Download Adrenergic_antagonists

Classification of
Adrenoreceptor Antagonists

α– blockers
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β– blockers
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Non selective
Relatively selective
Selective
Non selective
Relatively selective
Selective
Both α and β adrenergic antagonists
Adrenergics &
Antiadrenergic drugs
1
α– Adrenoceptor Antagonists
(α– blockers)
‫يؤثر على واحدة واذا‬
‫زدنا الجرعة فانه يؤثر‬
‫على األخرى‬
Non selective
Relatively
selective
selective
phenoxybenzamine
prazosin
tamsolusin
phentolamine
terazosin
alfuzosin
tolazoline
doxazosin
Adrenergics &
Antiadrenergic drugs
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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
3
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:

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Tachycardia (Reflex Type)
Cardiac arrhythmia
Angina pectoris
Peptic ulcer
Sexual dysfunction
4
Cont….

2) They produce tachycardia more than the α1 – selective blockers by

Producing reflex tachycardia.
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Increase HR by
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
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
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.
Adrenergics &
Antiadrenergic drugs
So both drugs block α2
leading to ↑NE but
pehnoxybenzamine block
reuptake of NE leading to
more NE in synap
5
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)
Side effects of Phenoxybenzamine
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Fatigue
Nausea (because it enters CNS)
Diarrhea
Postural hypotension.
Tachycardia.
Adrenergics &
Antiadrenergic drugs
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α– blockers
Relatively selective
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
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Prazosin
Terazosin
Doxazosin
Adrenergics &
Antiadrenergic drugs
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1. Prazosin
Mechanism of action


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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:

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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
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In heart failure the following happens:
1. Decreased C.O leads to sympathetic stimulation.
2. 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.
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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 nonselective.
α– blockers
Relatively selective
2. Terazosin & Doxazosin:

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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
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α– blockers
Selective
Tamsolusin & Alfuzosine
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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
14
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
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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
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Clinical Uses of adrenergic aantagonists:
1) 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)
Name of
antagonist
Act on
T1/2
treatment
Phentolamine &
tolazoline
Alpha 1 , 2
3-5 hours
Hypertension
pheochromocytoma
phenoxybenzamine
Alpha 1 , 2
14-48
same
prazosin
Alpha 1
3
Hypertension
Congestive heart
Failure
Protect against
ischemic disease
Raynaud phenomenon
terazosin
Alpha 1
12
Hypertension
Urinary retention
doxazosin
Alpha 1
22
same
Tamsolusin &
Alfuzosin
Alpha 1A
Adrenergics &
Antiadrenergic drugs
Urinary retention
18
Adrenoreceptor Antagonists
β– blockers:
Non selective
Relatively
selective
Alpha and beta
blockers
Propranolol
Atenolol
Labetalol
Timolol
Esmolol
carvedilol
Nadolol
Metoprolol
Labetalol
Practolol
pindolol
Acebutol
bisoprolol
More potent
than atenolol
Adrenergics &
Antiadrenergic drugs
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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:
metabolism
Has anesthetic
action
In liver (they cross BBB):
Propranolol
Pindolol
timolol
In kidney:
Atenolol
nadolol
propranolol
Has partial
agonistic
activity
pindolol
acebutolol
labetolol
esmolol
esmolol
timolol
pindolol
acebutolol
β– blockers
Pharmacological actions:

CVS

Angiotensin normally
induces the release
of NE from
postganglionic
sympathetic fibers
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


‫بالعربي يطلع‬
‫يلقى‬NE
‫الريسيبتور مقفلة‬
‫يضطر انه يروح‬
2α ‫لـ‬



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
Cont….
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The respiratory system
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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
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Cont….
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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
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Cont….
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Metabolic and endocrine effects
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
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
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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

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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
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Cont….
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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
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β– blockers
Side effects of β blockers

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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
work load & O2 consumption on the )see slide 11)
myocardium
Adrenergics &
Antiadrenergic drugs
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β– blockers
Contraindications of β-blockers:
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Bronchial asthma
Peripheral vascular disease
Heart failure (in severe cases only)
(acute)
Adrenergics &
Antiadrenergic drugs
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β– blockers
Drug interactions:


Verapamil (Ca++ ) channel blocker
If it is combined with β – blockers, this
can cause :

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Congestive heart failure
Severe bradycardia
Severe hypotension
Adrenergics &
Antiadrenergic drugs
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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
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β– blockers
Propranolol
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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
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Cont….
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It is excreted in urine as Propranolol or as
Glucouronide conjugate
It’s duration of action is increased in

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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
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Side effect of propranolol
Bradycardia
Cold extremities
Fatigue
Sedation
Mental depression
Sleep disturbances
Heart failure
A – V block
Bronchospasm
Impotence
32
β– blockers
Timolol:
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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
33
β– blockers
Labetalol:
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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
34
Cont….

Adverse effects include:

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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
Adrenergics &
Antiadrenergic drugs
35
β– blockers
Pindolol:

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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
36
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
37
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




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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
38
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
39
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
40
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
Adrenergics &
Antiadrenergic drugs
41
hypertension
• atenolol
• Labetalol
• Pindolol
• Esmolol
• carvedilol
Ischemic heart
disease
Arrhythmia
• timolol
• Propranolol
• Propranolol
• Esmolol
• practolol
Heart failure
• Carvedilol
• Metoprolol
• Atenolol
glaucoma
• timolol
Hyperthyroidism
and anxiety
• propranolol
Migraine:
•Propranolol
Adrenergics &
Antiadrenergic drugs
42
Centrally acting sympatholytic
drugs
Adrenergics &
Antiadrenergic drugs
43
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
44
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
45
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


Lead to increase ECF and increase in BP slightly
This negates it’s therapeutic use
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
46
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
47
Clonidine:

Already mentioned in α2 agonist.
Alfa – methydopa
Clonidine
Route of
administration
I.V , orally
I.V , orally, I.M
t1/2
2–4h
5–7h
Dose
800 – 1200mg total / dose/day 125 – 250 ug/day
Metabolism
To give alfa – methyl NE, then
conjugated in urine and some
of it secrete in faeces
Adrenergics &
Antiadrenergic drugs
To give inactive form and secreted in
the urine after conjugation
48
Adrenergics &
Antiadrenergic drugs
49
:‫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).