Drugs acting on autonomic nervous system

1. The autonomic nervous system (ANS), is a division of the
peripheral nervous system that acts largely
unconsciously/involuntarily and regulates bodily
functions such as
❖ heart rate,
❖ digestion,
❖ respiratory rate,
❖ pupillary response,
❖ urination, and
❖ sexual arousal.
Autonomic nervous system

2. The autonomic nervoussystem has three branches:
1. the sympathetic nervous system,
2. the parasympathetic nervous system,
3. the enteric nervous system.
The sympathetic nervous system is often considered the
"fight or flight" system, while the parasympathetic
nervous system is often considered the "rest and digest"
or "feed and breed" system.

5. Drugs acting on ANS
Drugs that act on ANS can be broadly classified into two groups;
❖ Drugs that act on adrenergic receptors- Modify sympathetic
nervous system (Sympathomimetic and sympatholytic drugs).
❖ Drug that act on cholinergic receptors- Modify
parasympathetic nervous system (Parasympathomimetic and
parasympatholytic drugs).

6. Drugs acting on adrenergic receptors
a) Sympathomimetic drugs- Also known as adrenergic
agonists
b) Sympatholytic drugs- Adrenergic antagonists
Sympathetic division
Thoracic nerves and lumber nerves.
Thoracolumbar outflow (T1-L2)
Adrenergic receptorsare α1-α2 and β1-β3

7. A. Sympathomimetic drugs-
These are stimulant compounds which mimic the effects
of endogenous agonists of the sympathetic nervous
system. The primary endogenous agonists of the
sympathetic nervous system are the catecholamines
(adrenaline, noradrenaline, and dopamine), which
function as both neurotransmitters and hormones.
Sympathomimetic drugs are used to treat cardiac arrest
and low blood pressure, or even delay premature labor,
among other things.

8. Adrenaline
Nor adrenaline
Dopamine
Phenylephrine Isoprenaline
Dobutamine
Sympathomimetic agonists/drugs
Salbutamol

9. Classifications of sympathomimetic drugs
A. According to mode of action
1. Directly acting-
Adrenaline
Noradrenaline
Isoprenaline
Dopamine
2. Indirectly acting-
Tyramine
Amphetamine
Methamphetamine
3. By both mechanism-
Ephedrine

10. Classifications of sympathomimetic drugs
B. According to receptor selectivity
α1 agonist
✓phenylephrine
✓Methoxamine
α2 agonist
✓Clonidine
Both α1 and α2 agonist
✓Adrenaline
✓Noradrenaline
β1 agonist
✓Dobutamine
β2 agonist
✓Salbutamol
Both β1 and β2 agonist
✓Adrenaline
✓Isoproterenol
Both α-β agonist
✓Adrenaline
✓Ephedrine
C. According to Chemical Nature
Catecholamines
✓Adrenaline
✓Noradrenaline
✓Isoprenaline
✓Dopamine
Non-catecholamines
✓Ephedrine
✓Amphetamine
✓Phenylephrine

11. D. According to therapeutic utility
1. Vasoconstrictors
✓ Adrenaline
✓ Noradrenaline
✓ Metaraminol
2. Vasodilators
✓ Isoprenaline
✓ Dopamine
3. Bronchodilators
✓ Salbutamol
✓ Terbutaline
4. CNS stimulants
✓ Amphetamine
✓ Methamphetamine
5. Cardiac stimulants
✓Adrenaline
✓Isoprenaline
✓Ephedrine
6. Nasal decongestants
✓Ephedrine
✓Oxymethazoline
✓Dopamine
7. Uterine relaxants
✓Salbutamol
✓Nylidrin

12. Mechanismsof action
The mechanisms of sympathomimetic drugs can be
direct-acting (direct interaction between drug and
receptor), such as α-adrenergic agonists, β-adrenergic
agonists, and dopaminergic agonists; or indirect-acting
(interaction not between drug and receptor), such as
MAOIs, COMT inhibitors, release stimulants, and
reuptake inhibitors that increase the levels of
endogenous catecholamines.
COMT:Catechol-O-methyl transferase

13. Adrenergic receptor agonists- Direct acting
Direct stimulation of the α- and β-adrenergic receptors can produce
sympathomimetic effects. Salbutamol is a widely used direct-acting β2-
agonist. Other examples include phenylephrine, isoproterenol, and
dobutamine.
Indirect-acting
Dopaminergic stimulants such as amphetamine, ephedrine, and
propylhexedrine work by causing the release of dopamine and
norepinephrine, along with (in some cases) blocking the reuptake of
these neurotransmitters.
Dopaminergic agonists
Stimulation of the D1 receptor by dopaminergic agonists such as fenoldopam is
used intravenously to treat hypertensive crisis.

15. SAR of adrenergic drugs
• 1. All the adrenergic drugs contain aromatic nucleus.
• 2. Presence of (-NH2) group in the aromatic nucleus increase the
affinity for alpha receptor. Example-Noradrenaline
Noradrenaline

16. 3. Presence of (-CH3) group increase the affinity for beta-receptor. Example-
Isoprenaline.
4. Presence of (-NH2) and (-CH3) groups in the aromatic nucleus increase the
affinity for both alpha and beta receptors. Example- adrenaline.
adrenaline.

17. 5. Presence of (-OH) group in aromatic nucleus decrease lipid solubility. So,
can not cross BBB and does not exert effects on CNS. Example- dopamine. But
L-dopa can cross the BBB by LAT-1 transporter protein.
6. Absence of (-OH) group in the aromatic nucleus increases the lipid solubility
and cross BBB and exerts effect on CNS. Example- Amphetamine and
methamphetamine (Yaba???)
Amphetamine
Dopamine

18. Distributionof adrenergic receptors
Receptor and signaling Site Effects on activation
α 1
Activation causes
increase Ca+2
Blood vessels
Salivary glands
GIT
Male sex organ
Radial Muscle (pupil)
Liver
Pregnant uterus
Pancreas
Vasoconstriction
Salivation
Relaxation of GIT
Sphincter contraction
Contraction of radial
muscle
Glycogenolysis
Contraction of uterus
Decrease pancreatic
secretion
α 2
Activation decreases
cAMP
CNS
Pre-synaptic nerve
terminals
Blood vessels
platelets
Inhibition of
neurotransmitters
release from nerve
ending
vasoconstriction
Platelet aggregation

19. β1
Activation increasescAMP
Heart (dominant)
Fat cells
Juxtaglomerular cells
(Kidney cells)
Increase heart rate
Increase force of contraction
Lipolysis
Increase renin secretion
β2
Activationincreases cAMP
Bronchialsmooth muscle
Blood vessels of small
coronary artery, liver, skeletal
muscle
Beta cells of pancreas
Broncho dilation
vasodilation
β3
Activationincreases cAMP
Adipose tissue, CNS Lipolysis
D1
Smooth muscle Dilaterenal bloodvessels
D2
Nerve endings Modulatetransmitter release

21. Clinical uses of sympathomimetic drugs
❖ Norepinephrine, phenylephrine, metaraminol, mephenteramine
and methoxamine may be used to maintain blood pressure in
severe hypotension.
The use of these agents may be indicated if the hypotensive state is due to
sympathetic failure, such as possibly occurring following spinal anesthesia or injury.
In shock due to other causes, reflex vasoconstriction is typically intense; adding
alpha agonists may be harmful by further compromising organ (e.g. renal) perfusion.
α agonist

22. ❖ Dopamine, (Intropin), at low concentrations, acts at D1 receptors
and improve myocardial contractility (positiveinotropism).
❖ Centrally-acting sympathomimetics, such as clonidine or
methyldopa, are effective antihypertensive drugs.
❖ß adrenergic receptor agonists have had limited use in chronic
management of congestive heart failure.
❖ Epinephrine, a vasoconstrictor, is used in nose and throat surgical
procedures. Vasoconstriction-reduced bleeding in surgical
procedures.
❖ a adrenergic agonists may be injected into the penis for treatment
of priapism (persistent erection problem of penis)

23. ❖ß adrenergic receptor agonists have a prominent role in chronic
and acute management of asthma. ß2 selective adrenergic
receptor agonists (salbutamol) , mediating bronchodilation, are
preferable.
❖ Epinephrine is the agent of choice in emergency management of
acute hypersensitivity reactions (reaction to food, insect bites,
drug allergy)
❖ Subcutaneous epinephrine administration alleviate symptoms
rapidly and may be lifesaving when airway is compromised or in
hypotensive shock.
Mechanism: ß adrenergic receptor activation may suppress mast
cell release of histamine and leukotriene mediators.

24. Organ Effect
Eye Dilates
Heart Increases rate and force of contraction
Lungs Dilates bronchioles via circulating adrenaline
Blood
vessels
Dilate in skeletal muscle (in animals).
Constricts in gastrointestinal organs
Sweat
glands
Activates sweat secretion
Digestive
tract
Inhibits peristalsis
Kidney Increases renin secretion
Penis Inhibits Tumescence
Ductus
deferens
Promotes emission prior to ejaculation
Functions of sympathetic nervoussystem

26. B. sympatholytic drugs- Antiadrenergic drugs
is a medication that opposes the downstream effects
of postganglionic nerve firing in effector organs
innervated by the sympathetic nervous system (SNS).
They are indicated for various functions; for example,
they may be used as antihypertensives. They are also
used to treat anxiety, such as generalized anxiety
disorder, panic disorder and PTSD.
Antiadrenergic drugs-
1. Adrenergic receptor blockers
2. Adrenergic neuron blockers

27. • α1 blockers –
• prazosin
• terazocin
• β blockers-
• Non-selective beta blockers
• Alprenolol
• Bucindolol
• Carteolol
• Carvedilol (has additional α-blocking activity)
• Labetalol (has additional α-blocking activity)
• Nadolol
• Penbutolol
• Pindolol
• Propranolol
• Sotalol
• Timolol
1. Adrenergic receptor blockers

28. β1-selective agents
Acebutolol
Atenolol
Betaxolol
Bisoprolol
Celiprolol
Esmolol
Metoprolol
Nebivolol
β2-selective agents
Butaxamine
ICI-118,551

29. 2. Adrenergic neuron blockers
❖ synthesis blocker: α-methyl dopa
❖ Depletion of stores- Reserpine
❖ Release blocker: Guanethidine, Bretylium

30. Mechanismof actionof sympatholytic drugs
Adrenergic receptor antagonist- Direct acting
Direct inhibition of the α- and β-adrenergic receptors cancel the
receptor-mediated sympathomimeticeffects.
Indirect-acting
Adrenergic neuron blockers deplete catecholamines or prevent their
release at adrenergic neurons and thus abolish the catecholamine-
induced receptor-mediatedsympathomimetic effect.

31. Clinical uses of sympatholytic drugs

32. Make assignment on the following drugs with their mode of
action, pharmacological effects, clinical uses, doses and adverse
effects
• Sympathomimetic drugs- Isoprenaline,
Adrenaline/epinephrine, Salbutamol
• Sympatholytic drugs- Prazocin, Propranolol, alpha
methyl dopa

33. • Drugs acting on parasympathetic system

34. Drugs acting on Cholinergic receptors
1. Cholinergic drugs- Cholinomimetic or Parasympatho-
mimetic drugs
2. Anticholinergic drugs- Parasympatholytic drugs
Cholinergic receptors-
I. Muscarinic acetylcholine receptors (M1-M5 subtypes) are
G-protein couples receptors.
II. Nicotinic acetylcholine receptors (Approximately 17
subtypes) are ion channel receptors.

35. G protein coupled receptors(GPCRs)
GPCRs are seven transmembrane spanning receptors having three
subunits α, β, and γ, which bind to the G protein, a GTP binding
protein.

36. mAChRs subtypes
Characteristics M1 (neural) M2 (cardiac) M3
(glandular/smooth
muscle)
M4 M5
Main locations CNS: cortex,
hippocampus
Glands:
gastric,
salivary etc.
Heart: atria
Smooth muscle:
GIT
CNS: widely
distributed
Exocrine gland:
Gastric, salivary
Smooth muscle: GIT,
eye
Blood vessels:
endothelium
CNS: cortex,
striatum
CNS:
substantia
nigra
Cellular response  IP3, DAG
Depolarizatio
n
 cAMP
[Ca2+]
 K+
conductance
 IP3 stimulation,
 [Ca2+]
As M2 As M3
Functional
response
CNS
excitation,
gastric
secretion
Cardiac inhibition
Neural inhibition
Salivary secretion
Smooth muscle–
contraction
Enhanced
locomotion
Unknown

37. Muscarinic acetylcholine receptors (mAChRs)
mAChRs (M1-M5) belong to the superfamily of G-protein coupled receptors
that are broadly classified into two types based on their signal transductions.
mAChRs
subtype
Agonists Antagonists
M1 ACh, CCh,
Muscarine
Atropine, Muscarinic Toxin 7 (MT 7)
M2 ACh, CCh,
Muscarine,
Atropine, AF-DX 116
M3 ACh, CCh,
Muscarine
Atropine, Darifenacin
M4 ACh, CCh,
Muscarine
Atropine, Muscarinic Toxin 3 (MT 3)
M5 ACh, CCh,
Muscarine
Atropine, ?
Extracellular
Intracellular
Key
effectors
(examples)
Acetylcholine (ACh)
M1 M2
M3 M4
M5
Adenylyl cyclase
Gi
Gq
[Ca2+
]
MAP kinases
M current
PLCβ
MAP kinases
GIRK channels
Voltage-operated
Ca2+
channels
mAChRs agonists and antagonists

38. nAChRs, comprising 17 different subtypes (α1, β1, δ, γ/ε, α2−α10
and β2−β4) is a voltage-gated ion channel receptor. Functional
nAChR is a pentamer which can be homomeric or heteromeric.
Heteromeric
Homomeric
❖ Muscle-type nAChRs comprising of α1, β1, δ, γ/ε
❖ Neuronal-type nAChRs are various homomeric or heteromeric combinations
of twelve different subunits: α2−α10 and β2−β4
Nicotinic acetylcholine receptors (nAChRs)
❖ Ganglion-type nAChRs comprising of (α3)2 (β4)3

39. Distributionand Pathophysiological role of nAChRs
nAChRs are widely distributed throughout the nervous system
including the ganglia of suprarenal medulla, neuromuscular
junctions of skeletal muscles, CNS etc., and participate in a variety
of physiological responses, including–
anxiety, pain processing, feeding behavior and cognitive functions.
Dysfunctions of neuronal nAChRs have been associated with many
neurodegenerativediseases, including–
Alzheimer’s and Parkinson’s disease, autism spectrum disorders
and schizophrenia.

40. The nAChR, a ligand-gated ion channel, composed of five subunits. The receptor opens a
central transmembrane ion channel when ACh binds to sites on the extracellular domain
of its α subunits.

41. Ganglion type
The ganglion type nAChRs, consisting of the subunit
combination (α3)2(β4)3. It is located in the autonomic ganglia, where
activation yields EPSP, mainly by increased Na+ and K+ permeability.
Agonists
❖ Acetylcholine
❖ Choline
❖ Carbachol
❖ Nicotine
❖ Epibatidine
❖ Dimethylphenylpiperazinium
❖ Lobeline
Antagonists
❖α-Bungarotoxin
❖Mecamylamine
❖Hexamethonium
❖D-tubocurarine
❖Trimetaphan
❖Dextromethorphan
❖Methadone

42. Neuromuscular junction

43. Classificationof cholinergic drugs
Direct acting-
Acetylcholine, methacholine, bethanechol, carbachol, muscarine
(natural)
Indirect acting- Choline esterase enzyme inhibitor
i. Reversible- physostigmine, neostigmine, endrophonium
ii. Irreversible- (organophosphorous compounds-opc)
a. alkyl phosphate group- TEPP- (tetraethylpyrophosphate)
b. Aryl group- Chlorthion, malathion, parathion, diazinon

44. A. Antimuscarinic-
i. Natural-Atropine, scopolamine
ii.Synthetic- Homatropine, Ipratropium, Pirenzepine.
B. Nicotinic receptor antagonist-
Anti-cholinergic drugs
❖Mecamylamine
❖Hexamethonium
❖D-tubocurarine

45. Detailstudy on the following drugs
• Acetylcholine-Biosynthesis, Pharmacology, mode of action,
clinical applications.
• Physostigmine/neostigmine- Pharmacology,mode of action,
clinical applications, adverseeffects
• Atropine-Pharmacology, mode of action, clinical
applications, adverseeffects
• D-tubocurarine-Pharmacology, mode of action, clinical
applications, adverseeffects

46. Acetylcholine
• Biosynthesis
Choline+ Acetyl-Co-A
Acetylcholine
Choline acetyl transferase (CAT)
Packing of Ach into vesicles
Released by exocytosis process
Hydrolysis of ACh
Choline + Acetate
Choline esterase (ChE)
Therapeutic value of Ach
Ach has a very little therapeutic value,
because it is rapidly hydrolyzed by ChE, so it
has very short duration of action. It has less
selectivity and more toxicity

47. Pharmacological effects
Muscarinic action:
• Effect on cardiac muscle- decrease heart rate and cardiac contraction. Net
result is the fall of blood pressure.
• Effect on eye- Contraction of pupil of the eye (Miosis). Decrease intraocular
pressure. Increase lachrimal secretion.
• On lungs- Bronchoconstriction. Increase bronchial secretion.
• On GIT- Increase GI motility, HCl secretion and intestinal secretion.
• On urinary bladder- Relaxation of sphincter and promote micturation.
• On uterus- Contraction of uterine muscle.
• On Gall bladder and bile duct- Contraction.
• Exocrine glands- Increase secretion.

48. Nicotinic action:
• On CVS- sympathetic autonomic stimulation. Tachycardia and
increase BP
• On GIT- increase motility and secretion.
• Urinary bladder- promote micturation.
• On skeletal muscle- Muscle fasciculation
• On adrenal medulla- Increase secretion of adrenaline and nor-
adrenaline and thus increase BP.
• On CNS- Excitation followed by depression, anxiety, insomnia

49. Anti-cholinesterase
Reversible Anti-ChE Irreversible anti-ChE
Physostigmine Malathion
Neostigmine Parathion
Pyridostigmine Diazinon
Edrophonium
M/A-Anti-cholinesterase inhibits the enzyme cholinesterase and thus prevent
the hydrolysis of choline ester (Acetylcholine), thus increase the
concentration of acetylcholine and prolonging the action of acetylcholine.
Indications of reversible anti-ChE
Physostigmine: Treatment of glaucoma, Treatment of atropine poisoning.
Neostigmine: Treatment of myasthenia gravis, as antidote of neuromuscular
blocker, to stimulate bowels after surgery (paralytic ileus), to stimulate urinary
bladder after surgery (urinary retention).
Irreversible anti-ChE such as diazinon, malathion are used as insecticide.

50. Myasthenia Gravis
An autoimmune disease that causes the production of antibodies against
nicotinic receptors on the post-junctional end plate and thus decrease the
number of functional nAChRs.
Treatment-
1. Anti-cholinesterase- neostigmine, physostigmine
2. Immunosuppressant therapy- adrenocorticosteroid, cyclophosphamide.
3. Thymectomy- because thymus is responsible for antibody production.

51. Cholinergic crisis-
Excessive doses of anti-cholinesterase drug during the treatment of Myasthenia
Gravis produce a clinical condition, known as cholinergic crisis. It is due to increase
concentration of Ach.
Clinical features
Muscarinicsigns- Miosis, sweating, salivation, lacrimation, hyperactive bowel
(diarrhea)
Nicotinic signs- muscle fasciculation, muscle paralysis.
Treatment- Withdrawal of drug, Inj. Atropine sulfate i/v to counteract muscarinic
action), Inj. Pralidoxime i/v to counteract nicotinic action. Artificial respiration.

52. Atropine- Muscarinic antagonist
M/A- Reversibly competes with muscarinic receptor of acetylcholine and
antagonizes the muscarinic action of cholinergic agonists.
Pharmacological actions-
Effect on smooth muscle- Relaxation of all smooth muscle.
On GIT- Reduction of tone and peristalsis
Lungs- Relaxation of bronchial smooth muscle
Bladder- Relaxation of detrusor muscle (urinary retention)
Effects on eye-
Mydriasis- pupillary dilatation
Photophobia- due to wide pupillary dilatation.
Cycloplegia- paralysis of accommodation for near vision (by paralysis of ciliary
muscle)

53. Effects on CVS- Bradycardia followed by tachycardia. Bradycardia
due to vagal stimulation and tachycardia due to Antimuscarinic
effects.
Effects on CNS- Stimulation of CNS, Agitation, restlessness,
hallucination.
Effects on exocrine glands-Decrease secretion.
Salivary- Decrease salivation (dry mouth)
Lacrimal- Decrease lacrimation (dry eye)
Sweat- Decrease sweating (dry skin)
Gastric- Decrease HCl secretion
Bronchial-Decrease bronchial secretion.

54. Therapeutic applications
• Treatment of OPC poisoning
• As anti-spasmodic
• In GI colic
• Peptic ulcer
• Acute pancreatitis
• Dysmenorrhea
• As mydriatic
• As preanesthetic medication
• Anti-motion sickness
• In excessivesweating
• In hiccup and rhinitis
Contraindications
• Acute Glaucoma
• CCF with tachycardia
• Prostatic enlargement
• Chronic lung disease
Adverse effects
Hyperpyrexia
Dryness of mouth
Constipation
Blurred vision
Glaucoma
Tachycardia, palpitation
Retention of urine
Convulsion, restlessness
Dermatitis, Conjunctivitis

55. Neuromuscular blocker
• Drugs that block the transmission of nerve impulse at neuromuscular
junction, are called NM blocker. They are used to produce skeletal
muscle relaxation (anesthetic purpose)
Neuromuscular junction

56. • M/A- It is a competitive blocker of nicotinic receptor. It competes with Ach for
nicotinic receptor at neuromuscular junction and prevents Ach. As a result,
Ach released from the nerve ending fails to occupy the nicotinic receptor and
muscle is relaxed.
• Indications-
• In surgery- for muscle relaxation.
• In convulsions- Tetanus or convulsive drug poisoning
• Contraindications- On bronchial asthma, Myasthenia Gravis, Hyperthermia,
Electrolyte imbalance, Acidosis, Impaired cardiac, renal and hepatic
functions, pregnant and lactating mother.
• Adverse effects: Dizziness, muscle weakness, Feeling of warmth,
hypotension, Bronchospasm, prolonged apnea, cardiovascular collapse.
• Route of administration- I/V or I/M route.
D-tubocurarine