ANTICHOLINERGICS and

MUCOLYTICS

Varun Kumar VarshneyDepartment of Anaesthesiology & critical Care

JAWAHARLAL NEHRU MEDICAL COLLEGE,ALIGARH

INTRODUCTION

• Blocks the action of ACETYLCHOLINE on

MUSCARINIC RECEPTORS

• Also called as CHOLINERGIC BLOCKING

AGENTS or PARASYMPATHOLYTICS

MECHANISM OF ACTION AND

EFFECTS

• Act by occupying receptor sites at

PARASYMPATHETIC NERVE ENDINGS,

thereby leaving fewer receptor sites free to

respond to ACETYLCHOLINE

• Distribution of cholinergic receptor is broad so

effects of ANTICHOLINERGICS will be

diffuse.

CHOLINERGIC SYSTEM

• NEUROTRANSMITTER

• RECEPTORS

• EFFECTS OF CHOLINERGIC SYSTEM

NEUOTRANSMITTER

CHOLINE + ACETYLCoA

ACETYLCHOLINE

CHOLINE

ACETYLASE

CHOLINE + ACETATE

ACETYL

CHOLINESTERASE

M1 M2 M3 M4 M5

LOCATION -CNS

-Gastric

Glands

-Heart

-Autorecept

ors

-SM(visceral)

-Exocrine

glands

-Vascular

endothelial

cells

-CNS

-Heart

-CNS

EFFECTS Acid

secretion

-Bradycardia

-Av block

Contractility

of ventricles

-SM

Contraction

-Secretion

-Vasodialati

on

? ?

ANTAGONI

STS

Pirenzepin

e

Methoctramin

eSolifenacin No No

• NICOTINIC RECEPTORS

NM – Neuromuscular junctions

NN - Ganglion cells

- Adrenal medullary cells

- Spinal cord &

- Brain

EFFECTS OF CHOLINERGIC

SYSTEM

• CVS -Bradycardia

-Decreased velocity of conduction in

AV node & Purkinje fibres

-Decreased contractility of atria and

ventricles

• BLOOD VESSELS -Vasodilatation

• GIT - Increased tone and peristalsis

- Sphincters relax

- Evacuation of bowel

- Increased acid secretion

• RESPIRATORY SYSTEM

-Constriction of bronchial muscles

-Precipitation of asthmatic attack

• RENAL SYSTEM

-Increased peristalsis of ureter

-Detrussor contracts Voiding

-Trigone relax of

-Sphincter relax Bladder

• GLANDS -Increased secretions from all

parasympathetically innervated

glands

ANTICHOLINERGIC DRUGS

• CLASSIFICATION

NATURAL ALKALOIDS

Atropine

Hyoscine(Scopolamine)

SEMISYNTHETIC DERIVATIVES

Homatropine

Ipratropium bromide

Tiotropium bromide

SYNTHETIC COMPOUNDS

Cyclopentolate Mydriasis

Tropicamide

Glycopyrrolate Quarternary

Propantheline ammonium

Oxyphenonium compounds

Dicyclomine Tertiary

Pirenzepine Amines

Telenzepine

Biperiden Central

Benzhexol anticholinergics

Benztropine

ACTIONS/EFFECTS

• CNS -Excitation / Depression

-Anti motionsickness property

• CVS -Tachycardia

(transient initial bradycardia)

-Increased A-V conduction

-Increased contractility of atria &

ventricle

• GIT -Decreased tone & contraction

Constipation

• RESPIRATORY SYSTEM

-Bronchodilatation

(especially in COPD & Asthma)

• RENAL SYSTEM -Relax Ureter & Bladder

-Urinary retention

(especially in elderly)

• EYE -Mydriasis &

-Cycloplegia

• GLANDS - Decreased secretions of all

exocrine glands

• BODY TEMPERATURE

-Inhibits sweating Increased

-(+) temperature regulating temp.

centre in Hypothalamus

PHARMACOKINETICS

• Good absorpsion from g.i.t.

• I/V or I/M route used intraoperatively

• Atropine

Onset of action– 1 min

Duration– 30-60 min

18% eliminated unchanged in urine

~50% is metabolised in liver

• Glycopyrrolate

Onset of action– 2-3 min

Duration– 2-3 Hrs

80% is excreted unchanged in urine

• Scopolamine

Broken down almost entirely in body

Only 1% appearing unchanged in

urine

• Atropine Easily cross BBB

Scopolamine

Glycopyrolate – minimally cross BBB

CLINICAL USES

PRE MEDICATION• To produce sedation

• Antisialogogue effect

• Dose:

Atropine – 0.01-0.02mg/kg (0.4-0.6mg) i.m.

Scopolamine – 0.3-0.5mg i.m.

Glyco-p – Usually ½ of Atropine

i.e 0.005-0.01mg/kg i.m.

SEDATIONScopolamine – Agent of choice

- 100X more potent than

atropine

- decreases activity of RAS

-Amnesia

-Enhance sedative effect of other

drugs ex- Opioids & BZD.

Atropine – Produces sedation & amnesia

Glyco-p – Lacks sedative axn

ANTISIALOGOGUEScopolamine

- 3X more potent than atropine

- Agent of choice when ANTISECRETORY

EFFECT + SEDATION is required.

Glycopyrolate

- 2X more potent than atropine

- Agent of choice when ANTISECRETORY

EFFECT without SEDATION is required.

BRADYCARDIA

- Atropine (15-70mcg/kg) i.v. increases H/R

- Effect less pronounced & onset slower with

Scopolamine & Glyco-p.

COMBINATION WITH

ANTICHOLINESTERASES

- During pharmacological Antagonism of

NDMRs by Anticholinesterases.

-To prevent Parasympathomimetic effects

of Anticholinesterases

- Atropine: Rapid onset & longer duration

-Glyco-p: Slower onset & short duration

COPD & BRONCHIAL ASTHMA

- Cause bronchodilatation

- Decrease Airway resistance & increase

dead space.

HICCUPS- Atropine 0.5mg i.v. used for terminating

hiccups following placement of LMA.

MYDRIASIS & CYCLOPLEGIA-Mydriatic effect: Scopolamine > Atropine>

Glyco-p

-Scopolamine used cautiouly in patients

with GLAUCOMA

-Usual doses of Atropine & Glyco-p in

Premedication & for reflex Bradycardia

don’t produce any adverse effect in

Glaucomatic patients

BILIARY & URETERAL COLICAntispasmodic action

PARKINSONISM- Central anticholinergics

- Drug induced Extrapyramidal

Syndrome

MOTION SICKNESS

ATROPINE HYOSCINE GLYCOPYRROL

ATE

SEDATION + +++ 0

ANTISECRETOR

Y

++ +++ +++

HEART RATE +++ + ++

SMOOTH

MUSCLE

RELAXATION

++ + ++

MYDRIASIS + +++ 0

ANTIMOTION

SICKNESS

PROPERTIES

+ +++ 0

GASTRIC ACID

SECRETION

+ + +

Ipratropium-(nonselective on all

muscarinic receptor)

• Asthma and bronchospastic disorders

• Quaternary ammonium compound.

• Poorly absorbed when inhaled and few

extrapulmonary affects

• Supplied as metered dose inhaler that dispenses

18 microgram per puff

TIOTROPIUM- SELECTIVE M1 AND M3

RECEPTOR

Contraindications

• BPH

• Myasthenia gravis

• Hyperthyroidism

• Glaucoma

• Tachydysrhythmias

• Not in situations whereby delaying of gastric

emptying is a concern

Recent advances:

• Nano-atropine-

– Under clinical trial

– Dry powder inhaler

– Organophosphorus poisoning

ADVANTAGES

- ease of administration

- rapid bioavailability

- less side affects

MUCOLYTICS -moa

• Alter consistency of gel layer of mucus

Act by –

1. Weakening intermolecular forces that bind adjacent glycoprotein chains– Disruption of intermolecular Disulfide Bonds (NAC,

Mesna)

2. Alteration of pH to weaken carbohydrate side chains of glycoproteins (Sodium bicarbonate)

3. Destruction of protein (Proteolysis) contained in the glycoprotein core– Breaking down of DNA in mucus (Dornase alpha)

MUCOLYTICS

• Agents capable of dissolving, digesting or liquefying mucus –reducing their viscosity.

• Classified under ‘mucokinetic drugs’ - a class of drugs which aid in the clearance of mucus from the airways, lungs, bronchi, and trachea.

• Useful in patients in the intensive care unit (ICU) with compromised lung function who often have excessive pulmonary secretions and have difficulty clearing mucus.

MUCOLYTIC drugs

• N-acetylcysteine (NAC)

• Sodium bicarbonate.

• Ambroxol

• Bromhexine

• Dornase alpha (Pulmozyme)

• Others – carbocisteine, erdosteine, letosteine,

sobrerol, stepronin, tiopronin.

N-acetylcysteine (NAC)

• Sulfhydryl - containing tripeptide.

• Better known as the antidote for acetaminophen

overdose.

• Used to help clear mucus in COPD, cystic fibrosis,

pneumonia, and in tracheostomy care

• Primarily a mucolytic agent that acts by disrupting

the disulfide bridges between mucoprotein strands in

mucus.

• NAC can be taken orally, inhalation or direct

instillation.

MOA of nac

• Disruption of Disulfide Bonds– Acetylcysteine breaks the bonds by substituting a

sulfhydril radical –HS

NAC (contd.)• Available in a liquid preparation (10 or 20%

solution) that can be given as an aerosol spray, or

injected directly into the airways.

• Aerosolized NAC should be avoided when possible

because it is irritating to the airways and can

provoke coughing and bronchospasm - particularly

in asthmatics.

• Direct instillation of NAC into the tracheal tube is

preferred, especially when there is an obstruction.

• Daily use of NAC is not advised because the drug

solution is hypertonic and can provoke

bronchorrhea

Dosage of acetylcysteine

• Dosage

– 3-5 mL of a 20% solution TID or QID

• Maximum dose 10 mL.

– 6-10 mL of a 10% solution TID or QID

• Maximum dose 20 mL.

• 1-2 mL of a 10% or 20% solution for

direct instillation.

• Oral dosage:

Available as 200 mg , 600 mg tablets

and given in twice daily dosage.

Adverse effects of acetylcysteine

• Bronchospasm – concurrent bronchodilater may

be needed.

• Nausea /Rhinorrhoea.

• Causes decreased ciliary activity-Suction should

be ready for patient who cannot cough or who is

intubated

• Reacts with metal and rubber.

• Acetylcysteine has been assigned to pregnancy

category B . Recommended in pregnancy when

benefits outweigh risks.

disadvantages

• Should not be mixed with antibiotics in the same nebulizer -

Inactivates some antibiotics if they are aerosolized with NAC

• Nausea & Vomiting

– Disagreeable odor (smells like rotten eggs) due to the

hydrogen sulfide.

• Has a shelf life of 96 hours after opening.

sodium bicarbonate

• Weak base.

• MOA- Causes Alteration of pH – 2% NaHCO3 solution is used to increase the pH of

mucus by weakening carbohydrate side chains

– Can be injected directly into the trachea or

aerosolized.

• Available as 1.4%, 5%, and 7.5% solutions.

• Dosage: 2-5 mL of a 2.5% solution .– Mixed with equal volume of sterile water and

aerosolised.

BROMHEXINE• A derivative of an alkaloid – vasicine obtained from

Adhatoda vasica .

• It induces thin copious bronchial secretion

• It depolymerises mucopolysaccharides directly as

well as by liberating lysosomal enzymes .

Bromhexine undergoes extensive first-pass

metabolism in the liver. Excreted 80% by the

kidney.

• Side effects : Rhinorrhoea & Lacrymation, gastric irritation,

hypersensitivity .

• Disrupts gastric mucosal barrier -Used cautiously in patients

with peptic Ulceration.

Oral Preparation :

Tablets- 8mg

Syrup 4mg / 5ml

Ambroxol

• A metabolite of bromhexine

• MOA- similar to bromhexine

When administered orally onset of action occurs

at about 30 minutes.

The breakdown of mucopolysaccharide side

chains makes the sputum thinner and less

viscous and therefore more easily removed by

coughing.

• It also stimulates synthesis and release

of surfactant by type II pneumocytes.

Disadvantages :

Known to increase liver transaminase activity in

some patients.

Crosses the placenta-Contraindicated in first

trimester of pregnancy

Preparations : oral tablets available as 10,

30,50,100, 120 mg tablets . Dose is 30- 120 mg

daily in two divided doses.

Syrup : 30mg / 5ml.

DORNASE ALPHA (PULMOZYME)

• Highly purified solution of recombinant human

deoxyribonuclease I (rhDNase), an enzyme

which selectively cleaves DNA

• Produced in Chinese hamster ovary cells

• Hydrolyzes the DNA present in mucus of cystic

fibrosis patients and reduces viscosity in the

lungs, promoting improved clearance of

secretions

Function of dorNase - alfa

Concentration and Dosage

• Supplied in single dose vials .

• Concentration is 1 mg/mL (0.1% solution) and

each vial contains 2.5 mg /2.5 mL.

• Administered as one unit dose vial (2.5 mL) /day

through nebuliser.

• Should not be mixed or diluted with other drugs.

• Daily administration of Pulmozyme

(dornase alfa) Inhalation Solution in conjunction

with standard therapies is indicated in the

management of cystic fibrosis patients to improve

pulmonary function.

• Shown to reduce the risk of respiratory tract

infections requiring parenteral antibiotics in these

patients

Common Side Effects of dornase

alfa.

• Voice Alteration

• Pharyngitis/Laryngitis

• Rash

• Chest pain

• Conjunctivitis

THANKS