Sympatholytics

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Antiadrenergic Drugs

(Adrenergic Receptor
Antagonists,
Sympatholytics)

By K. Hari Kamesh Kiran


Sympatholytics
These are drugs which antagonize the receptor
action of adrenaline and related drugs.

They are competitive antagonists at α or β or both


α and β adrenergic receptors
α ADRENERGIC BLOCKING DRUGS -
I. Nonequilibrium type
(i) β-Haloalkylamines—Phenoxybenzamine.
II. Equilibrium type (competitive)
A. Nonselective
(i) Ergot alkaloids—Ergotamine, Ergotoxine
(ii) Hydrogenated ergot alkaloids—
Dihydroergotamine (DHE), Dihydroergotoxine
(iii) Imidazoline—Phentolamine
(iv) Miscellaneous–Chlorpromazine
Cont…
B. α1 selective—Prazosin, Terazosin, Doxazosin,
Alfuzosin, Tamsulosin
C. α2 selective—Yohimbine
GENERAL EFFECTS OF α BLOCKERS
1. Blockade of vasoconstrictor α1 (also α2)
receptors reduces peripheral resistance

venous return and cardiac output are reduced

fall in BP.

Postural hypotension

dizziness and syncope.


Cont…
The α blockers abolish the pressor action of
Adr which then produces only fall in BP due to
β2 mediated vasodilatation.(vasomotor reversal
of Dale).
2. Reflex tachycardia occurs due to fall in
mean arterial pressure and increased release of
NA due to blockade of presynaptic α2 receptors.
3. Nasal stuffiness and miosis result from
blockade of α receptors.
4. Intestinal motility is increased
Cont…
5. Hypotension produced by α blockers can
reduce renal blood flow → g.f.r. is reduced
6. Tone of smooth muscle in bladder trigone,
sphincter and prostate is reduced by blockade of
α1 receptors, urine flow in patients increases.
7. Contractions of vas deferens and related organs
which result in ejaculation are coordinated through
α receptors—α blockers can inhibit ejaculation.
The α blockers have no effect on adrenergic
cardiac stimulation, bronchodilatation,
vasodilatation
Phenoxybenzamine
The α blockade is of nonequilibrium (irreversible) type
and develops gradually, lasts for 3–4 days till fresh
receptors are synthesized.
The fall in BP caused by phenoxybenzamine is mainly
postural because venodilatation is more prominent
than arteriolar dilatation.
Pharmacokinetics: Phenoxybenzamine Oral
absorption is incomplete; i.m. and s.c. injections are
very painful
It is lipid soluble, penetrates brain, most of it is
excreted in urine in 24 hours,.
Chronic administration leads to accumulation in
adipose tissue.
Adverse effects:
Phenoxybenzamine is lipid soluble, penetrates
brain and
Rapid i.v. injection can produce CNS stimulation,
nausea and vomiting on.
Oral doses produce depression, tiredness and
lethargy.
Major side effects are postural hypotension,
palpitation, nasal blockage, miosis, inhibition of
ejaculation.
Dose: 20–60 mg/day oral;
Natural and hydrogenated ergot alkaloids
Ergot alkaloids are the adrenergic antagonists with
which Dale demonstrated the vasomotor reversal
phenomenon.
The amino acid alkaloids ergotamine and ergotoxine
are partial agonists and antagonists at α adrenergic,
serotonergic and dopaminergic receptors.
Ergometrine has no α blocking activity.
The natural ergot alkaloids produce long lasting
vasoconstriction —peripheral vascular insufficiency and
gangrene of toes and fingers occurs in ergotism.
Cont…
Ergotoxine is a more potent α blocker and less
potent vasoconstrictor than ergotamine.
used in migraine
Dihydroergotoxine has been used as a cognition
enhancer.
Phentolamine
This is a rapidly acting α blocker with short
duration of action(blocks α1 and α2 receptors)
It is used as a quick and short acting α blocker for
diagnosis and intraoperative management of
pheochromocytoma & control of hypertension due
to clonidine withdrawal, cheese reaction, etc.
Dose: 5 mg i.v. repeated as required;
Chlorpromazine
Chlorpromazine and some other neuroleptics have
significant α adrenergic blocking activity—cause fall
in BP, nasal stuffiness and inhibition of ejaculation
as side effect.
Prazosin
It is first of the highly selective α1 blockers having α1
: α2 selectivity ratio 1000:1. All subtypes of α1 receptor
(α1A, α1B, α1D) are blocked equally.
It blocks sympathetically mediated vasoconstriction
and produces fall in BP.
Prazosin dilates arterioles more than veins.
ADR: Postural hypotension is less marked, may cause
dizziness and fainting as ‘first dose effect’.
Should start with a low dose and taking it at bedtime.
Causes miosis, nasal stuffiness, inhibition of
ejaculation
Pharmacokinetics:
Prazosin is effective orally,
highly bound to plasma proteins
metabolized in liver and excreted primarily in
bile.
Its plasma t½ is 2– 3 hours; effect of a single dose
lasts for 6–8 hours.
Uses: antihypertensive, Raynaud’s disease and
benign hypertrophy of prostate
Terazosin
pharmacologically similar to prazosin;
Pharmacokinetics:
bioavailability (90%) and longer plasma t½ (~12 hr); a
single daily dose lowers BP over 24 hrs.
Uses: benign hypertrophy of prostate(apoptosis
promoting effect)
Dose: usual maintenance dose 2–10 mg OD.
Doxazosin Another long acting (t½ 18 hr) congener of
prazosin
Uses: Has apoptosis promoting effect on prostate.
Dose: 1 mg OD initially, increase upto 8 mg BD;
Alfuzosin
This short acting (t½ 3–5 hours) congener of
prazosin.
Use: benign hypertrophy of prostate
The metabolism of alfuzosin is inhibited by
CYP34A inhibitors.
Interactions: Concurrent treatment with
erythromycin, ketoconazole, ritonavir etc. is to be
avoided.
Dose: 2.5 mg BD-QID or 10 mg as extended release
(ER) tablet.
Tamsulosin
This relatively uroselective α1A/ α1D blocker.
 Its plasma t½ is 6–9 hrs.
Use: benign hypertrophy of prostate
 However, it lacks the prostatic apoptosis
promoting property.
 ADR: Postural hypotension is infrequent, dizziness
and retrograde ejaculation are the only significant
side effects.
Dose: DYNAPRES 0.2, 0.4 mg MR cap;
Yohimbine
An alkaloid from the West African plant
Yohimbehe.
It is selective α2 blocker with short duration of
action. Also blocks 5-HT receptors.
 Heart rate and BP are generally elevated due to
increased central sympathetic outflow as well as
enhanced peripheral NA release.
ADR: excitation, tremor, ADH release
(antidiuresis), nausea and vomiting. may cause
congestion in genitals.
USES OF α BLOCKERS
1. Pheochromocytoma: It is a tumour of adrenal
medullary cells. Excess CAs are secreted which can
cause intermittent or persistent hypertension.
2. Hypertension
3. Benign hypertrophy of prostate (BHP)
4. Secondary shock
5. Peripheral vascular diseases
6. Congestive heart failure (CHF)
7. Papaverine/Phentolamine Induced Penile
Erection (PIPE) therapy for impotence
β-ADRENERGIC BLOCKING DRUGS

These drugs inhibit adrenergic responses mediated


through the β receptors.
All β blockers are competitive antagonists.
Propranolol blocks β1 and β2 receptors, but has
weak activity on β3 subtype.
β blockers like metoprolol, atenolol, etc.
preferentially block β1 receptors
CLASSIFICATION
Nonselective (β1 and β2)
a. Without intrinsic sympathomimetic activity
Propranolol, Sotalol, Timolol.
b. With intrinsic sympathomimetic activity
Pindolol
c. With additional α blocking property
Labetalol, Carvedilol
Cardioselective (β1) Metoprolol, Atenolol,
Acebutolol, Bisoprolol, Esmolol, Betaxolol,
Celiprolol, Nebivolol
Another system classifies β blockers into 3 generations

First Second Third


generation generation generation

Propranolol Metoprolol Labetalol


Timolol Atenolol Carvedilol
Sotalol Acebutolol Celiprolol
Pindolol Bisoprolol Nebivolol
Esmolol Betaxolol
PHARMACOLOGICAL ACTIONS
1. CVS
(a) Heart: Propranolol decreases heart rate, force of
contraction and cardiac output. BP falls.
Cardiac work and oxygen consumption are reduced as
the product of heart rate and aortic pressure
decreases.
Total coronary flow is reduced (blockade of dilator β
receptors)
 The A-V conduction is delayed.
Myocardial oxygen requirement is reduced due to
reduced cardiac work
(b)Blood vessels
Propranolol blocks vasodilatation and fall in BP
evoked by isoprenaline and enhances the rise in BP
caused by Adr.
Vasomotor reversal is seen after a blockade.
 Propranolol has no direct effect on blood vessels
& there is little acute change in BP.
On prolonged administration BP gradually falls in
hypertensive subjects but not in normotensives.
Decreased renin release from kidney, Propranolol
causes a more marked fall in BP in hypertensives
2. Respiratory tract
Propranolol increases bronchial resistance by
blocking dilator β2 receptors. Causes asthma.
3. CNS No overt central effects are produced by
propranolol.
Causes behavioural changes, forgetfulness,
increased dreaming and nightmares with long-term
use & High doses.
4. Local anaesthetic Propranolol is as potent a
local anaesthetic as lidocaine, but is not clinically
used for this purpose because it causes irritation at
the injected site.
5. Metabolic
Propranolol blocks adrenergically induced lipolysis
and consequent increase in plasma free fatty acid
levels.
It also inhibits glycogenolysis in heart, skeletal
muscles and in liver
6. Skeletal muscle Propranolol inhibits
adrenergically provoked tremor.
It tends to reduce exercise capacity by
attenuating β2 mediated increase in blood flow to
the exercising muscles, & by limiting glycogenolysis
and lipolysis
7. Eye
Reduces secretion of aqueous humor, i.o.t. is
lowered.
8. Uterus Relaxation of uterus in response to
isoprenaline.
PHARMACOKINETICS
Propranolol is well absorbed orally.
Has low bioavailability due to high first pass
metabolism in liver.
Propranolol is lipophilic and penetrates into brain
Chronic use of propranolol itself decreases
hepatic blood flow: its own oral bioavailability is
increased and its t½ is prolonged.
hydroxylated product of it has β blocking activity.
excreted in urine, mostly as glucuronides.
Dose: Oral—10 mg BD to 160 mg QID
INTERACTIONS
 Additive depression of sinus node and A-V
conduction with digitalis and verapamil
Delays recovery from hypoglycaemia due to insulin
and oral antidiabetics.
Phenylephrine, ephedrine and other α agonists
can cause marked rise in BP.
Indomethacin and other NSAIDs reduce the
antihypertensive action of β blockers.
Cimetidine inhibits propranolol metabolism.
ADVERSE EFFECTS
Propranolol can accentuate myocardial insufficiency
and can precipitate CHF/edema by blocking
sympathetic support to the heart.
 Bradycardia
Cold extremities
Worsens chronic obstructive lung disease & asthma
Carbohydrate tolerance may be impaired in
prediabetics.
Total triglycerides and LDL-cholesterol tend to
increase while HDL-cholesterol falls.
Cardioselectivity
Cardioselectivity in metoprolol, atenolol,
acebutolol, bisoprolol, nebivolol.
These drugs are more potent in blocking cardiac
(β1) than bronchial (β2) receptors.
Contraindications
Propranolol is contraindicated in partial and
complete heart block.
Hypotension
Bradycardia
Heart block
Asthma
 COPD
Membrane stabilizing activity
In propranolol, oxprenolol, acebutolol, This
activity leads to antiarrhythmic action.
Lipid insolubility (atenolol, celiprolol, bisoprolol,
sotalol) less likely to produce sleep disturbances
and nightmares.
They are incompletely absorbed orally, but do not
undergo first pass metabolism and are primarily
excreted unchanged in urine: are longer acting (t½
6–20 hours)
1. Sotalol
Nonselective β blocker with low lipid solubility.
It has K+ channel blocking and class III antiarrhythmic
property.
2. Timolol It is topically used in eye for glaucoma.
used in hypertension, angina and prophylaxis of myocardial
infarction.
Betaxolol, Levobunolol, Cartiolol and Metipranolol are β
blockers employed exclusively for topical application to
the eye
3. Pindolol A potent β blocker with prominent intrinsic
sympathomimetic activity.
used primarily as antihypertensive
Dose: PINADOL 5 mg tab
4. Metoprolol
 It is the prototype of cardioselective (β1) blockers
 It is less likely to worsen asthma, but is not entirely
safe.
Firstpass metabolism of metoprolol is less marked
than propranolol, but 90% or more is hydroxylated by
CYP2D6.
 Uses: Hypertension, angina and CHF,
Buti.v. injection (5–15 mg) has been used in
myocardial infarction provided bradycardia is absent.
Dose: 12.5–50 mg OD–BD.
5. Atenolol
Selective β1 blocker having low lipid solubility.
It is incompletely absorbed orally, but first pass
metabolism is not significant.
It is one of the most commonly used β blockers for
hypertension and angina.
Dose: 12.5–50 mg OD;
6. Acebutolol cardioselective agent with significant
partial agonistic and membrane stabilizing properties.
It is rapidly metabolized to an active metabolite
diacetolol which is primarily excreted by kidney and
has a longer t½ (8–12 hours).
7. Esmolol
 It is an ultrashort acting β1 blocker
 It is inactivated by esterases in blood;
plasma t½ is < 10 min;
 Rapid onset, short lasting fall in BP attends i.v.
infusion of esmolol
A loading dose of 0.5 mg/kg is given followed by 0.05–
0.2 mg/kg/min infusion
Used to terminate supraventricular tachycardia,
episodic atrial fibrillation or flutter, arrhythmia during
anaesthesia, to reduce HR and BP during and after
cardiac surgery, and in early treatment of myocardial
infarction.
8. Bisoprolol
A cardioselective β blocker lacking intrinsic
sympathomimetic activity.
Used in hypertension and CHF
9. Celiprolol
It is a selective β1 blocker having additional weak
β2 agonistic activity which reduces vascular
resistance and holds promise of safety in
asthmatics.
Dose: 200–600 mg OD
10. Nebivolol
This highly selective β1 blocker also acts as a NO
donor, produces vasodilatation.
It has the potential to improve endothelial
function, which may delay atherosclerosis.
It has been used in hypertension and CHF.
Dose: 5 mg (elderly 2.5 mg) OD;
USES
1. Hypertension β blockers are relatively mild
antihypertensives.
2. Angina pectoris 10. Anxiety
3. Cardiac arrhythmias 11. Essential tremor
4. Myocardial infarction 12. Glaucoma
5. Congestive heart failure
6. Dissecting aortic aneurysm
7. Pheochromocytoma
8. Thyrotoxicosis 13. Hypertrophic
9. Migraine obstructive cardiomyopathy
α + β ADRENERGIC BLOCKERS
Labetalol It is the first adrenergic antagonist
capable of blocking both α and β receptors.
There are 4 diastereomers of labetalol, each of
which has a distinct profile of action on subtypes of
α and β receptors.
Commercial preparation has equal parts of each
diastereomer and displays β1 + β2 + α1 blocking as
well as weak β2 agonistic activity.
Labetalol is 5 times more potent in blocking β
than α receptors.
Cont…
High doses reduce both c.o. and t.p.r.
Heart rate is unchanged or slightly decreased.
It has also been shown to inhibit NA uptake.
Pharmacokinetics
Labetalol is orally effective
but undergoes first pass metabolism.
Uses: potent hypotensive and useful in
pheochromocytoma
ADR
postural hypotension,
Failure of ejaculation
Rashes and liver damage have been reported.
Dose: Start with 50 mg BD, increase to 100–200
mg TDS
Carvedilol
It is a β1 + β2 + α1 adrenoceptor blocker;
produces vasodilatation due to α1 blockade as well as
calcium channel blockade,
It has antioxidant property.
It has been used in hypertension, used as as
cardioprotective in CHF.
PK: Oral bioavailability of carvedilol is 30%.
It has a t½ of 6–8 hrs.
CHF Dose: Start with 3.125 mg BD for 2 weeks, if
well tolerated gradually increase to max. of 25 mg BD.
Hypertension/angina: 6.25 mg BD initially, titrate to
max. of 25 mg BD.
Thank You

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