Classification of Adrenoreceptor Antagonists

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1 Classification of Adrenoreceptor Antagonists
130 saeed Classification of Adrenoreceptor Antagonists α– blockers Non selective Relatively selective Selective β– blockers Both α and β adrenergic antagonists Adrenergics & Antiadrenergic drugs

2 α– Adrenoceptor Antagonists (α– blockers)
130 saeed α– Adrenoceptor Antagonists (α– blockers) يؤثر على واحدة واذا زدنا الجرعة فانه يؤثر على الأخرى selective Relatively selective Non selective tamsolusin prazosin phenoxybenzamine alfuzosin terazosin phentolamine doxazosin tolazoline Adrenergics & Antiadrenergic drugs

3 Non selective α– blockers (act on α1 and α2 receptors)
130 saeed 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 Adrenergics & Antiadrenergic drugs

4 Pharmacological effects of α– blockers
130 saeed 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

5 B. Non-cardiac Effects of α– blockers A) Miosis b) Nasal stuffness
130 saeed 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)

6 Side effects of Phenoxybenzamine
130 saeed Side effects of Phenoxybenzamine Fatigue Nausea (because it enters CNS) Diarrhea Postural hypotension. Tachycardia. Adrenergics & Antiadrenergic drugs

7 α– blockers Relatively selective
130 saeed α– blockers Relatively selective Prazosin Terazosin Doxazosin Please remember that they act on α1 only but in case of higher doses they might act on α2 وصلنا إلى هنا ؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟ Adrenergics & Antiadrenergic drugs

8 1. Prazosin Mechanism of action
130 saeed 1. Prazosin Mechanism of action It is a relatively selective α1 – adrenoceptor competitive antagonist reversible T1/2 = 3 hours Adrenergics & Antiadrenergic drugs

9 130 saeed Prazosin Actions: 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). Adrenergics & Antiadrenergic drugs

10 Side effect of prazosin
130 saeed 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.

11 α– blockers Relatively selective 2. Terazosin & Doxazosin:
130 saeed α– blockers Relatively selective 2. 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). Adrenergics & Antiadrenergic drugs

12 α– blockers Selective Tamsolusin & Alfuzosine
130 saeed α– blockers Selective Tamsolusin & 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

13 Tamsolusin Adverse affects:
130 saeed Tamsolusin Adverse 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. Adrenergics & Antiadrenergic drugs

14 Tamsolusin Contraindications:
130 saeed 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 Adrenergics & Antiadrenergic drugs

15 Clinical Uses of adrenergic a-antagonists:
130 saeed Clinical Uses of adrenergic a-antagonists: Pheochromocytoma (phenoxybenzamine, phentolamine) with β blockers to reduce cardiac effect from increased catecholamines 2) 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)

16 treatment T1/2 Act on Name of antagonist
130 saeed treatment T1/2 Act on Name of antagonist Hypertension pheochromocytoma 3-5 hours Alpha 1 , 2 Phentolamine & tolazoline same 14-48 phenoxybenzamine Congestive heart Failure Protect against ischemic disease Raynaud phenomenon 3 Alpha 1 prazosin Urinary retention 12 terazosin 22 doxazosin Alpha 1A Tamsolusin & Alfuzosin Adrenergics & Antiadrenergic drugs

17 Adrenoreceptor Antagonists β– blockers:
130 saeed Adrenoreceptor Antagonists β– blockers: Alpha and beta blockers Relatively selective Non selective Labetalol Atenolol Propranolol carvedilol Esmolol Timolol Metoprolol Nadolol Practolol Acebutol pindolol bisoprolol More potent than atenolol Adrenergics & Antiadrenergic drugs

18 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: Has anesthetic action propranolol esmolol timolol pindolol acebutolol metabolism In liver (they cross BBB): Propranolol Pindolol timolol In kidney: nadolol Atenolol Has partial agonistic activity pindolol acebutolol labetolol esmolol

19 β– blockers Pharmacological 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 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 بالعربي يطلع NE يلقى الريسيبتور مقفلة يضطر انه يروح لـ α2

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– blockers Side 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– blockers Contraindications of β-blockers:
Bronchial asthma Peripheral vascular disease Heart failure (in severe cases only) (acute) Adrenergics & Antiadrenergic drugs

26 β– blockers Drug 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– blockers Withdrawal 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 It has no ISA
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 Adrenergics & Antiadrenergic drugs

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

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
130 saeed 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) idiopathic paroxysmal bilateral cyanosis of the digits due to arterial and arteriolar contraction; caused by cold or emotion. See Also: Raynaud phenomenon. 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 Carvedilol Beta 1,2 7-10 yes Esmolol 10 min Labetalol Yes 5 Pindolol 3-4 Propranolol 3-6 Timolol 4-5 Adrenergics & Antiadrenergic drugs

40 Migraine: Propranolol Adrenergics & Antiadrenergic drugs hypertension
atenolol Labetalol Pindolol Esmolol carvedilol Ischemic heart disease timolol Propranolol Arrhythmia practolol Heart failure Carvedilol Metoprolol Atenolol glaucoma Hyperthyroidism and anxiety propranolol Migraine: Propranolol Adrenergics & Antiadrenergic drugs

41 Centrally acting sympatholytic drugs
130 saeed Centrally acting sympatholytic drugs Adrenergics & Antiadrenergic drugs

42 Centrally acting sympatholytic drugs
130 saeed 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
130 saeed 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: Side effects include:
130 saeed 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 Hepatitis & drug fever (can be serious) Impotence
130 saeed 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. 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 Adrenergics & Antiadrenergic drugs

47 Adrenergics & Antiadrenergic drugs
130 saeed Adrenergics & Antiadrenergic drugs

48 قواعد جوهرية: All adrenergic blockers reduce BP But :
130 saeed قواعد جوهرية: All adrenergic blockers reduce BP But : 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).