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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