Atropine Substitutes

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Chapter: Essential pharmacology : Anticholinergic Drugs And Drugs Acting On Autonomic Ganglia

Many semisynthetic derivatives of belladonna alkaloids and a large number of synthetic compounds have been introduced with the aim of producing more selective action on certain functions. Most of these differ only marginally from the natural alkaloids, but some recent ones are promising.


ATROPINE SUBSTITUTES

 

Many semisynthetic derivatives of belladonna alkaloids and a large number of synthetic compounds have been introduced with the aim of producing more selective action on certain functions. Most of these differ only marginally from the natural alkaloids, but some recent ones are promising.

 

Quaternary compounds

 

These have certain common features—

 

§  Incomplete oral absorption.

 

§  Poor penetration in brain and eye; central and ocular effects are not seen after parenteral/oral administration.

 

§  Elimination is generally slower; majority are longer acting than atropine.

 

§  Have higher nicotinic blocking property. Some ganglionic blockade may occur at clinical doses postural hypotension, impotence are additional side effects.

 

§  At high doses some degree of neuromuscular blockade may also occur.

 

Drugs in this category are—

 

1. Hyoscine butyl bromide 20–40 mg oral, i.m., s.c., i.v.; less potent and longer acting than atropine; used for esophageal and gastrointestinal spastic conditions.

BUSCOPAN 10 mg tab., 20 mg/ml amp.

 

2. Atropine methonitrate 2.5–10 mg oral, i.m.; for abdominal colics and hyperacidity.

MYDRINDON 1 mg (adult), 0.1 mg (child) tab; in SPASMOLYSIN 0.32 mg tab;

 

3. Ipratropium bromide 40–80 μg by inhalation; it acts selectively on bronchial muscle without altering volume or consistency of respiratory secretions. Another desirable feature is that in contrast to atropine, it does not depress mucociliary clearance by bronchial epithelium. It has a gradual onset and late peak (at 60–90 min) of bronchodilator effect in comparison to inhaled sympathomimetics—more suitable for regular prophylactic use rather than for rapid symptomatic relief during an attack. Action lasts 4–6 hours. It acts on receptors located mainly in the larger central airways (contrast sympathomimetics whose primary site of action is peripheral bronchioles, see Fig. 16.2). The parasympathetic tone is the major reversible factor in chronic obstructive pulmonary disease (COPD). Therefore, ipratropium is more effective in COPD than in bronchial asthma. Transient local side effects like dryness of mouth, scratching in trachea, cough, bad taste and nervousness are reported in 20–30% patients, but systemic effects are rare because of poor absorption from the lungs and g.i.t. (major fraction of inhaled drug is swallowed).

IPRAVENT 20 μg and 40 μg/puff metered dose inhaler, 2 puffs 3–4 times daily; 250 μg/ml respirator soln., 0.4– 2 ml nebulized in conjunction with a β2 agonist 2–4 times daily.

 

Also used to control rhinorrhoea in perennial rhinitis and common cold; IPRANASEAQ 0.084% nasal spray (42 μg per actuation), 1–2 sprays in each nostril 3–4 times a day.

 

4. Tiotropium bromide A recently developed congener of ipratropium bromide which binds very tightly to bronchial M1/M3 muscarinic receptors producing long lasting bronchodilatation. Binding to M2 receptors is less tight confering relative M1/M3 selectivity. Like ipratropium, it is not absorbed from respiratory and g.i. mucosa and has exhibited high bronchial selectivity of action.

TIOVA 18 μg rotacaps; 1 rotacap by inhalation OD.

 

 Propantheline 15–30 mg oral; it has been the most popular anticholinergic used for peptic ulcer and gastritis. It has some ganglion blocking activity as well and is claimed to reduce gastric secretion at doses which produce only mild side effects. Gastric emptying is delayed and action lasts for 6–8 hours. Use has declined due to availability of H2 blockers which are more efficacious.

PROBANTHINE 15 mg tab.

 

Oxyphenonium 5–10 mg (children 3–5 mg) oral; similar to propantheline, recommended for peptic ulcer and gastrointestinal hypermotility.

ANTRENYL 5, 10 mg tab.

 

Clidinium 2.5–5 mg oral; used in combination with benzodiazepines for nervous dyspepsia, gastritis, irritable bowel syndrome, colic, peptic ulcer, etc.

In SPASRIL, EQUIREX 2.5 mg tab with chlordiazepoxide 5 mg. NORMAXIN 2.5 mg with dicyclomine 10 mg and chlordiazepoxide 5 mg.

 

8. Pipenzolate methyl bromide 5–10 mg (children 2–3 mg) oral; used for flatulent dyspepsia, infantile colics and other gastrointestinal spasm.

In PIPTAL, PIPEN 4 mg + dimethylpolysiloxane 40 mg/ ml drops.

 

9. Isopropamide 5 mg oral; indicated in hyperacidity, nervous dyspepsia, irritable bowel and other gastrointestinal problems, specially when associated with emotional/mental disorders.

In STELABID, GASTABID 5 mg tab. with trifluoperazine 1 mg.

 

10. Glycopyrrolate 0.1–0.3 mg i.m., 1–2 mg oral; potent and rapidly acting antimuscarinic lacking central effects. Almost exclusively used for preanaesthetic medication and during anaesthesia.

GLYCOP 0.2 mg/ml amp., 1 mg in 5 ml vial, PYROLATE 0.2 mg/ml, 1 ml amp, 10 ml vial.

 

Tertiary Amines

 

1. Dicyclomine 20 mg oral/i.m., children 5–10 mg; has direct smooth muscle relaxant action in addition to weak anticholinergic; exerts antispasmodic action at doses which produce few atropinic side effects. However, infants have exhibited atropinic toxicity symptoms and it is not recommended below 6 months of age. It also has antiemetic property: has been used in morning sickness and motion sickness. Dysmenorrhoea and irritable bowel are other indications.

CYCLOMINOL, 20 mg tab., 10 mg/ml liquid; DIOSPAS 10 mg, 20 mg tabs, CYCLOPAM INJ. 10 mg/ml in 2 ml, 10 ml, 30 ml amp/vial, also 20 mg tab with paracetamol 500 mg; in COLIMEX 20 mg with paracetamol 500 mg tab, 10 mg/ml drops with dimethicone.

 

2. Valethamate: The primary indication of this anticholinergicsmooth muscle relaxant is to hasten dilatation of cervix when the same is delayed during labour, and as visceral antispasmodic.

Dose: 8 mg i.m., 10 mg oral repeated as required.

VALAMATE 8 mg in 1 ml inj, EPIDOSIN 8 mg inj., 10 mg tab.

 

3. Pirenzepine 100–150 mg/day oral; it selectively blocks M1 muscarinic receptors and inhibits gastric secretion without producing typical atropinic side effects (these are due to blockade of M2 and M3 receptors). The more likely site of action of pirenzepine in stomach is intramural plexuses and ganglionic cells rather than the parietal cells themselves. It is nearly equally effective as cimetidine in relieving peptic ulcer pain and promoting ulcer healing, but has been overshadowed by H2 blockers and proton pump inhibitors.

 

 

Vasicoselective Drugs

 

1. Oxybutynin This recently introduced antimuscarinic has high affinity for receptors in urinary bladder and salivary glands with additional smooth muscle relaxant and local anaesthetic properties. It is relatively selective for M1/M3 subtypes than for M2. Because of vasicoselective action it is used for detrusor instability resulting in urinary frequency and urge incontinence. Beneficial effects have been demonstrated in neurogenic bladder, spina bifida and nocturnal enuresis. Anticholinergic side effects are common after oral dosing, but intravasical instillation increases bladder capacity with few side effects.

Dose: 5 mg BD/TDS oral; children above 5 yr 2.5 mg BD.

OXYBUTIN, CYSTRAN, OXYSPAS 2.5 mg and 5 mg tabs.

 

2. Tolterodine: This relatively M3 selective muscarinic antagonist has preferential action on urinary bladder; less likely to cause dryness of mouth and other anticholinergic side effects. It is indicated in overactive bladder with urinary frequency and urgency. Since it is metabolized by CYP3A4, dose should be halved in patients receiving CYP3A4 inhibitors (erythromycin, ketoconazole, etc.)

Dose: 2 mg BD oral; ROLITEN, TORQ 1, 2 mg tabs.

 

3. Flavoxate has properties similar to oxybutynin and is indicated in urinary frequency, urgency and dysuria associated with lower urinary tract infection.

URISPAS, FLAVATE 200 mg tab, 1 tab TDS.

 

Drotaverine It is a novel nonanticholinergic smooth muscle antispasmodic which acts by inhibiting phosphodiesterase4 (PDE4) selective for smooth muscle. Elevation of intracellular cAMP/cGMP attends smooth muscle relaxation. Changes in membrane ionic fluxes and membrane potential have also been shown. It has been used orally as well as parenterally in intestinal, biliary and renal colics, irritable bowel syndrome, uterine spasms, etc. without anticholinergic side effects. Adverse effects reported are headache, dizziness, constipation and flushing. Fall in BP can occur on i.v. injection.

Dose: 40–80 mg TDS; DROTIN, DOTARIN, DOVERIN 40, 80 mg tabs, 40 mg/2 ml inj.

 

Mydriatics

 

Atropine is a potent mydriatic but its slow and long lasting action is undesirable for refraction testing. Though the pupil dilates in 30–40 min, cycloplegia takes 1–3 hours, and the subject is visually handicapped for about a week. The substitutes attempt to overcome these difficulties.

 

1.  Homatropine It is 10 times less potent than atropine. Instilled in eye, it acts in 45–60 min, mydriasis lasts 1–3 days while accommodation recovers in 1–2 days. It often produces unsatisfactory cycloplegia in children who have high ciliary muscle tone.

HOMATROPINE EYE, HOMIDE 1%, 2% eye drops.

 

2. Cyclopentolate It is potent and rapidly acting; mydriasis and cycloplegia occur in 30–60 min and last about a day. It is preferred for cycloplegic refraction, but children may show transient behavioural abnormalities due to absorption of the drug after passage into the nasolacrimal duct. It is also used in iritis and uveitis.

CYCLOMID EYE 0.5%, 1%; CYCLOGYL 1% eye drops.

 

3. Tropicamide It has the quickest (20–40 min) and briefest (3–6 hours) action, but is a relatively unreliable cycloplegic. However, it is satisfactory for refraction testing in adults and as a short acting mydriatic for fundoscopy.

OPTIMIDE, TROPICAMET, TROMIDE 0.5%, 1.0% eye drops. TROPACP, TROPICAMET PLUS 0.8% with phenylephrine 5% eye drops.

 

Antiparkinsonian drugs (see No. 31)

 

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