Anti-Cholinergics (Cholinergic blockers)

By Akeberegn G 1
Introduction

By Akeberegn G 2
 Introduction
Muscarinic antagonists are sometimes called para sympatholytic (anti
muscarinic)
- reduce the effects of ACh by competitively inhibiting its binding to
muscarinic cholinergic receptors
- Has lesser effect on the nicotinic receptors.
-But Naturally occurring compounds have also effect on the nicotinic
receptor
 Atropine is the prototype of these drugs.
Based on their structure classified in to 2
Tertiary: Atropine, Scopalamine, Dicyclomine, Tropicamide, Benztropine, Pirenzipine)
Quaternary: Ipratropium, Propentheline, Glycopyrolate

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 Introduction…..
Atropine (hyoscyamine) is found in the plants
 Atropa belladonna,
 Datura stramonium,

Where as Scopolamine (hyoscine) occurs in

Hyoscyamus niger, or henbane

The structure of atropine (oxygen [red] at [1] is missing) or scopolamine (oxygen present).

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 Introduction…..
The effectiveness of anti muscarinic drugs varies depending up on
 The type tissue which they acts on (e.g salivary, bronchial, and
sweat glands ) are the most sensitive to atropine where as gastric
parietal cells is least sensitive

The source of the agonist where they will block.

• In most tissues, anti muscarinic agents block exogenously administered
cholinoceptor agonists more effectively than endogenously released
acetylcholine.

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 Introduction…..
Pharmacokinetic Profiles

 Absorption : Natural alkaloids and most tertiary anti muscarinic drugs are
well absorbed from the gut and conjunctival membranes.
 In contrast, only 10–30% of a dose of a quaternary anti muscarinic drug is absorbed after
oral administration,

Distributions : tertiary agents are widely distributed in the body.

Significant levels are achieved in the CNS within 30 minutes to 1 hour,

- limit the dose tolerated when the drug is taken for its peripheral
effects.
 In contrast, the quaternary derivatives are poorly taken up by the brain

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Pharmacokinetic profiles

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 Pharmacokinetic profiles…..

Metabolism and excretions:. About 50% of the dose is excreted

unchanged in the urine. The drug’s effect on parasympathetic function

declines rapidly in all organs except the eye ( persists for ≥ 72 hours).
Pharmacodynamics
 Atropine causes reversible (surmountable) blockade of cholinomimetic

actions at muscarinic receptors

(can be reversed by larger concentration of acetylcholine or equivalent

muscarinic agonist).

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 Pharmacodynamics….

Receptor selectivity
Atropine has equal effect on (M1=M2=M3)
The following anti muscarinic agents are more selective for each of
receptors
For M1=Pirenzepine, telenzepine, dicyclomine, trihexyphenidyl
M2= Gallamine, methoctramine
M3 = Darifenacin, solifenacin, oxybutynin, tolterodine
Most synthetic antimuscarinic drugs are considerably less selective than
atropine in interactions with non muscarinic receptors.
-some quaternary amine muscarinic agents have significant ganglion-
blocking actions, and others are potent histamine receptor blockers.
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 Organ System Effects

Central nervous system : ( Scopolamine > >Atropine ) in producing

drowsiness when given in recommended dosages and amnesia in sensitive
individuals.
• In toxic doses, scopolamine, and to a lesser degree atropine, can cause excitement,
agitation, hallucinations, and coma.
 Eye : produce the following effects on the eye
Mydriasis (dilations of the pupil)
Cycloplegia (weaken contraction of the ciliary muscle ) results in loss of the
ability to accommodate (cannot focus on near vision)
reduce lacrimal secretion. Patients occasionally complain of dry or “sandy”
eyes when receiving large doses of anti muscarinic drugs.
Cardiovascular system : Moderate to high therapeutic doses of atropine
cause tachycardia but lower doses often result in initial bradycardia.
 Constricts the coronary arteries
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 Organ System Effects
Respiratory system :
 Both smooth muscle and secretory glands of the airway
receive vagal innervation and contain muscarinic receptors.
 the effects of anti muscarinic agents reduce secretion and
result in Broncho dilations.
Gastrointestinal tract :
 Blockade of muscarinic receptors decreases motility and
some of the secretory functions of the gut. They results in
 Xerostomia (dry mouth)
 Reduce acid secretions ( such as pepsin, and mucin )

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 Organ System Effects

Genitourinary tract :
The anti muscarinic action of atropine and its analogs relaxes
smooth muscle of the ureters and bladder wall and slows
voiding.
useful in the treatment of spasm induced by mild
inflammation, surgery, and certain neurologic conditions
Sweat Glands
Suppresses thermoregulatory sweating because cholinergic
fibers innervate eccrine sweat glands, and their muscarinic
receptors are readily accessible to antimuscarinic drugs

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 Therapeutic Applications

The anti muscarinic drugs have applications in several of the major organ systems
 CNS
 Parkinson’s disease : is associated in increasing the cholinergic transmission.
 Motion sickness : Certain vestibular disorders respond to anti muscarinic drugs (and
to antihistaminic agents with anti muscarinic effects).
Scopolamine is one of the oldest remedies for seasickness.
Ophthalmologic Disorders
 ophthalmoscopic examination e.g mydriasis greatly facilitates examination of the
retina
- glycopyrrolate is better than atopine in penetrating as well as in its longer
duration of action at conjunctiva.
 prevent synechia (adhesion) formation in uveitis and iritis

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 Therapeutic Applications…

Respiratory Disorders :
Atropine and scopolamine decreases an increased airway
secretions which is associated with laryngospasm is caused
by irritant anesthetics…..used in pre anesthetics cases.
COPD : Ipratropium, tiotropium (t1/2 =25 hours), aclidinium
(t1/2=6 hours) , and umeclidinium (t1/2 =11 hours) are used.
Cardiovascular Disorders :
For pain of myocardial infarction (eg, vasovagal
attack)

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 Therapeutic Applications…

 Gastrointestinal Disorders
 PUD and for travelers diarrhea (Atropine can be used in combination with
diphenoxylate ).
Urinary Disorders
 symptomatic relief in the treatment of urinary urgency.
Oxybutynin = to relieve bladder spasm after urologic surgery and to reduce
involuntary voiding.
Others used for this setting (Trospium, Darifenacin and solifenacin)
Cholinergic Poisoning (Antimuscarinic therapy and Cholinesterase
regenerator compounds).
 Severe cholinergic excess due to insecticides and nerve gases” be treaded
with anti cholinergic.

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 Contraindications…
 glaucoma, especially angle-closure

 Anti muscarinic drugs slow gastric emptying, they may increase symptoms
in patients with gastric ulcer.

 Anti muscarinic drugs should always be used with caution and should be
avoided in those with a history of prostatic hyperplasia

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 Ganglion-blocking drugs ….

 Ganglion-blocking agents competitively block the action of acetylcholine

and similar agonists at neuronal nicotinic receptors of both
parasympathetic and sympathetic autonomic ganglia.
 they lack selectivity

 General classifications relates to the duration of drug action

 long- D-tubocurarine, metocurine, pancuronium, and doxacurium

 Intermediate - vecuronium and atracurium

 short-acting - mivacurium
 In terms of potency: long > intermediate > short acting
 in terms of onset: short > intermediate
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G long 17
 GANGLION-BLOCKING DRUGS…

 Based on their mechanism of action can be classified

as
I. Depolarizing Blockers
II. Non-Depolarizing Blockers

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 Depolarizing Blockers

 Produce a two phased block (same mechanism of

block as nicotine )
 Phase I: Depolarization block
 Phase II: Desensitization block

Drugs include :Decamethonium Succinylcholine

 Succinylcholine is the only therapeutically useful

drug in this group.
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 Succinylcholine

 Acts at NMJ and has little effect at autonomic ganglia or muscarinic junctions.
 Does not cross the BBB and placental barrier.
 It causes release of histamine from mast cells.
 The principal advantage of succinylcholine is its rapid onset and ultra-short
action.
- produces flaccid paralysis in less than 1 minute and lasts about 10 minutes.
 Suitable for short term procedures such as endotracheal intubation, setting of
fractures, and prevention of injury.

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 Non-Depolarizing Blockers
 Tubocurarine is the prototype drug in this group.

 Others include
 Atracurium,

 Mivacurium,
 Vecuronium,
 Rocuronium,

 Rapacuronium

 Are all reversible antagonists of Ach at NMJ

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Adrenoceptor Agonists & Sympathomimetic
Drugs
Drugs that mimic the actions of epinephrine or norepinephrine is termed
sympathomimetic drugs.
Classified in to three.
Direct agonists; they directly interact with and activate adrenoceptors.
Indirect agonists because their actions are dependent on their ability to enhance
the actions of endogenous catecholamines by
 Inducing the release of catecholamines by displacing them from adrenergic nerve
endings (eg, the mechanism of action of tyramine and amphetamine),
 Decreasing the clearance of catecholamines by inhibiting their neuronal reuptake
(eg, the mechanism of action of cocaine and tricyclic antidepressants), or
 Preventing the enzymatic metabolism of norepinephrine (monoamine oxidase
and catechol-O-methyltransferase inhibitors).
Some drugs have both direct and indirect actions.

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By Akeberegn G 23
 Adrenergic agonists
 Classified based on chemistry as:
 catecholamines
 non- catecholamines
 catecholamines:
– Naturally occurring:-Norepinephrine epinephrine and Dopamine
– Synthetic : - Isoproterenol (isopropyl norepinephrine)
 They have the following characteristics:
 High potency
 Rapid enzymatic inactivation by MAO & COMT as well as neuronal &
non-neuronal uptake
 Therefore, they have short duration when given parenterally and are
inactive orally
 Poor ability to pass the CNS
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 B. Non-catecholamines

 Non-catecholamines are adrenergic agonists lacking

the catechol hydroxyl groups
 They are not inactivated by COMT
Therefore, they have of longer duration,
 Can be given orally
 They include
• phenylephrine
• ephedrine
• terbutaline, and amphetamine

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Adrenergic receptors

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 Nonselective(alpha and beta) Adrenergic Agonists

 Act nonselectively both at alpha and beta receptors

-Epinephrine
-Dopamine
A. Epinephrine/Adrenaline
 Potent stimulant of α and β receptors
 Actions on target organs
 Blood Pressure
– Most potent vasopressor known – Both systolic and Diastolic BP rise
 Heart
– Direct myocardial stimulation- +ve inotropic
– Increased heart rate -+ve chronotropic
– Increased conduction- +ve dromotropic

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 Epinephrine ---
 Blood vessels
– Vasoconstriction in skin and mucus membranes – α effect
– Vasodilation in skeletal muscles- (β-2 effect)
• Counterbalanced
– Vasoconstriction which leads to increased peripheral resistance
– Reflex Bradycardia
 Respiratory
• Powerful bronchodilator(β-2 mediated effect)
• Nasal dcongestion (alpha1 mediated effect)
• Inhibition of antigen-mediated production of inflammatory
mediators(β-2 mediated effect)

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 Epinephrine ---
 Smooth Muscles
• Relaxation of GIT and Urinary tract smooth muscle
are( but are clinically not important)
• In the pregnant uterus there is inhibition of tone and
contractions
– β2-adrenoceptors agonists used to delay premature labor
 Metabolic effects
• Increases concentration of glucose(hyperglycemia)
– Increase Hepatic & Skeletal Muscle Glycogenolysis
– Decreases uptake of glucose by peripheral tissue
• Increases free fatty acid concentration in blood(Lipolysis)

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 Epinephrine --
Pharmacokinetics
• Ineffective orally
• Absorbed slowly from subcutaneous tissue
• Faster from IM site
• Inhalation is locally effective
• Not usually given IV
• Rapidly inactivated in Liver by MAO

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 Epinephrine --
Clinical uses
– Drug of choice for allergic reactions(Including Anaphylactic shock)
– Prolong action of local anesthetics
– Broncho spasm
– Cardiogenic arrest
– topical hemostatic agent- control of local hemorrhage
-open angle glaucoma- promotes an increase in the outflow of
aqueous humor
Adverse effects
• Cerebral hemorrhage
• Cardiac arrhythmias
• Rapid heart rate By Akeberegn G 31
 B. Norepinephrine
 Pharmacological effects differ with Epinephrine
in ratio of their effectiveness in stimulating  &
2 receptors

 Epinephrine and NE are equipotent at 1

 NE is potent at  & has little action on 2

 NE is less potent than Epinephrine on most 

receptors By Akeberegn G 32
 C. Dopamine

 Neurotransmitter in the brain.

 Precursor in the synthesis of NE
 Stimulates dopaminergic, beta-1 and alpha-receptors.
 Use as a drug
 Dopamine exerts its cardiovascular actions by
1. Releasing NE from adrenergic neurons
2. Interacting with -and -ARs
3. Interacting with specific dopamine receptors

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 Dopamine---

Dose dependent Effect of Dopamine

DOPAMINE RECEPTORS EFFECTS

DOSE STIMULATED

Low dose Stimulate dopaminergic Increased renal blood flow

(D1) receptors in the renal (vasodilatation).
blood vessels.

Moderate dose Stimulates beta-1 receptors Increase myocardial

in the heart. contractility.

Higher dose Stimulate alpha-receptors Produces vasoconstriction.

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 Dopamine---
 Clinical use
 Treatment of severe congestive failure

 Treatment of cardiogenic and septic shock

 Adverse effect:

 tachycardia, anginal pain, headache, hypertension, and peripheral

vasoconstriction.

 Contraindicated or used at a much reduced dosage if patient has received

a MAO inhibitor. Careful adjustment of dosage also is necessary in
patients who are taking tricyclic antidepressants.

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 Non selective(alpha1 and alpha2) agonists

 Drugs which directly activate both alpha 1 and alpha2

Receptors.
 Drugs include
– Xylometazoline
– oxymetazoline
 Use- Topical decongestants because of their ability to
promote constriction of the nasal mucosa.
Adverse effect:
• oxymetazoline may cause hypotension (large doses)-may
be due to α2 agonist effect 36

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 Selective α1-Adrenergic Agonists
 Include: Phenylephrine, mephentermine,
Phenylephrine
• selective α1 receptor agonist
• Increase total peripheral resistance (inc. SBP & DBP) through
their vasoconstrictor action .
• Not inactivated by COMT and has a much longer duration of
action than the catecholamines.
• Use- treatment of glaucoma
– Local nasal decongestant
– To overcome hypotension induced by some general
anesthetic agent
– raise the blood pressure (followed by reflex bradycardia)
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 α2-Selective Agonists
 Activation of presynaptic α2 receptors
 Inhibits the release of norepinephrine from PNS
 Inhibits sympathetic nervous system activity and leads to
a fall in blood pressure in CNS .
 Blockade of α2 receptors can increase sympathetic outflow
 Potentiate the release of norepinephrine from nerve
endings
 Increase BP
 Drugs include: Clonidine & Methyldopa

38

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 Clonidine
 Agonist to presynaptic α2 adrenoceptors in brain,
 stimulation suppresses sympathetic outflow and reduces blood
pressure
Use- treatment of systemic hypertension.
 Adverse effects:
 Dry mouth
 Sexual dysfunction
 Bradycardia
 Withdrawal syndrome (rebound hypertension)

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 Methyldopa
Centrally acting antihypertensive agent.
Metabolized to α-methylnorepinephrine in the
brain
 activate central α2 receptors and lower blood
pressure in a manner similar to that of clonidine.
Safe and preferable anti-hypertensive agent
during pregnancy

40

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 β1-Adrenergic Agonists
Dobutamine
 Is a synthetic dopamine analog and selective β1-agonist.
 On the heart, it produces a more pronounced positive inotropic
effect than its chronotropic effect when compared to dopamine.
 It produces renal and mesenteric vasodilatation (D1-receptors)
similar to dopamine
 Therapeutic use of dobutamine is based on its ability to
increase cardiac output via the positive inotropy with little effect
on heart rate and myocardial oxygen consumption
o Hence, it is used in cardiogenic shock and decompensated heart
failure
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 β2 adrenergic receptor agonists

 Are selective β2 adrenergic receptor agonists with a little effect/no effect

on β1 cardiac receptors
 Hence, they have the advantage of producing bronchodilation without
cardiac stimulation
 Two types:
 Short acting :Terbutaline, albuterol (salbutamol),
 Long acting :Salmeterol ,Formoterol ,ritodrine
 They are given orally, IV or by inhalational and possess no CNS
stimulation
 Effects:
 Uterine relaxation
 Bronchodilation
 Uses
 bronchial asthma and bronchospasm
By Akeberegn G associated with bronchitis 42
 Albuterol (Salbutamol)
 Inhalation- produce significant bronchodilation within 15
minutes
- Hence, indicated for acute symptom relief (quick).
– Duration for 3 to 4 hours.
 Oral administration-onset delayed by 1 to 2 hours.
– Oral albuterol has the potential to delay preterm labor.
– CNS and respiratory side effects are sometimes
observed
– Has no advantage than inhalation
43

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 Salmeterol
 Highly lipophilic and has a sustained duration of action
 This long action reflects binding to a specific site within
the B2 receptor that allows for its prolonged activation.
 may also have anti inflammatory activity.
 Since onset of action of inhaled salmeterol/formeterol is
relatively slow, it is not suitable monotherapy for acute
breakthrough attacks of bronchospasm.
 Not given based on PRN bases rather on regular bases
for chronic management of asthma

44

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 Clinical uses of Adrenergic Agonists
 Treatment of hypotension
 Selective α1-agonists like phenylephrine

 Cardiogenic shock: Dobutamine is the drug of choice

 Anaphylactic Shock : Epinephrine is drug of choice

 Treatment of asthma : selective β2 agonists such as albuterol

are drugs of choice)
 Relieve of congestion: phenylephrine is preffered
 To prolong action of local local anesthetics:(Adrenalin is widly
used}

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Indirectly Acting Adrenergic Drugs
Tyramine
 By-product of tyrosine metabolism in the body
 Found in high concentrations in some foods such as cheese
and fish.
 Readily metabolized by MAO in the liver.
– MAO inhibitors in conjunction with tyramine-
containing foods may lead to rapid release of NE &
severe hypertension
 Has an indirect sympathomimetic action caused by the
release of stored catecholamines.
– It enters synaptic vesicle and causes displacement & 46

release of NE & normally degraded by MAO

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 Amphetamine
Amphetamine
 causes release of NE from adrenergic nerve endings
 blocks its reuptake into the cytoplasm of the nerve terminal.
 has potent peripheral effects on α1, α2 and β1 receptors, but not β2 receptors.
 potent CNS stimulant which is orally effective.
CNS effects
 Stimulating the CNS.
 CNS effects include :
• Increased alertness;
• Decreased sense of fatigue
• Elevation of mood, with increased initiative,
• Self-confidence, and
• Ability to concentrate; elation and euphoria;
• Performance of simple mental tasks is improved 47

 Finaly ,performance is reduced by fatigue and lack of sleep.

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 Mixed-acting Agent
Ephedrine
Chemically related to EP and stimulates release of
NE
It is not a substrate for COMT or MAO & hence
has long duration of action
It activates β2 as well as α- and β1-aderenergic
receptors
It is used to treat mild cases of asthma
It crosses BBB giving rise to CNS stimulant
action
It is now replaced by more selective β2 agonists 48

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 Adrenergic Antagonists /Sympatholytics
• Classification according to MOA:
1. Direct-acting
– Adrenergic receptor antagonists
• Alpha receptor blockers- limited use
• Beta receptor blockers- widely used
• Selective & non-selective
2. Indirect-acting
– Act by inhibiting:
1. Synthesis of NE- metyrosine
2. Storage of NE- reserpine
3. Release of NE- bretylium, guanethidine
– Used only to treat HTN

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 Direct-acting Adrenergic Blockers
 β-antagonists
α-antagonists • Selective β1 blockers
• Selective α1 blockers (Cardioselective)
– Prazosin, » Acebutolol, alprenolol,
– Terazosin, » Atenolol, betaxolol,
» Celiprolol, esmolol,
– Doxazosin » Metoprolol, Nebivolol
• Non-selective α blockers • Non-selective β blockers
» Phenoxybenzamine » Carteolol,
» Phentolamine » Propranolol,
» Penbutolol,
α2 antagonists
» Pindolol,
» Yohimbine, » Timolol
» Tolazoline, Mixed antagonists (blockers)
» Rauwolscine – Block beta1, beta2, alpha1,
Carvedilol
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 Clinical Uses of Alpha Blockers
 Hypertension

• Hypertensive Emergencies,
– - Adrenoceptors antagonists are most useful when there is
excess of circulating -agonists: epinephrin or norepinephrin
 Pheochromocytoma

• Pheochromocytoma is a tumor usually found in the adrenal medulla

that releases a mixture of epinephrine and norepinephrine.
– Patients have many signs of catecholamine excess, including
hypertension, tachycardia and arrhythmias.
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 Alpha Blockers (Adverse effects)

 Orthostatic-hypotension and syncope:- causing dizziness,

lightheadedness, and even syncope (fainting)
 most common side effect at first dose (first-dose effect)
 Fist dose should be small (≤ 1 mg ) and administered at
bed time
 Advise the patient to sit or lie down
 Reflex tachycardia - by triggering the baroreceptor reflex
 blocked by beta blockers
 Nasal congestion

 Inhibition of ejaculation- cause drug-induced impotence

 Change the drug if the patient feels discomfort

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 -Adrenergic Receptor Antagonists
• Based on their relative affinity for 1 and 2 receptors they are
grouped into: -
– None Selective  blockers: -

• Propranolol, Carteolol, Penbutolol, Pindolol, Sotalol,

Timolol, Nadolol, Bucindolol.
– 1 selective agents: -

• Metoprololol, Acebutolol, Atenolol, Esmolol, Betaxolol,

Celiprolol, Alprenolol, Bisoprolol, Nebivolol
• Also referred to as cardio-selective beta blockers.
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 -Adrenergic Receptor Blockers

Pharmacological Actions :
 CVS:
a. Heart (1):
•  myocardial contraction
•  HR
•  AV-conduction & automaticity
 On Pulmonary System

– Bronchoconstriction (Nonselectives,propranolol)

• Contraindicate in patients with asthma

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 Pharmacological Actions--
 CNS/Neurological:

Sedation ( with propranolol, carvedilol)

 Metabolic Effects

– Decrease glycogenolysis Hypoglycmia

– Inhibit sympathetic stimulation of lypoiysis.

– reduce HDL cholesterol, increase LDL cholesterol

 On the eye: Reduce IOP in glaucoma ,decreased production of aqueous
humor. By Akeberegn G 55
 Therapeutic uses of  blockers
 Cardiovascular Diseases
 Hypertension
 Angina Widely used

 Congestive heart failure

 Hyperthyroidism
 To reduce the peripheral manifestations of hyperthyroidism

 Treatment of Glaucoma
 Anxiety :
  sympathetic manifestations of anxiety (e.g., palpitations)

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 Adverse effects

 CVS:
 Bradycardia,
 hypotension, heart failure, 1 blockers
 AV block
 Bronchoconstriction, ( 2 blockers)

 Muscle pains & fatigue ( 2 blockers)

 Increase hypoglycemic effect of anti-diabetic drugs ( 2 blockers)

 Sleep disturbances, nightmares ( with  lipid soluble  blockers)

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 Contra-indications

 Heat failure (acute)

 Peripheral vascular disease
 Asthma
 Diabetes taking hypoglycemic drugs
 Hypothyroidism
 Combination with Ca-channel blockers

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