1. Autonomic nervous system
pharmacology
Assist prof Dragana Drakul

2. ANS drugs

4. Sympathicus Parasympathicus
mydrasis myosis
Inhibition of salivation Stimulation of salivation
Bronchodilation, secretion inhibition Bronchoconstriction, secretion of bronchial
glands
Tachycardia, ↑MV , ↑BP Bradycardia
Glyconeogenesis, glycoogenolysis Glycogen synthesis
↑ sphyincter tone in GIT, inhibition of peristalsis HCl secretion, stimulation of peristalsis, ↓
sphincter tone
Stimulation of adrenal medulla Inhibition of adrenal medulla
Relaxation of the bladder, ↑ sphyncter tone of
the bladder
Contraction of the smooth muscles of the
bladder, ↓ sphyncter tone of the bladder
Ejaculation, vaginal contractions Erection, sexual arousal

8. Cholinergic receptors
Muscarinic receptors Nicotinic
• Ionotropic
• Excitatory
• NM: muscle type
• NN: nervous type
• Metabotropic
• Excitatory i inhibitory
• M1, M2, M3, M4, M5

9. Muscarinic receptors
M2, M4
• Gi
M1, M3, M5
• Gq
G
protein
Receptor Signal pathway
Gi Alpha2
adrenergic,
muscarinic
M2 i M4,
opioid
Decrease in cAMP, K
channels opening,
inhibition
Gq muscarinic
M1 i M3,
alpha1
adrenergic,
V1
vazopressin
PLC – IP3 i DAG,
increase in
intracellular Ca2+,
excitation

10. Cholinergic drugs
Direct
• Muscarinic
• Cholin esters
• pilocarpine
muscarine
• Nicotinic
• ganglia
• neuromuscular
junction (NMJ)
Indirect
•Reversible
• edrophonium
• carbamate
•Irreversible
• organophosphate

11. Direct cholinergic drugs
Choline esters
• acetylcholine –short acting
(↓ MV and Fr, BP, ↑GIT
peristalsis, eyedrops, myosis i
↓IOP)
• Karbachol (long acting, eye),
• metacholine (short acting –
diagnosis of asthma),
• bethanechol (long acting, ind.
urinary bladder atony, urinary
retention)

13. Pharmacology of nitric oxide (NO)
 EDRF (NO) discovery 1980–1987.
 Originate from L-arginine under cathalic
influence of NO-synthase.
 Sodium-nitroprusside reacts with physiologic
sulphhydryl groups and releases NO
 NO activate guanylate cyclase and cyclic GMP
sinthesis (it can be inhebited by methylen
blue).
 NO can be inactivated by free oxygen radicals.

14. Direct cholinergic drugs
pilocarpine, muscarine
• Natural origin: Pilocarpus jaborandi, Amanita muscaria
• Pilocarpine 1%, eyedrops (myosis, ↓IOP)
TROVANJE GLJIVAMA:
 Amanita muscaria:
Symptoms of poisoning appear in 15 to 30 min, it can
be stopped by atropine.
 Amanita phalloides, Amanita virosa, Galerina
automnalis i Galerina marginata
Symptoms of poisoning appear in 6 to 12 hours. Liver
and kidney damage. Atropine is not efficient,
Hemodialysis!

15. Indirect cholinergic drugs or
anticholinesterase supstances
Reversible
• Short acting
• edrophonium (2-10 min) (dij –
Myasthenia gravis)
• Carbamate: enzyme carbamylation
(30 min- 2h), spontaneous
hydrolysis
• neostigmine (polar, N Rc, My g,
↑GIT and bladder tone, antagonist
of NMJR)
• piridostigmine,
• fizostigmine (N and M receptors,
CNS, long acting, atropine
poisoning)
• Alzheimer’s desease (donepezil,
galantamine, rivastigmine)
Irreversible
• Long acting (insekticides
and nerve agents)
• Organophosphates, organic
derivates of phosphoric
acids
• They phosphorilate
enzyme, >500h aging of
enzyme
• Insecticides: paraoxon,
malation
• Nervous agents: sarin,
tabun, soman, VX

16. Regeneration of ACH-esterase
• Oxime drugs can
regenerate enzyme If
they are given on time
• Nukleophilic agents
(pralidoxime) bind to
active place on
enzyme
• If the complex
“poison-enzyme” is
aged, oximes do nor
have any effect

17. Therapy of organophosphates
poisoning
1. Atropine
2. Oxyme
3. Diazepam
(comvulsion)
4. Maintenance of
respiration
• Atropinization signs:
– Increased heart rate
120/min
– Mydriasis
– Dry mouth
– Flushed skin

18. Cholinergic effects
muscarinic nicotinic central
Bronchoconstriction Skeletal muscles fasciculation Restlessness and insomnia
Increased bronchial glands
secretion
Tachicardia Confusion and ataxia
Sweating Hypertension Convulsion
Salivation Respiratory depression
Bradicardia Cirkulatory collapse
Myosis and sight disturbance
Intestinal cramping and
diarrhea
Urinary incontinence

19. Indications, side effects and
contraindications for cholinergic drugs
Indications
• Glaucoma
• Postoperative ileus
• Postoperative atony of urinary
bladder
• Myasthenia gravis
• Reversion of peripheral
myorelaxant acting
• Alzheimer’s disease
• Diagnosis: asthma, Myastenia
gravis
• Anticholinergic agents
poisoning
• Sjogren’s syndrome
SE
• Myosis, lacrimation
• Salivation
• Bronchoconstrictio,
bronchorrea
• Bradicardia
• Nausea, emesis
• Diarrea
• Urinary incontinence
• Sweating
• Muscle weakness
CI
• Bronchial asthma
• Peptic ulcer

20. Anticholinergic drugs
Antimuscarinic
Blockage of M
Rc
atropine,
scopolamine
Ganglionic
blockers
Blockage of NN
Rc
hexamethonium,
mekamylamine
Muscle
relaxants
Blockage NM Rc
* Numberous CNS drugs have anticholinergic effects

21. Antimuscarinic drugs
Alcaloids (natural)
atropine, scopolamine
Semisynt. and
syntethic (tertiary
ammonium compound)
Mydriatics; tropicamide
cyclopentolate
Parkinson’s disease: biperiden,
benztropine, trihexyphenidyl
Hyperactive bladder:
darifenacin, solifenacin
tolterodine
Semisynt. and
syntethic (quaternary
ammonium compound)
Antispasmodics:
scopolamine-butylbromide,
homatropine-methybromide
Bronchodilators: ipratropium
i tiotropium;

22. Atropine Scopolamine
short acting long acting
CNS

23. Mydriatics
atropine
• Long acting (days)
Semi synthetic and synthetic
• Short acting
• tropikamide
• cyclopentolate
• homatropine

24. Parkinson’s disease
• biperiden
• benztropine
• trihexyphenidyl

25. Hiperactive bladder; urinary
incontinence
• M3 selective drugs:
– darifenacin
– solifenacin
– oxybutynin
– fesoterodine
– tolterodine

26. Antispasmodics
• Quaternary ammonium
compounds
• Decreased liposolubility
• Do not pass HEB
• Ind: spasms in GIT, renal
and biliary colic
– scopolamine-
buthylbromide
– trospium

27. Anticholinergic bronchodilators
ipratropium-bromide
• Inhalatory
• Neselective blockage of M
Rc
• Short acting
• Ind: COPD, asthma
tiotropijum-bromide
• Inhalatory
• Neselective blockage of M
Rc
• Long acting
• Ind: COPD, asthma

28. Indication, SE and CI of antimuscarinic
drugs
Indication
• Poisoning with
organophosphates, fungi
• GIT cramps
• Motion sickness
• In ophthalmology: mydriasis
and cycloplegia
• Parkinson’s disease
• Preanesthetic medication
• Bronchial asthma and COPD
• Urinary incontinenced
• Cardiology: removing of vagal
bradycardia
SE
• Sight disturbance
• Dry mouth
• Tachycardia
• Constipation
• Urinary retention
• Dry skin, hyperthermia
• Irritation, confusion, manic
behavior
CI
• Prostate hypertrophy
• Postoperative urine retention
• Glaucoma