Para-sympathomimetics can directly activate cholinergic receptors as agonists or indirectly increase acetylcholine levels by inhibiting acetylcholinesterase. Direct agonists include natural alkaloids like muscarine and synthetic ones like carbachol. Indirect anticholinesterases prevent acetylcholine degradation, either reversibly like neostigmine or irreversibly like organophosphates. Their effects are mediated through muscarinic and nicotinic receptors in the autonomic ganglia, neuromuscular junction and central nervous system. They have therapeutic uses for conditions like glaucoma and myasthenia gravis but overdose can cause toxic effects that require atropine and oxime

1. Para-sympathomimetics
(Cholinergics)
Aasifa shaikh
Sem I
Department of Pharmacology
SSR COLLEGE OF PHARMACY

2. •These are the drugs that produce
actions similar to that of Ach
either by directly interacting with
cholinergic receptors (cholinergic
agonists) or by increasing
availability of ACh at these sites
(anticholinesterases).

3. Parasymapathomimetic
Directly acting Indirectly acting

4. Directly acting
Choline esters
Eg-
acetylcholine
carbachol
Natural
alkaloids
Eg- muscarine
pilocarpine
Synthetic
alkaloids
Eg-areclidine
oxotremorine

5. Mechanism of directly acting
•The drug directly bind to the
receptor and prevents the binding
of agonist to the recptor.

6. Indirectly acting
(Anticholine
esterase)
Natural
Eg- physostigmine
Synthetic

7. Synthetic
Reversible
Eg- Neostigmine
Pyridostigmine
Irreversible
Eg- Sarin
Parathion, methation

8. Mechanism of indirectly acting
•This is non receptor blocker
•Drug do not bind to the receptor
site but they indirectly inhibit the
activity of Ach esterase and thus
preserve Ach at nerve endings.

9. • There are 2 types of choline
esterase enzyme:
True choline esterase
Pseudo choline esterase

10. True choline esterase(specific)
•Found in nervous tissue, human
placenta, erythrocytes.
•Hydrolyse Ach liberated at nerve
endings.(mainly endogeneously released
Ach)
•Have high affinity for Ach.

11. Pseudo choline esterase(non-specific)
•Found in blood serum, intestine, skin
•Have low affinity for Ach

12. Mechanism of anti-choline esterase
•The anti-ChEs react with the
enzyme essentially in the same way
as ACh. The carbamates and
phosphates respectively are
carbamylate and phosphorylate the
esteratic site of the enzyme

13. •The active region of AChE forms a
gorge which contains an anionic site
ie. glutamatic acid and an esteratic
site formed by serine and histidine.

14. Hydrolysis of ACh involves electrostatic
attraction of positively charged N+ of ACh to
the anionic site and nucleophilic attack by
serine-OH which is activated by the adjacent
histidine leading to acetylation of serine

15. • The acetylated enzyme reacts with water
to produce acetic acid and choline.
•Whereas the acetylated enzyme reacts
with water extremely rapidly and the
esteratic site is freed in a fraction of a
millisecond

16. •The intermediate formed is
carbamylated enzyme.
•Its half life is 30min (slow reaction)

17. •Irreversible AntiCEs act on the
enzyme CE in a similar fashion.
•Organophosphorus compound bind
to the esteric site only and the
intermediate formed is
phosphorylated enzyme which is
stable.

18. • The phosphorylated enzyme may
also undergo ‘aging’ by the loss of
one of the alkyl groups and
become totally resistant to
hydrolysis

19. •The enzyme is never regenerated &
return of the activity depends on the
synthesis of new enzyme hence, these
are irreversible blocking agents.

20. •These compounds are useful in
reversing neuro muscular paralysis due
to organophosphorus compound
where atropine is ineffective or
contraindicated.

21. •Organophosphorus compound
poisoning may occur due to accidental
consumption of agricultural product
spread with insecticides/ pesticides, or
if the person is occupationally involved
in spraying insecticides.
•Poisoning may occur in suicidal cases.

22. Pharmacological actions: (directly)
Muscarinic agonists
1- Heart
M2receptor
s present in
atria &
ventricles
which are
negatively
coupled
with
adenylate
cyclase
Reduce
cAMP
formation
so Decrease
Ca+2 release
Open K+
channel
Increase
permeabilit
y of K+ ion
Produce
hyperpolari
zation
Decrease
heart
rate

23. Blood vessel
M3 receptor is
present in
blood vessel
endothelium
Causes
activation of
protein kinase
C and releases
Ca+2 which
combine with
calmoduline
and form its
complex
Activation
of NO
synthase
(increase
NO)
Vasodialati
on
(decrease
B.P)

24. • When the endothelium is
damaged by disease, ACh can
diffuse to the vascular smooth
muscle and cause vasoconstriction
via M3 receptors located on their
plasma membrane.

25. M3 receptor causes activation of PKC
Release of Ca+2
Contract smooth muscle
2- Smooth muscle

26. Respiratory system
These types of drugs are
contraindicated in Asthma as the
bronchial muscles are contracted
to produce bronchospasm.

27. Urinary bladder
•Contraction of the middle layer
termed as DETRUSOR muscle
& relaxation of the sphincter
muscle , hence produce
micturition.

28. •Bethanechol is used to
stimulate bladder emptying.

29. Effects on eye
•Cholinergic drugs produces
miosis of eye causing
contraction of circular muscle.

30. •Contraction of ciliary muscle
leads to spasm increased
outflow facility reduction in
intraocular tension (especially in
glaucomatous patients).

31. Drugs used to lower intraocular
pressure
•Timolol (eye drop) acts as β-
adrenoceptor antagonist is used
•Clonidine as α2-adrenoceptor
agonist
•Pilocarpine as muscarinic agonist

32. •In addition to these peripheral
effects, muscarinic agonists that
are able to penetrate the blood–
brain barrier produce marked
central effects due to
activation mainly of M1
receptors in the brain.

33. •These include tremor,
hypothermia and increased
locomotor activity, as well
as improved cognition as in
Mysthenia Gravis.

34. Nicotinic agonists
1. Autonomic ganglia
Both sympathetic and parasympathetic ganglia are stimulated.
High dose of ACh given after atropine causes tachycardia
rise in BP due to stimulation of sympathetic ganglia and release
of catecholamines

35. 2. Skeletal muscles
•Causes contraction through nicotinc effect
3. CNS
•Ach when injected through IV donot
cross BBB , but when given directly in
brain it produces aurosal response
followed by depression

36. Acetyl choline ester
•It is rapidly hydrolysed , so ineffective
orally. (therapeutically ineffective)
•Carbachol and bethanichol are absorbed
orally & are relatively resistant to
choline ester.

37. Pharmacological actions of indirectly
acting drugs
1-Autonomic cholinergic synapses- These mainly
reflect enhancement of Ach activity at
parasympathetic postganglionic synapses.
Large doses will first stimulate & later block the
autonomic ganglia producing complex autonomic
effect.
The depolarization block occurs and is associated
with a build-up of Ach in the plasma and body
fluids.

38. 2-Effect on neuromuscular junction-
The twitch tension of a muscle stimulated
via its motor nerve is increased by
anticholinesterases.
Normally, the Ach is hydrolysed so quickly
that each stimulus initiates only one action
potential in the muscle fibre, but when
AChE is inhibited this is converted to a short
train of action potentials in the muscle fibre,
and hence greater tension.

39. 3- Effect on CNS
•Tertiary compounds, such as physostigmine,
and the non-polar organophosphates penetrate
the blood–brain barrier freely and affect the
brain. The result is an initial excitation, which
can result in convulsions, followed by
depression, which can cause unconsciousness
and respiratory failure. These central effects
result mainly from the activation of mAChRs,
and are antagonized by atropine.

40. 4- CVS
• Cardiovascular effects are complex.
•Whereas muscarinic action would produce bradycardia
and hypotension.
• Ganglionic stimulation would tend to increase heart rate
and BP.
•Action on medullary centres (stimulation followed by
depression) further complicates the picture, so does
ganglionic blockade with high doses.
•Thus, the overall effects are often unpredictable and
depend on the agent and its dose.

41. 5-Neurotoxicity of organophosphates
•Many organophosphates can cause a severe type of
delayed peripheral nerve degeneration, leading to
progressive weakness and sensory loss.
•This is not a problem with clinically used
anticholinesterases but occasionally results from
poisoning with insecticides or nerve gases.
• The mechanism of this reaction is only partly
understood, but it seems to result from inhibition
of a neuropathy target esterase distinct from
cholinesterase.

42. Physostigmine
•It is an alkaloid obtained from dried
ripe seeds of Physostigma venenosum.
•A tertiary ammonium compound
•Well absorbed from GIT and can cross
BBB.
•Equally active against both true and
pseudo CE.

43. Therapeutic uses of physostigmine
1. Pilocarpine- to treat glaucoma.
2. Atropine poisoining
3. Early stages of Alzhemier’s disease and
improve memory.

44. Therapeutic uses
1. Glaucoma- by contracting ciliary and circular
muscle
Drug useful is physostigmine in doses of 0.1- 1% aq
solution or
Pilocarpine 0.5- 4% Aq sol.

45. 2. Mysthenia gravis –
• by contraction of muscle
• Drug used is neostigmine
• As it cannot cross BBB and it directly produces
cholinomimetic action
• It has selective action on skeletal muscle

46. 3. Atropine poisoining-
physostigmine is commonly used as it can cross BBB
4. Curare poisoining- neostigmine is used
5. Misce. Use –
Physostigmine is used in Alzhemiers disease by decreasing
the metabolism of Ach
•Methacholine & neostigmine are sometimes used in
tachycardia

47. • Attony of bladder and paralytic ileus– if the spasm of
bladder is not proper than Methacholine carbachol is
prescribed

48. ANTICHOLINESTERASE POISONING
•Anticholinesterases are easily available and
extensively used as agricultural and household
insecticides; accidental as well as suicidal and
homicidal poisoning is common.
•Local muscarinic manifestations at the site of
exposure (skin, eye, g.i.t.) occur immediately
and are followed by complex systemic effects
due to muscarinic, nicotinic and central actions.

49. They are—
• Irritation of eye, lacrimation, salivation,
sweating, copious tracheo-bronchial secretions,
miosis, blurring of vision, bronchospasm,
breathlessness, colic, involuntary defecation and
urination.
•Fall in BP, bradycardia or tachycardia, cardiac
arrhythmias, vascular collapse.

50. • Muscular fasciculations, weakness, respiratory
paralysis (central as well as peripheral).
• Irritability, disorientation, unsteadiness,
tremor, ataxia, convulsions, coma and death.
• Death is generally due to respiratory failure

51. Treatment
1. Termination of further exposure to the poison—
fresh air, wash the skin and mucous membranes with
soap and water, gastric lavage according to need.
2. Maintain patent airway, positive pressure
respiration if it is failing.
3. Supportive measures—maintain BP, hydration,
control of convulsions with judicious use of
diazepam.
4. Specific antidotes—

52. (a) Atropine :
•It is highly effective in counteracting the muscarinic
symptoms, but higher doses are required to antagonize
the central effects.
•It does not reverse peripheral muscular paralysis which is
a nicotinic action.
•All cases of anti-ChE (carbamate or organophosphate)
poisoning must be promptly given atropine 2 mg i.v.
repeated every 10 min till dryness of mouth or other signs
of atropinization appear (upto 200 mg has been
administered in a day). Continued treatment with
maintenance doses may be required for 1–2 weeks.

53. (b) Cholinesterase reactivators
•Oximes are used to restore neuromuscular transmission
only in case of organophosphate anti-ChE poisoning.
•The phosphorylated ChE reacts very slowly or not at all
with water.
•However, if more reactive OH groups in the form of
oximes (generic formula R–CH = N–OH) are provided,
reactivation occurs more than a million times faster.

54. •Pralidoxime (2-PAM) has a positively
charged quaternary nitrogen: attaches to
the anionic site of the enzyme which
remains unoccupied in the presence of
organophosphate inhibitors.
•Its oxime end reacts with the phosphorus
atom attached to the esteratic site: the
oxime-phosphonate so formed diffuses
away leaving the reactivated ChE.

55. • Pralidoxime is ineffective as an antidote to
carbamate anti-ChEs (physostigmine,
neostigmine, carbaryl, propoxur) in which case
the anionic site of the enzyme is not free to
provide attachment to it.
•It is rather contraindicated in carbamate
poisoning, because not only it does not
reactivate carbamylated enzyme, it has weak
anti-ChE activity of its own.

56. Chronic organophosphate poisoning
• Repeated exposure to certain fluorine
containing and triaryl organophosphates
results in polyneuritis and demyelination after
a latent period of days to weeks.
•Sensory disturbances occur first followed by
muscle weakness, tenderness and depressed
tendon reflexes—lower motor neurone
paralysis.

57. •In the second phase, spasticity and upper
motor neurone paralysis gradually
supervenes.
•Recovery may take years.
• The mechanism of this toxicity is not known,
but it is not due to inhibition of ChE; there is
no specific treatment.

58. Adverse effects of
parasympathomimetics
• Excessive salivation
• Asthma
• Peptic ulcer
• Coronary insuffiency
• Hyperthyrodism
• Apnoea
• Nausea vomiting
• Contraindication