These are the drug which act against autonomic nervous system disorder

1. UNIT-2
DRUGS ACTING ON THE
AUTONOMIC NERVOUS SYSTEM
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2. Organization of the Nervous System
2

3. INTRODUCTION TO ANS
• The nervous system is conceptually divided into the central
nervous system (CNS) and peripheral nervous system
• The CNS consists of the brain and spinal cord.
• The PNS consists of
– all afferent (sensory) neurons,which carry nerve impulses
into the CNS from sensory end organs in peripheral
tissues, and
– all efferent (motor) neurons, which carry nerve impulses
from the CNS to effector cells in peripheral tissues.
• The peripheral efferent nervous system is divided into
somatic (voluntary) and the autonomic system (involuntary)

4. Autonomic Nervous System
• Nervous system that controls many involuntary
functions of the body.
• ANS effects (controls) organs which are under
involuntary control.
• Effectors ofANS usually are:
– Cardiac Muscle
– Smooth Muscle
– Glands
HEART
Many internal Organs

6. Anatomy…
• 2 divisions:
– Sympathetic
• “Fight or flight”
– Parasympathetic
• “Rest and digest”

7. Functions of symp & parasympathetic neurons
• The sympathetic division has the property of adjusting
in response to stressful situation (fight or flight
response).
• The parasympathetic division maintains essential bodily
functions (rest & digest).
• Most organs in the body are innervated by both
systems.
• Adrenal medulla, kidney, pilomotor muscles & sweat
glands, receive innervations only from the sympathetic
system.

8. Organ Sympathetic systems Parasympathetic system
Eye Contraction of iris radial
muscle (pupil dilates)
Contraction of iris sphincter
muscle (pupil contracts)
Ureters & bladder Relaxes detrusor & contract of
sphincter
Contraction of detrusor &
relaxation of sphincter
Genitals male Stimulates ejaculation Stimulate erection
Lacrimal glands Stimulate tear
Heart Increased rate & contraction Decreased rate & contraction
Gastro intestinal Decrease in muscle motility
and tone, contraction of
sphincter
Increase muscle motility and
tone
Genitals female Relaxation of uterus
Blood vessels
(skeletal muscle)
Dilatation
Blood vessels (skin
& mucus membrane
Constriction

9. Neurotransmitters
• communication between nerve cells & nerve cells,
nerve cells & effectors organs occur through the release
of specific chemical signals called neurotransmitters
(from the nerve terminals)
• If transmission is mediated by acetylcholine, the neuron
is termed as cholinergic
• If epinephrine or nor-epinephrine is the transmitter,
the fiber is called adrenergic

10. Step in neurotransmission at
cholinergic neurons
1. Synthesis of acetyl choline
– from choline and acetyl CoA which catalyzed by
choline acetyl transferase
2. Up take to storage vesicle
3. Release of acetyl choline by exocytosis
4. Binding to receptor
5. Degradation of acetyl choline by cholinesterase
– to acetate & choline
6. Recycling of choline

12. Cholinergic Receptors

13. Cholinergic receptors
• Two families
– muscarinic & nicotinic receptors
• Muscarinic receptors:
– these receptors, in addition to binding Ach, also recognize
muscarine; an alkaloid that is present in certain poisonous
mushrooms, but show a weak affinity for nicotine
• Using binding studies several subclasses have been
distinguished
– M1, M2, M3, M4 & M5.

14. Drugs acting on cholinergic system

15. Autonomic drugs
Drug acting on SNS
Sympathomimetic
Sympatholytic
Drug acting on PSNS
Para-
sympathomimetics
Para-sympatholytics

16. Cholinergic drugs
(Cholinomimetic, parasympathomimetic)
• drugs which produce actions similar to that of Ach,
• Direct acting
– by directly interacting with cholinergic receptors (cholinergic
agonists)
a) Esters of Choline: Methacholine, Carbachol, Betanechol
b) Cholinergic alkaloids: Pilocarpine, Muscarine, Nicotine,
Arecoline
• Indirect acting
– by increasing availability of Ach (anticholine esterases)
a) Reversible: Neostigmine, Physostigmine, Edrophonium
b) Irreversible: Organophosphate cpds, Echotiophate

17. Direct Acting Cholinomimetics
Acetylcholine and Choline Esters
• The therapeutic usefulness of ACh is limited by;-
– Its lack of selectivity as an agonist for
different types of cholinoreceptors; and
– Its rapid degradation by cholinesterases.
– Now Ach is used for experimental purpose
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18. Direct cont..
• Methacholine differs from ACh only in the addition of a
methyl group at the -carbon of Ach.
– This modification greatly;-
•  its selectivity for muscarinic receptors relative to
nicotinic receptors,
• Decreases its susceptibility to AChE, thereby increasing
its potency.
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19. direct acting cont..
• Carbachol differs from ACh only in the substitution of a
carbamoyl group for the terminal methyl group of ACh.
– This substitution makes
• It completely resistant to degradation by
cholinesterases
• But does not improve its selectivity for muscarinic
versus nicotinic receptors.
• Ophthalmic (topical) 0.75, 1.5, 2.25, 3% drops
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20. Direct cont…
• Bethanechol (Urecholine) combines the addition of the
methyl group and the substitution of the terminal
carbamoyl group,
 is a selective agonist of muscarinic receptors
 Is resistant to degradation by cholinesterases
• Oral: 5, 10, 25, 50 mg tablets
• Parenteral: 5 mg/mL for SC injection
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21. Bethanechol
• Therapeutic application:
– in post-operative urinary retention, post operative
abdominal distention
• Side effects:
– sweating, salivation, flushing, decreased blood
pressure, abdominal pain, diarrhea and
bronchospasm.

22. Cholinergic alkaloids

23. Pilocarpine
• Muscarinic activity and is used in ophthalmology
• Actions: rapid miosis and accomodation for near vision
• Therapeutic use: in glaucoma
– Is the drug of choice in the emergency lowering of intraocular
pressure (glaucoma) as a result of the increased drainage of
aqueous humor.
• ADR: enters brain and cause CNS disturbances, sweating
and salivation
• Action lasts up to 1 day
• available as 0.5-4% eye drops

24. Indirectly acting
Parasympathomimetics

25. Anticholinesterases
Reversible
• Carbamates
• Physostigmine
• Neostigmine
• Pyridostigmine
• Edrophoniuim
• Demecarium
• Rivastigmine
Irreversible
• Organophosphates
• Diisoproyl fluorophosphates
• Echothiophate
• Parathion
• Malathion
• Diazinon (Tlk-20)
• Tabun
• Sarin
• Soman
Nerve gases for
chemical warfare

26. Reversible..
A. Physostigmine
• a substrate for acetylcholine esterase,
reversibly inactivates the enzyme
• Actions:-
– It stimulates both Muscarinic & Nicotinic sites of
the ANS & nicotinic receptor of neuromuscular
junction
– Duration of action: 2-4 hours

27. Physostigmine
• Therapeutic use:-
– Increase intestinal & bladder motility (in atony of
either organ)
– Used as meiotic agent for the treatment of
Glaucoma [But pilocarpine is more effective]
– T/t of overdose of anticholinergic drugs such as
attropine, phenothiazine & tricyclic anti depressants

28. Physostigmine
• Adverse effect:-
– Effect on CNS may lead to convulsions with high doses
– Bradycardia and fall in CO
– Parenteral: 1 mg/mL for IM or slow IV injection

29. B. Neostigmine
• Is more polar
• It’s effect on skeletal muscle is greater than that of
physostigmine
• It is used to stimulate the bladder and GI tract
• Antidotes for tubocurarine and other competitive
neuromuscular blocking agents
• Used in symptomatic treatment of myasthenia gravis
(weakening of muscle caused by antibodies to the
nicotinic receptor)
• Duration of action 2-4 hours

30. Neostigmine
• Adverse effect:-
– Generalized cholinergic stimulation such as
salivation, flushing, decreased blood pressure,
nausea, abdominal pain, diarrhea and broncho
spasm

31. C. Edrophonium
• Similar to neostigmine except
– it is more rapidly absorbed and
– has a short duration of action of 10 to 20 minutes (prototype short-
acting agent).
• Edrophonium is a quaternary amine and is used in the diagnosis
of myasthenia gravis
 Intravenous injection of edrophonium leads to a rapid increase
in muscle strength
• Excess drug may provoke a cholinergic crisis [antidote=Atropine]

32. Irreversible inhibitors
• Bind covalently to acetyl cholinesterase which is
extremely stable
• leads to long lasting increase in Ach act all sites where it
is released
• Extremely toxic & used as nerve agents in military &
insecticides
• Easily available and extensively used as agricultural and
household insecticides accidental as well as suicidal and
homicidal poisoning.

33. Irreversible cont…
• Initially: miosis, salivation, sweating, vomiting,
diarrhea and bronchial constriction, followed by
involvement of nervous systems
• Cause persistent depolarization of muscle and plates
resulting in blockade of neuromuscular transmission +
weakness and paralysis
• Respiratory paralysis (central as well as peripheral)
• Death is generally due to respiratory failure

34. ANTICHOLINERGICS

35. CHOLINOCEPTER BLOCKING DRUGS
• Also called as Cholinergic antagonists
• Bind to cholinergic receptor but do not triger the usual receptor
mediated intracellular effects
• These drugs are classified as:
1. Antimuscarinic agents: atropine, hyoscine (scopolamine) etc
2. Ganglionic blockers: hexamethonium, trimethaphan, etc.,
3. Neuromuscular blocking drugs: D-tubocurarine,
Suxamethonium etc.,
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36. Antimuscarinic agents
• Pharmacological actions of antimuscarinic
agents (atropine as prototype):- Can be
predicted from the knowledge of
parasympathetic responses
• Atropine an alkaloid found in Atropa
belladonna
• It blocks all subtypes of muscarinic receptors
(central & peripheral)
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37. Pharmacological actions
Eye
• Mydriasis (dilation of pupil)
• Cycloplegia (paralysis or relaxation of ciliary
muscles); this may causes:
– loss of the ability to accommodate
– Precipitation of glaucoma.
• Reduce lachrymal secretion (dry eye)

38. Pharmacological actions….
CVS
• Heart ~ Initial bradycardia followed by
tachycardia
• Blood vessels ~ constriction of blood vessels in
the heart and skeletal muscle
• Blood pressure ~ is not affected significantly
GIT
• Decrease in peristaltic movement.
• Exocrine glands - Decrease in secretion.

39. Pharmacological actions….
Respiratory system
• Bronchodilation
• Decrease in secretion
Genitourinary tract
• Urinary tract - relaxation of smooth muscles of the
bladder & ureter → this causes urinary hesitancy or
retention.
• Have no significant effect on the uterus

40. Pharmacological actions….
Sweat glands
• Suppress thermoregulatory sweating
CNS
• Usual doses of atropine cause initial stimulation followed
by long lasting sedative effect. Scopolamine may cause
drowsiness & amnesia in normal doses in sensitive
individuals.
• Reduce tremor in Parkinson’s disease.
• Suppress vestibular disturbance, especially motion
sickness.
• Toxic doses cause excitement, agitation, hallucination &
coma.

41. Therapeutic uses of atropine:-
-Ophthalmic: for diagnostic use in retinal examination.
-Antispasmodic agent: to relax GIT and urinary bladder
-As antidote for cholinergic agonists for Rx. of overdoses of
organophosphates and some type of mushroom poisoning.
-Anti-secretory agent: to block secretion in the upper and lower
respiratory tracts prior to surgery
Pharmacokinetics :- is readily absorbed, partially metabolized by
the liver and is eliminated primarily in urine
Adverse effect:-dry mouth, blurred vision, tachycardia, constipation
Presentation: - atropine sulphate 1mg/ml inj. 1% eye drop &
ointment is available. Or 0.025 mg tablet
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42. Therapeutic Uses
1. CNS
• For Parkinson’s disease ~ trihexiphenidyl,
procyclidine, benzhexal
• Motion sickness ~ scopolamine & other tertiary
amines, especially those with additional
antihistaminic action.
2. Ophthalmologic disorders
• As mydriatric and cycloplegic agents in eye
examinations.
– But use for their mydriatric effects only is not recommended unless
cycloplegia & prolonged action is required.

43. Therapeutic Uses…
3. Respiratory disorders
– As part of routine preoperative medication: to
decrease secretion & for bronchodilation.
– In asthma & COPD
4. In CV disorders
• In the management of depressed SA & AV
nodal function, especially due to marked
reflex vagal discharge that accompanies the
pain myocardial infarction.

44. Therapeutic Uses…
5. In GI disorders
• In the symptomatic treatment of diarrhea especially in
common travelers diarrhea. In other mild or self-limited
conditions of hypermotility
• Clidinium, Propantheline, Pirenzepine - used for peptic
ulcer as they reduce gastric acid secretion with fewer
adverse effects than atropine and other less selective
agents.
6. In urinary disorders
• To relieve urinary urgency and in enuresis (involuntary
voiding) in children. To relieve bladder spasm after urologic
surgery.

45. Cont…
• Hyoscine (scopolamine)
• Hyoscine butylbromide (Butopan, Farcolexin ,
Colospan S.C. Nospasmine )
 It is an alkaloid obtained from hyoscyamys
niger
 It produces peripheral effects similar to those
of atropine
 It has greater action on the CNS
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46. Adverse effects of antimuscarinic drugs
• Mydriasis when antimuscarinic agent is used
• Cycloplegia overdose to reduce GI secretion/ Motility
• Poisoned individuals
- Dry mouth - Agitation
- Mydriasis - Delirium
- Tachychardia - Hot & flushed skin
• Over dose of atropine & its congeners treated symptomatically
by:
- Physostigmine or Neostigmine
Contraindication
– Glaucoma
– Elderly men with prostatic hypertrophy
– Gastric ulcer (they may increase symptoms)
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47. DRUGS ACTING ON THE
SYMPATHETIC NERVOUS SYSTEM

48. Adrenergic system & drugs
• The adrenergic neuron:-
• Adrenergic neurons release nor epinephrine
as the neurotransmitter.
• These neurons are found in the CNS, and also
in the sympathetic nervous system
• The adrenergic receptors are located either
presynaptically on the neuron or post-
synaptically on the effector organ.
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49. Adrenergic receptors (adrenoceptors)
• Two families of receptors,
– “α” and “β” were identified on the basis of their
response to
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50. Cont…
• Characteristic responses mediated by adrenoceptors
• α1
-Vasoconstriction (skin & abdomen)
Mydriasis (eye)
α 2
-Inhibition of nor-epinephrine release
-Inhibition of insulin release (β -cells of pancreases)
β1
-Tachycardia
-Increased lipolysis
-Increases myocardial contraction
β2
-Vasodilation (Skeletal. Muscle)
-increases muscle & liver glycogenolysis
-Increases release of glucagon
-Relax uterine smooth muscle
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51. Drugs acting on the sympathetic NS
Over View of Adrenergic Agonists
Adrenergics
Drugs that stimulate the sympathetic nervous system (SNS)
Also known as adrenergic agonists or sympathomimetics
Mimic the effects of the SNS neurotransmitters:
norepinephrine (NE) and epinephrine (EPI)
•The adrenergic agonists can be placed into two major
groups:
1. catecholamine and
2. non-catecholamine on the basis of chemical structure
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52. Mechanism of action of adrenergic agonists
Direct-acting agonists:- act directly on α or β receptors,
producing effect similar to adrenaline (epinephrine) or nor-
epinephrine e.g. Epinephrine, nor-epinephrine, isoproterenol &
phenylephrine.
Indirect-acting agonists:- taken up into the presynaptic neuron
and cause the release of nor-epinephrine from the cytoplasmic
pools or vesicles of the adrenergic neurons e.g. Amphetamine &
tyramine
Mixed –action agonists:- these agents have the capacity both to
directly stimulate adrenoceptors and to release NE from the
adrenergic neuron e.g. Ephedrine
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53. Direct acting adrenergic agonists
A. Epinepherine:- is one of the catecholamines
• Commonly used in therapy
• Interacts with both α and β receptors
Actions
• Cardiovascular
• Respiratory system
• Hyperglycemia
• Lipolysis
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54. Cont…
• Therapeutic uses
Bronchospasm
In anesthetics
Anaphylactic shock
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55. Cont…
• Adverse effects
i. CNS disturbances :anxiety, fear, tension,
headache and tremor
ii. Hemorrhage
iii. Cardiac arrhythmias
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56. ‘
B) Isoproterenol
– Stimulates 1 & 2 adreneceptor
– action on CVS : increase rate & force of contraction; ↓se
peripheral resistance
– Action on Pulmonary: Bronchodilation
C) Dopamine
• D1 & D2 receptor, B1-receptor
Action
CVS: Inotropic & chronotropic effect at high dose →
Vasoconstriction (-receptor)
Renal & visceral: ↑ blood flow
• Therapeutic use: Shock (drug of choice)
Adverse effect: Same effect as sympathetic stimulation
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57. Direct acting cont’d
Phenylephrine
– Non-catecholamine
– Favors 1 –receptor
– Vasoconstrictor
– Nasal decongestant (topically)
Clonidine
– 2 –agonist
– Lower BP by acting on centrally located 2 receptors and
mainly used for treatment of HTN.
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58. Direct acting cont’d
Terbutaline
– Selective β2 agonist, longer duration
– Used as a bronchodilator for asthma & reduce uterine
contraction in pregnancy
Albuterol /Salbutamol
– Similar to terbutaline
– Used in the treatment of Asthma
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59. INDIRECT ACTING ADRENERAGIC AGONISTS
 Cause norepinephrine release from presynaptic terminals
Amphetamine
- central stimulatory action
- used in hyperactivity in children, narcolepsy & appetite control
Tyramine
- not clinically useful
- can enter the nerve terminal & displace stored norepinephrine
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60. MIXED ACTION ADRENERGIC AGONIST
• Induce release of norepinephine & activate adrenergic
receptor
Ephedrine - releases norepinephrine
- Stimulates both  & B receptors
- Ephedrine is poor substrate for COMT & MAO
- Eliminated unchanged
- Raises systolic & diastolic BP
- Produces bronchodilation
- Used prophylactically in chronic treatment of
asthma.
- Increases alertness, decreases fatigue
- Used to treat nasal congestion.
Metaramil- used to treat shock & acute hypotension
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61. Cont…
• Adrenergic Antagonists:-
• The adrenergic antagonists (also called
blockers) bind to adrenoceptors but do not
trigger the usual receptor mediated
intracellular effect
61

62. Cont…
α -adrenergic blocking agents
α -adrenoceptors profoundly affect blood
pressure
They decreased peripheral vascular resistance,
which induces a reflex tachycardia resulting from
the lowered blood pressure.
A. Phenoxybenzamine
B. Phentolamine
C. Prazosin, terazosin & doxazosin
62

63. Cont…
• Therapeutic uses: - used as antihypertensive
63

64. ß-adrenergic blocking agents
-The names of all  blockers end in “-olol” except for labetalol
 β1-selective:
Metoprololol,
Acebutolol
 atenolol
betaxolol
esmolol
• β-non selective blockers:
Propranolol
Pindolol
Timolol
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65. Therapeutic application of beta blockade
a) Hypertension
b) Angina pectoris
c) Cardiac Arrhythmias
d) Glaucoma
e) congestive heart failure
Adverse Effects of Beta1 Blockade
1) Bradycardia
2) Reduction of cardiac output
Adverse Effects of Beta2 Blockade
a. Bronchial constriction
b. Inhibition of Glycogenolysis
65

66. a. Propranolol
Prototype β-adrenergic antagonist blocks ß1 & ß 2- receptor
Has negative inotopic & chronotropic effect
Bronchoconstriction
Disturbances in glucose metabolism [decreased glycogenolysis
& glucagon)
Therapeutic effect
Hypertension
Glaucoma
Hyperthyroidism
Angina pectoris
66

67. ß-adrenergic blocking cont’d
• Adverse effect – Bronchoconstriction
Arrhythmias
Disturbances in metabolism
• Drug interaction
Cimetidine
Furosemide Potentiate its antihypertensive effect
Chlorpromazine
Barbiturate
Phenytion mitigate its effect
Rifampin
67

68. ß-adrenergic blocking cont’d
b. timolol & nadolol
-Nonselective ß-antagonists, more potent than propranolol
-Timolol reduces the production of aqueous humor in the eye
& used in the treatment of chronic open angle glaucoma
(timolol eye drop)
c. Acebutolol, atenolol, metoprolol & esmolol
-Selective ß1-antagonist
-Lower blood pressure in hypertension
-Useful in hypertensive patients.
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