1. Classification of Adrenoreceptor Antagonists
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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)
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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)
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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 alkylates the receptors & binds by methyl covalent bond. Thus, it produces irreversible α– blockade which cannot be overcome by increase of NE
t1/2 = 14 – 48 hours
Adrenergics & Antiadrenergic drugs

4. Pharmacological effects of α– blockers
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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

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Cont….
2) They produce tachycardia more than the α1 – selective blockers by
Producing reflex tachycardia.
All α blocker (selective and non selective) block α1 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 α2 cause increase NE in synapse. NE will bind to β1 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 α2 leading to ↑NE but pehnoxybenzamine block reuptake of NE leading to more NE in synap
Adrenergics & Antiadrenergic drugs

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

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

8. α– blockers Relatively selective
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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

9. 1. Prazosin Mechanism of action
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1. Prazosin Mechanism of action
It is a relatively selective α1 – adrenoceptor competitive antagonist
Its action can be overcome by increasing agonist concentration(reversible)
T1/2 = 3 hours
Adrenergics & Antiadrenergic drugs

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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

11. Heart failure In heart failure the following happens:
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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 β blockers to decrease HR and contractility and inhibit renin release.

12. Side effect of prazosin
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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.

13. α– blockers Relatively selective 2. Terazosin & Doxazosin:
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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) in which prostate compresses the urethra & prevent micturition.
Adrenergics & Antiadrenergic drugs

14. α– blockers Selective Tamsolusin & Alfuzosine
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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

15. Tamsolusin Adverse affects:
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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

16. Tamsolusin Contraindications:
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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
Adrenergics & Antiadrenergic drugs

17. Clinical Uses of adrenergic a-antagonists:
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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)

18. treatment T1/2 Act on Name of antagonist
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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
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

19. Adrenoreceptor Antagonists β– blockers:
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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

20. 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

21. 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

22. 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

23. 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 ↓ intraocular pressure (IOP)
Block β2 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
Adrenergics & Antiadrenergic drugs

24. 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. 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
Adrenergics & Antiadrenergic drugs

25. 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

26. 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
Some β 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
Adrenergics & Antiadrenergic drugs

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

28. 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

29. 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

30. 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

31. Cont….
It is excreted in urine as Propranolol or as Glucouronide conjugate
It’s 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
Adrenergics & Antiadrenergic drugs

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

33. 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

34. 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 block α1 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 α blockers
It is used in Pheochromocytoma and hypertension of pregnancy
Adrenergics & Antiadrenergic drugs

35. Cont…. Adverse effects include: Nausea skin rash tiredness
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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 β blockers)
Postural hypotension (because it is selective α1 blocker)
Raynaud syndrome (peripheral vasospasm)
It is intermittent claudication or peripheral vascular disease
It is due to decreased blood supply to the periphary by β blockers due to
Bradycardia
Block β 2 in blood vessels to skeletal muscle causing VC and decrease blood supply
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

36. 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

37. 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 can neutralize (scavenge) the free radicals which cause heart failure
It used in renal impairment
Because it improves kidney function. So, it’s used in patients with Renal impairment
Adrenergics & Antiadrenergic drugs

38. 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

39. 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

40. 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

41. 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

42. 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

43. Centrally acting sympatholytic drugs
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Centrally acting sympatholytic drugs
Adrenergics & Antiadrenergic drugs

44. 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:
α-methyldopa
Clonidine
Adrenergics & Antiadrenergic drugs

45. α– methyldopa Mechanism of action
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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 then It will decrease the sympathetic tone to blood vessels (VD)  ↓BP
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

46. Cont…. Clinical uses: Side effects include:
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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 it’s therapeutic use
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

47. Cont…. Lactation Hepatitis & drug fever (can be serious) Impotence
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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
Adrenergics & Antiadrenergic drugs

48. 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

49. Adrenergics & Antiadrenergic drugs
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Adrenergics & Antiadrenergic drugs

50. قواعد جوهرية: All adrenergic blockers reduce BP But :
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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).