pharmacology

1. CHOLINERGIC RECEPTOR
ANTAGONISTS
They are also called, muscarinic receptor
antagonists, anticholinergic, atropinics,
parasympatholytics.
Those that block effects of ACH at nicotinic
receptors are called: nicotinic receptor
antagonists .
The nicotinic receptor antagonists are either
ganglion blockers or neuromuscular blockers.

2. CLASSIFICATION OF ANTICHOLINERGICS
1)Natural alkaloids e.g. atropine,hyoscine
(scopolamine)
2)Atropine derivatives:
a)Semi-synthetic derivatives e.g. homatropine,
atropine methonitrate, hyoscine N-butyl
bromide(buscopanR) ipratropium bromide and
tiotropium bromide
b) Synthetic compounds
i) Mydriatics:e.g. cyclopentolate, tropicamide.
ii)Antisecretory-antispamodics
a) Quaternary compounds e.g. propantheline,
oxyphenonium, clidinium, pipenzolate, methyl
bromide, isopropamide, glycopyrolate.

3. CLASSIFICATION OF ANTICHOLINERGICS
Cont..
b) Tertiary amines e.g. dicyclomine, valethamate,
pirenzepin
c) Vasico selective or urinary antispasmodic e.g.
oxybutynin, flavoxate (urispasR), tolterodine
d) Antiparkinsonian e.g. trihexyphenidyl,
procyclidine, biperidin.
Other classes of drugs with
anticholinergic activity: tricyclic
antidepressants, phenothiazines,
antihistamines, disopramide,

4. SOURCE OF NATURAL ALKALOIDS
• They are obtained from plants of
Solanaceae family.
• The deadly night shade, Atropa
belladonna, contains mainly atropine
whereas the thorn apple
(Daturastramonium) contains mainly
hyoscine.
• They exist in levo and dextro forms with
the levo forms being more active
• Atropine is racemic(dl-hyoscyamine) and
scopolamine is l-hyoscine

5. MUSCARINIC RECEPTOR ANTAGONISTS
• These are drugs that block effects of
acetyl choline at muscarinic receptors
(M1-M5) at parasympathetic neuro
effector junctions.
• They inhibit the effects of parasympathetic
nerve stimulation .(i.e. they are
parasympatholytics)
• Blockade at muscanic receptors is
competitive i.e. It can be reversed when
high doses of ACH are administered.

6. Pharmacokinetics of atropine,
scopolamine
– Lipid soluble and well absorbed from
the GIT,mucous surfaces and intact
skin.
– Widely distributed in the body i.e. it
crossesBBB, placental barriers and is
secreted in milk and saliva.
– Bound to plasma proteins and partly
metabolized in the liver as
glucoronide.

7. Pharmacokinetics of atropine,
scopolamine Cont..
–Half-life of atropine is 4hrs,50% is
excreted unchanged ,the rest is excreted
as metabolites in urine.
–Effects of atropine decline rapidly except
on the eye which takes 7-12 days after
local application as eyedrops.The
pigments of the iris bind atropine, which
is then release it over many days.
–Hyoscine crosses the BBB better than
atropine. It is also more completely
metabolized than atropine.

8. PHARMACOLOGICAL EFFECTS OF
ATROPINE AND SCOPOLOMINE
(PROTOTYPES)
• Central Nervous System:
• A low dose of atropine has no effect on CNS
since there is restricted entry into the brain.
• Hyoscine crosses the BBB even at low doses,
causing a central depressant effect (sedation).
• At therapeutic doses, atropine stimulates many
medullary centers-vagal, respiratory, vasomotor.

9. Central Nervous System Cont..
• It depresses vestibular excitation at therapeutic doses-
used in motion sickness.
• It reduces cholinergic over activity in the basal ganglia at
therapeutic doses, thereby suppressing tremors and
rigidity in Parkinsonism.
• At higher toxic doses atropine crosses the BBB and
causes: cortical excitation, restlessness, dis orientation,
hallucination, delirium, respiratory depression and coma.
• Most of CNS effects are due to blockade of muscarinic
receptors in the brain, but some actions may have a
different mechanism.

10. Cardio-Vascular System Cont..
1)Heart :
• Small doses of atropine given
intravenously cause a paradoxical
bradycardia due to transient stimulation of
the vagal centre.
• At full therapeutic doses, atropine causes
tachycardia-by blocking M2 receptors on
SAN through which vagal tone decreases
heart rate.

11. 2)Blood Vessels:
• Cholinergic neurons are not involved in
maintenance of vascular tone, and atropine
produces no consistent or marked effect on BP
• Tachycardia and vasomotor stimulation tend to
raise BP , while histamine release and direct
vasodilator action of atropine tend to lower BP
• Very large doses of atropine tend to cause
cutaneous vasodilation in face and neck
(atropine flush) due to direct action not related to
cholinergic innervation.

12. SMOOTH MUSCLES
1)Gastro-intestinal tract:
• Tone and motility of g.i.t is decreased
leading to prolongation of gastric emptying
time, closure of sphincters and decrease
in tone, amplitude and frequency of
peristaltic movements.
• The antispasmodic effects may be
variable and to some extent depend on
other mediators apart from ACH e.g. 5HT,
enkephalins and others.

13. Bronchioles.
• Atropine causes bronchodilation and reduces
airway resistance in COPD and asthma patients.
• Atropine only reduces bronchospasm as a result
of excessive cholinergic activity. It may not be
very useful in asthma because
otherspasmogense.g. histamine, prostaglandins
and kinins, may be involved. These mediators
have a direct action on bronchial muscles and
glands, they also increase vagal activity.

14. Ureter And Urinary Bladder.
• Atropine relaxes ureter and urinary
bladder. This can cause urinary retention
in older males with prostatic hypertrophy.
• In neurogenic bladder/enuresis the
relaxant effect of atropine controls
detrusor hyperreflexia and increase
bladder capacity.
• In the biliary tract, there is slight relaxation
of the bile duct,
• In the uterus .there is minimal effect.

15. GLANDS
• Sweat Glands
• These are supplied by sympathetic cholinergic
neurons and are blocked by atropine. The skin
becomes hot and dry.
• Toxic doses produce hyper pyrexia, as there is
no heat loss due to lack of sweating. Children
are more sensitive to this effect.
• Tracheobronchial, lachrymal secretions are also
reduced due to blockade of M3 receptors.
Talking and swallowing may become difficult.

16. Gastrointestinal Secretions.
• Secretion of HCL, pepsin and mucus is
reduced. However, the secretion of
bicarbonate is also reduced which tend to
raise the PH and counteracts the acid
reducing property of atropine.
• Atropine is therefore less efficacious than
H2 blockers in reducing acid production.
Very high doses of atropine are required.
• Pancreatic secretions are not significantly
affected and so is bile production which is
not under cholinergic control.

17. Eye
• Atropine blocks the muscarinic receptors of
circular muscles of the iris leading to un opposed
sympathetic activity on the radial muscles causing
mydriasis(pupillary dilation)
• The ciliary muscles are also paralyzed leading to
loss of accommodation (cycloplegia) i.e. the lens
is focused for distant vision (near vision is
impaired), light reflex is impaired and there may
be photophobia.
• Atropine causes a rise in intraocular tension. This
may not be important in normal individuals, but
may be dangerous in glaucoma, or in the elderly
who are prone to glaucoma.

18. Effect Of Atropine On Body Temperature
• High doses cause an increase in body
temperature by:
• a) Decreasing secretions from the sweat
glands
• b) Stimulation of temperature regulating
centre in the hypothalamus.
• Children are more susceptible to atropine
fever.
Local Anaesthetic Effect
• Atropine has a mild anaesthetic action on
the cornea by blocking sensory nerves.

19. ATROPINE DERIVATIVES
• Naturally occurring belladonna alkaloids are
used clinically but they have the following short
comings:
a)Non selectivity
b) Long duration of action.
c) Individual intolerance.
d) Toxicity.
Semi synthetic and synthetic derivatives have
been developed with the following properties:
a) Relatively selective in their activity:
i) Drugs for peripheral conditions are mainly
quaternary compounds which cannot cross BBB
and hence devoid of central effects.

20. ATROPINE DERIVATIVES Cont..
ii) Drugs for central effects as in
Parkinsonism are able to cross BBB rapidly
and they have minimal peripheral effects.
iii) They are structurally dissimilar, hence can
be used as substitutes in atropine
intolerance.
iv) At higher doses, they can block autonomic
ganglia and neuro muscular junction
v) They have a shorter or longer duration of
action.

21. THERAPEUTIC USES OF ANTICHOLINERGICS
(ATROPINE AND ITS DERIVATIVES)
1)THERAPEUTIC USES IN CNS
a)Parkinsonism
• Results from excessive cholinergic activity
at the basal ganglia. Synthetic muscarinics
e.g. benzhexol, procyclidine and biperidin
are used.
• The drugs improve siallorhea and tremors
more than rigidity and akinesia

22. b).Motion sickness
• Hyoscine N butyl bromide is preferred to
atropine because of its central effects
• It blocks cholinergic impulses from the
vestibular apparatus to the vomiting
centre.
• It is used orally or as transdermal patches.

23. c) Twilight sleep
• Hyoscine is used together with a narcotic
analgesic, meperidine to produce
amnesia, analgesia and a relaxed state
during labour.
d) Maniacal state
• This occurs during withdrawal of alcohol in
chronic alcoholics, and hyoscine can be
used due to its central sedating effects.

24. THERAPEUTIC USES IN EYE
CONDITIONS
a)Ophalmoscopicexaminations
• Atropine eye drops is used as a potent mydriatic
and cycloplegic agent for examination of the
retina and measurement of refractive error (error
in focusing of light by the eye and a frequent
reason for reduced visual acuity.
• The draw back with atropine is that cycloplegia
takes one week during which the subject is
visually impaired.Synthetic analogues tend to
overcome these difficulties.

25. Ophalmoscopic examinations Cont..
• Homatropine eye drops is ten times less
potent than atropine but cycloplegia takes
only 1-2 days.It however, produces
unsatisfactory cycloplegia in children who
have high ciliary muscle tone.
• Cyclopentolate eye drops produce rapid
cycloplegia in 30-60 minutes with duration
of 1 day

26. Ophalmoscopic examinations Cont..
• Cyclopentolate may produce transient
abnormal behavior in children(dis
orientation, incoherent speech, visual
disturbance) when the drug is absorbed
from the eye.
• Tropicamide eye drops have the quickest
onset of action of 20-40 minutes, with
duration of 3-6 hours. It is however un
reliable as cycloplegic, but is satisfactory
for refractory testing and a short acting
mydriatic in eye exams.

27. THERAPEUTIC USES IN GASTRO INTESTINAL
CONDITIONS.
1)Peptic ulcer.
• Antimuscarinics may be used in peptic
ulcer because they reduce gastric acid
secretions and motility of the stomach.
Pirenzepine and telenzepine are used with
telenzepine being more potent.
• H2 receptor blockers have largely
replaced these muscarinic receptor
antagonists but they can still be used in
combination.

28. 2)Antispasmodics.
• In the g.i.t, atropine,hyoscine and synthetic atropine
hyper motility conditions e.g. intestinal
colic,ulcerative and biliary colics .
• Atropine derivatives are more useful in the
followinginconditions:
• Nervous and drug induced diarrhea, but not in
infective diarrhea.
• Irritable bowel syndrome and functional diarrhea.
• To relieve increased urinary frequency in old age
and enuresis in children .Oxybutynin, tolterodine,
and flaxovate are used. Dry mouth and anti-
cholinergic effects are dose limiting.
• Dysmenorrhea- the drugs are not very effective.

29. Bronchial Asthma
• Ipratropium bromide inhalation gives
complete protection against
bronchospasm induced by cholinergic
agents and irritant gases without
interfering with mucociliary movement. It is
also effective in chronic obstructive
pulmonary disease.

30. Cardiac Indications
• Increased vagal tone may cause
symptomatic sinus bradycardia, as
happens immediately after myocardial
infarction. Atropine can be used to
counteract this...Atropine can also be
used to increase the atrioventricular
conduction velocity in patients with atrio
ventricular block.

31. Cholinergic Poisoning
• Treatment of mushroom poisoning (Amanita
mascara) which contains muscarine, a
cholinergic agent. It is also used in
organophosphate poisoning (1-2 mg i.v every 5-
15 minutes till reversal of cholinergic activity
occurs.
Myaesthenia Gravis (MG)
• When anticholinesterase neostigmine is used in
MG, it may produce excessive muscarinic effects
.Atropine or its substitutes may be used to block
these effects without interfering with the effects
of neostigmine on Nm receptors.

32. Pre-Anaesthetic Medication
• Irritant general anaesthetics e.g. ether
cause increased salivary, trachea and
bronchial secretions. Atropine, hyoscine
and glycopyrrolate are used to counteract
this .However with increasing use of non
irritatinganaesthetics e.g. halothane the
requirement has decreased.
• Atropine is still being used for the
following reasons ;

33. Pre-Anaesthetic Medication
Cont..
• Halothane sensitizes the heart to the
actions of catechol amines, leading to
arrhythmias .Small doses of atropine are
used because of bradycardia it causes.
• Atropinic drugs also prevent
laryngospasm by reducing respiratory
secretions that reflexly predispose to
laryngospasm.
• Halothane also causes bradycardia and
hypotension which are blocked by
atropine.

34. PRECAUTIONS WITH ANTICHOLINERGICS
• Elderly patients- may precipitate glaucoma.
• Elderly with enlarged prostate –may cause
retention of urine due to complete closure of
sphincter.
• Very high doses of atropine cause tachycardia –
not good in myocardial infarction and angina.
• When used alone in peptic ulcers, they may
delay gastric emptying and expose the mucosa
to acid for a long time causing further damage.
Therefore they should be used with antacids or
H2 receptor antagonists.

35. ADVERSE REACTIONS/TOXICITY WITH
ANTICHOLINERGICS
• They are of plant origin, therefore accidental or
homicidal poisoning may occur. Acute poisoning
may also occur during therapeutic use as in
nocturnal enuresis in children.
• Atropine has a relatively wide margin of safety in
adults but infants and children are more
susceptible.
• Acute poisoning produce central and peripheral
effects by blocking muscarinic receptors.
• Semi synthetic substitutes have no central
effects since they do not cross the BBB,

36. ADVERSE REACTIONS/TOXICITY WITH
ANTICHOLINERGICS Cont..
Peripheral anti muscarinic effects include:
• Dryness of mouth, intense thirst, dysphagia,
constipation, dysuria and retention of urine.
• Dilatation of pupils dimness of vision, loss of
accommodation, photophobia.
• Tachycardia,
• Dry, hot flushed skin, hyper pyrexia, drug rush and
atropine flush over neck and upper part of the trunk.
• Central effects include:
• Restlessness, rapid breathing confusion ,hallucinations ,
delirium
• Convulsions followed by coma .Death is due to respiratory
depression and vasomotor collapse.

37. MANAGEMENT OF TOXICITY OF
ANTICHOLINERGICS
Control of hper pyrexia:
Ice bag, coldsponges,artificial respiration
oxygen by face mask.
Removal Of Un absorbed poison
• Gastric lavage with potassium
permanganate, or universal antidote which
contains charcoal.
Control of Excitement
Diazepam 10 mg i.v

38. Specific Treatment
• Physostigmine 1-4 mg by slow i.v in adults
and, 1-2 mg hourly in children until
satisfactory control of anti muscarinic
effects. .5-1mg in children
• In case of poisoning with quaternary anti
muscarinic compounds which do not cross
the BBB, neostigmine can be used instead
of physostigmine to counteract peripheral
anti muscarinic, ganglion blocking and
neuro muscular blocking action of these
drugs.

39. DRUG INTERACTIONS INVOLVING ANTI
CHOLINERGICS
• Absorption of most drugs ( those that
are absorbed in the small intestine) are
delayed because atropine delays
gastric emptying i.e. slows absorption
of L-dopa .
• Antacids reduce absorption of
anticholinergics.

40. DRUG INTERACTIONS INVOLVING ANTI
CHOLINERGICS Cont..
• Anti histamines, TCAs phenothiazines,
disopyramide, pethidine have anti
cholinergic properties ,and additive side
effects occur with atropinics.
• MAOI interferes with metabolism of
anticholinergic and anti parkinsonian
drugs and may cause delirium.

41. #THE END#