive care unit for
severe ventricular arrhythmia It is not used to treat hypertension
because of it’s side effect
Adrenergics & Antiadrenergic drugs 38
β– blockers Esmolol : It is a selective β1 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 β blockade is
required Safer to use than longer acting antagonists in
critically ill patients.
Adrenergics & Antiadrenergic drugs 39
Name of Drug
Selectivity
ISA MSA T1/2 Lipid solubility
Atenolol Beta 1 No no 6-9 noCarvedilol Beta 1,2 No No 7-10 yesEsmolol Beta 1 No No 10 min no
Labetalol Beta 1,2 Yes Yes 5 yesPindolol Beta 1,2 Yes Yes 3-4 yes
Propranolol Beta 1,2 No Yes 3-6 yesTimolol Beta 1,2 No No 4-5 yes
Adrenergics & Antiadrenergic drugs 40
Migraine:•Propranolol
Adrenergics & Antiadrenergic drugs 41
Centrally acting sympatholytic drugs
Adrenergics & Antiadrenergic drugs 42
Centrally acting sympatholytic drugs These drugs have the opposite
effect to those of the sympathomimetic drugs by acting on the CNS.
Examples: α-methyldopa Clonidine
Adrenergics & Antiadrenergic drugs 43
α– methyldopa Mechanism of action
α–methyldopa is given orally then absorbed from GIT & enters the circulation
It freely passes BBB & reaches CNS then it is converted to α– methylenorepinephrine which acts as an agonist at central α2 – adrenoreceptors.
These α2 – adrenoreceptors are found in the medulla & pons
α– methylenorepinephrine is called “false neurotransmitter” or (reactive metabolic of α– methyldopa)
Action of α– methyldopa VD lead to decrease TVR without significant effects on CO
or HR or renal blood flow
Adrenergics & Antiadrenergic drugs 44
Cont…. Clinical uses:
Treat pregnancy – associated hypertension Treat mild to moderate hypertension (not common used)
Side effects include: It may cause fluid retention It may produce postural hypotension when standing from
the sleeping position This not severe like α– 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
Adrenergics & Antiadrenergic drugs 45
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
Adrenergics & Antiadrenergic drugs 46
Clonidine: Already mentioned in α2 agonist.
Adrenergics & Antiadrenergic drugs 47
: جوهر2ية قواعد
•All adrenergic blockers reduce BPBut :α blockers produce postural hypotension
•Any α2 agonist is considered an antagonist because it inhibits the release of NE.
•Relatively selective, means in high dose it may act on other receptors. (α1 blocker may act on α2 in high doses).
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