Pharmakologi Obat Pada

Gangguan Sistem Sensorik

Akhmd Edy Purwoko
Departmen Farmakologi & Toksicologi
FKIK UMY
Lima macam indra berfungsi sebagai alat
sensor dalam bahasa Sanskerta disebut
panca budi indriya dan dalam bahasa
Indonesia lebih dikenal sebagai panca
indra yaitu: alat pembantu untuk melihat
(Mata), alat pembantu untuk mengecap
(lidah), alat pembantu untuk membau
(hidung), alat pembantu untuk
mendengar (telinga), dan alat pembantu
untuk merasakan (kulit/indra peraba).
ETIOLOGI --> CINTA DENGANMU
congenital, inferior, neoplasma, degenration,missellaneus

Organ Sensorik
Mydriatic & Miotic
(Symphatethic,
Cholinergik &
Anticholinergik)
A. Review of Sympathetic Activation

‘Fight’ or ‘Flight’ on Stress

Heart
◦ HR, contractility, conduction
velocity
Vessels (arterioles)
◦ Skin, cutaneous, visceral :
constrict
◦ Skeletal muscle, coronary:
dilate
Sympathetic
A. Review of Sympathetic Activation
Vessels (Vein): constrict
Eye
◦ Radial muscle, iris:
contract
◦ Ciliary muscle: relax for
far vision Mydriatic
Lung
◦ Tracheal and bronchial
muscle: relax
Stomach and intestine
◦ Motility and tone
◦ Sphincters :
contraction
◦ Secretion (intestine):
inhibition
Urinary bladder
◦ Detrusor or bladder wall:
relax
◦ Trigone, sphincter:
constrict
Posterior pituitary: ADH
secretion
Liver: glycogenolysis,
gluconeogenesis
Pancreatic b cells
---stimulate insulin release
Skeletal muscle
◦ contractility,
glycogenolysis, K+ uptake
Fat cells: lipolysis
Uterus
◦ non-pregnant: relax
Sweat gland :
secretion
Hair : piloerection
The effects of adrenomimetic
drugs are similar to sympathetic
activation.
But why each adrenomimetic
drug can produce different
responses?
The differences in affinity to
adrenoceptor subtypes are
responsible for different
responses.
 Types and subtypes of
adrenoceptors
Adrenergic receptors locate on
smooth muscle, cardiac muscle,
exocrine glands, endocrine
glands and on nerve terminals.
the transmitter in all adrenergic
neurons was NE
When NE and Epi interacted with
an adrenoceptor, in some tissues
the response was excitatory
while in other tissues it was
inhibitory
Two subtypes of adrenoceptors (a and b)
 a - excitatory in most tissues
(except - intestinal smooth muscle)
 b - inhibitory in most tissues
(except - heart)
Rank Order of Potency
1. a receptors Epi > NE >> Isoprenarin
2. b receptors Iso > Epi > NE
Type of adrenoceptor
 a 1,a 2
b 1,b 2 , b 3
 DA1, DA2
Generally
a 1 ---Contraction of smooth
muscle
b 2 ---Relaxation of smooth
muscle
b 1 ---Stimulation in heart
a 2 ---Inhibition, for GI tract +saraf
simpatik ---Relaxation
Autonomic
control
of pupil (A)
and site
of action of
mydriatics (B)
and
miotics (C)
 1 receptor
β2 receptor
Radial muscle, iris (pupillary dilator)
◦ contraction (a 1) --> mydriasis
◦ topical phenylephrine and similar alpha agonists
◦ accommodation is not significantly affected
◦ outflow of aqueous humor may be facilitated
--> reduce intraocular pressure (IOP)
Ciliary muscle: relaxation for far vision (b 2)
Ophthalmic Application
Alpha agonists, especially phenylephrine, often
used topically to
◦ produce mydriasis, eg, ophthalmologic exam
◦ reduce the conjunctival itching and congestion
caused by irritation or allergy
◦ do not cause cycloplegia (paralysis of
accommodation)
Epi and prodrug, dipivefrin, sometimes used for
glaucoma. Phenylephrine also
 Parasympathetic Nervous System plays an important Role
in physiologic and pathophysiologic responses - “Rest and
Digest”
 Drugs that block Cholinoreceptors have important clinical
effects, some of which are of great clinical value
 Cholinoceptor antagonists are, like agonists - Muscarinic
and Nicotinic
 Antinicotinic – ganglion blockers and MN junction
blockers
◦ Discussed elsewhere
 Muscarinic blockers
◦ Atropine is the prototype – many synthetic and semi
synthetics are available now
◦ All are competitive blockers

Parasympathetic
Recall - Muscarinic (M) and
Nicotinic (N) Receptors:

Muscarinic (M) - Nicotinic (N) – ligand

GPCR gated
Muscarinic Receptor Subtypes: M1, M2, M3,
M4 and M5
M1 M2 M3
Location Autonomic ganglia, Heart and CNS SMs of Viscera,
Gastric glands and CNS Eye, exocrine
glands and
endothelium
Functions EPSP & Histamine Less impulse Visceral SM
release & acid secretion generation, less contraction,
with CNS learning and velocity of Constriction of
motor functions conduction, pupil, contraction
decreased of Cilliary muscle
contractility, and vasodilatation
less Ach release
Agonists Oxotremorine and MCN Methacholine Bethanechol
and MCN-343A
Antagonist Pirenzepine Methoctramine & Darifenacin
s Triptramine
 Nicotinic receptors: nicotinic actions of ACh
are those that can be reproduced by the
injection of Nicotine (Nicotiana tabacum)
 Can be blocked by tubocurarine and
hexamethonium
 ligand-gated ion channels
◦ activation results in a rapid increase in
cellular permeability to Na+ and Ca++
resulting - depolarization and initiation of
action potential

Nicotinic (N) Receptors

Sites of Cholinergic transmission
and types of Receptors
Site Types Selective Selective
agonist antagonist
All Postganglionic
Parasympathetic Muscarini Muscarine Atropine
Postganglionic sympathetic c
to sweat gland & BV
Ganglia (Both Para and NN DMPP Hexamethoniu
sympathetic and also m
Adrenal Medulla
Skeletal Muscle NM PTMA Curare
CNS Muscarini Muscarine Atropine
c Oxotremorin
e
 Muscarinic Agonists
Origin Nicotinic BBB Uses
Effect Permeabilit
y
(pembuluh
darah otak)
Methacholine synthetic low low challenge
for asthma
Carbachol synthetic high low miosis
glaucoma
Muscarine natural no low research
hallucinogin
Pilocarpine natural no high xerostomia

Brown & Laiken (2011). In Pharmacological Basis of Therapeutics, p. 219-237.

Bethanechol
Short-acting muscarinic
agonist
Used to treat non-
obstructive urinary
retention
 Natural: Atropine and Hyoscine (scopolamine)
 Semisynthetic derivtives: Homatropine, Atropine
methonitrate, Hyoscine butylbromide, Ipratropium
bromide, Tiotropium bromide
 Synthetic Compounds:

 Mydriatics: Cyclopentolate and Tropicamide

 Vasicoselective: Oxybutynin, Flvoxate, Tolterodine
 Antiprkinsonian: Trihexyphenidyl, Procyclidine, Biperiden
 Antisecretory:
 Quartenary ammonium compounds: Propantheline, Oxyphenonium,
Clidinium, Glycopyrrolate, Isopropamide

 Tertiary amines: Dicyclomine, Valethamate, Pirenzepine

Classification - Anticholinergics
 Atropine (hyoscyamine) is found in the plant Atropa
belladonna, or deadly nightshade
 Also in Datura stramonium, also known as jimsonweed
(Jamestown weed) or thorn apple
 Scopolamine (hyoscine) occurs in Hyoscyamus niger
 Many antihistaminics: Histamine, Serotonin, & Ergots
alkaloids, Antipsychotic Agents & Lithium and
antidepressant drugs have similar structures and,
predictably, significant antimuscarinic effects

Datura stramonium
Atropa belladona

Atropine as Prototype
 Atropine: Ester of tropic acid (aromatic acid) +
tropine
 Scopolamine: Ester of tropic acid (aromatic acid) +
scopine
 Chemically tropine and scopine are closely similar
 Most of the actions of both are similar

Atropine - Chemically
 Atropinecauses reversible (surmountable)
blockade of cholinomimetic actions at muscarinic
receptors
◦ blockade by a small dose of atropine can be overcome
by a larger concentration of acetylcholine or equivalent
muscarinic agonist
 Atropine is highly selective for muscarinic
receptors
 Does not distinguish between the M1, M2, and M3
 Some quaternary amine antimuscarinic agents
have significant ganglion-blocking actions

Atropine - Mechanism
 Absorption:
◦ The natural alkaloids and most tertiary antimuscarinic drugs are well
absorbed from the gut and conjunctival membranes – some even over
the skin (scopolamine)
◦ Quaternary ones – only upto 30%
 Distribution:
◦ Atropine and the other tertiary agents are widely distributed in the
body
◦ Scopolamine is rapidly and fully distributed into the central nervous
system where it has greater effects than most other antimuscarinic
drugs
◦ Quaternary derivatives are poorly taken up by the brain
 Metabolism:
◦ Atropine is metabolized in liver by conjugation and 60% excretes
unchanged in urine
◦ Effects disappear quickly within 2 Hrs except eye

Atropine - Pharmacokinetics
 Central Nervous System: Overall CNS stimulant
◦ Atropine has only peripheral effects and minimal stimulant
effect on CNS – low entry
◦ Atropine stimulates many medullary centres – vagal,
respiratory and vasomotor
◦ Depresses vestibular excitation – antimotion sickness property
◦ Scopolamine has more marked central effects – amnesia and
drowsiness
◦ Parkinson's disease is reduced by centrally acting
antimuscarinic drugs – acting on Basal ganglia (atropine)
 Eye:
◦ Topical atropine and other tertiary antimuscarinic drug - results
in unopposed sympathetic dilator activity and mydriasis
◦ Cycloplegia: desirable in Ophthalmology
 but hazardous in narrow angle glaucoma
◦ Dry Eye: Not desirable

Pharmacological Effects - Atropine

Paralysis of accommodations -
Atropine
Effect of Scopolamine
 CVS:
◦ Moderate and high doses: TACHYCARDIA
◦ More In young adults - Because of Vagotonia
◦ MOA: SAN, AVN are richly supplied by Parasympathetic Nerves
 Atropine produces PS blockade in SAN – tachycardia
 AVN – Atropine produces PS blockade – higher AV conduction rate
(reduced PR interval in ECG)
◦ IM/SC injection initially – transient BRADYCARDIA – may
be due to inhibition of presynaptic M1 autoreceptor inhibition
(not due to stimulation of vagal centre)
 Evidenced by Pirenzepine injection does not cross BBB
◦ BP: Parasympathetic nerve stimulation dilates coronary arteries, and
sympathetic cholinergic nerves (predominant) cause vasodilatation in
the skeletal muscle vascular bed - Atropine can block this
vasodilatation
 But, histamine release cause direct vasodilatation
◦ However, No marked effect on BP

Pharmacological Effects of Atropine

– contd.
Heart rate and salivary secretion
after Atropine
 Respiratory System:
◦ Smooth muscles and secretor glands receive
innervations from parasympathetic system
◦ Bronchodilatation and reduction in secretion in asthma
◦ Particularly used in COPD and prior to initiation of
inhalation therapy in asthma
 Sweat glands:
◦ Suppresses thermoregulatory sweating – peripheral and
central action
◦ May cause "atropine fever“ - children
 Urinary:
◦ Slows voiding
◦ Useful in spasm conditions – inflammation
◦ Danger – Elderly (BHP)

Pharmacological Effects of Atropine

– contd.
GIT:
◦ Decrease in GI motility
◦ Gastric emptying time is prolonged, and
intestinal transit time is lengthened
◦ Dry mouth occurs frequently in patients taking
antimuscarinic drugs
◦ Gastric secretion is blocked with larger doses –
blocks acid, pepsin and mucus secretion
◦ Pirenzepine is more effective

Pharmacological Effects of Atropine

– contd.
Various Effects of Atropine
Mydriatic and Cycloplegic
Used as eye drop or ointment:
◦ Diagnostic:
 Atropine 1% ointment is used
◦ Measurement of refractive error
◦ Ophthalmic examination of retina - fundoscopy
◦ Preferred ones: Homatropine, Tropicamide and
cyclopentolate – shorter action
◦ Therapeutic Uses:
 For resting eye: Iritis, iridocyclitis, keratitis,
corneal ulcer etc.
 Alternating with miotics (prevention of synechia)

Anticholinergics - Ophthalmic uses

 Antisecretory:
1. Preanaesthetic medication:
 To reduce secretions
 To prevent laryngospasm
2. Peptic ulcer
3. Pulmonary embolism
4. Hyperhidrosis
 Antispasmodic:
◦ Intestinal and renal colic – not in biliary colic
◦ Diarrhoea (nervous and drug induced) – Lomotil
◦ Pylorospasm, gastric hypermotility, gastritis, nervous
dyspepsia etc.

Therapeutic Uses Anticholinergics

 ◦ Parkinsonism: Mild cases of parkinsonism
(early cases), Drug induced Parkinsonism and
adjunct to Levodopa
◦ Motion sickness:
 Hyoscine (scopolamine) is the drug used – Oral,
injection and transdermal patch
 0.2 mg orally given as prophylaxis before journey
 Not effective in other type of vomiting
◦ Twilight sleep: sedation and amnesia
 Toantagonize Muscarinic effects of Drugs and Poisons:
Anti-ChE, Mushroom poisoning, and to block Muscarinic
effects of Neostigmine, Cobra envenometion

Uses Anticholinergics – contd.

 CVS:
◦ Vagolytic - Marked reflex vagal discharge in myocardial
infarction - depression of SA or AV node function to
impair cardiac output - Parenteral atropine or a similar
antimuscarinic drug
◦ Hyperactive carotid sinus reflexes
 Respiratory:
◦ Ipratropium Bromide – in COPD and chronic bronchitis
 Improves mucociliary clearance and bronchodilatation

Anticholinergics – uses
 Commonly occurring but of non serious type
 Mydriasis and cycloplegia – using as
antisecretory or Preanaesthetic medication
 Poisoning:
◦ Causes:
 Drug overdose
 Consumption of Belladona and Datura seeds
◦ Symptoms:
 Dry mouth, difficulty in swallowing and talking
 Dry, flushed and hot skin, fever, decreased bowel sound,
photophobia
 Excitement, psychotic behavior, delirium and
hallucinations
 Hypotension and cardiovascular collapse

Anticholinergic - ADRs
Diagnosis: Methacholine 5 mg or
Neostigmine 1 mg SC – no muscarinic
effects
Treatment:
◦ Gastric lavage in case of ingestion – KMNO4
◦ Dark Room
◦ Cold sponging and ice bags
◦ Physostigmine 1–3 mg SC or IV
◦ Maintenance of blood volume, assisted
respiration and Diazepam to control
convulsions

Atropine Poisoning – contd.

Glaucoma – Narrow angle (Precipitation
of angle closure)
BHP – urinary retention
Acid peptic ulcer diseases (Non-
selective ones) – precipitation of
symptoms

Anticholinergic - Contraindications
 Incomplete Oral absorption, Poor penetration in Eye and
CNS, Longer acting than Atropine, Higher Nicotinic
Blocking Property, NM Blockade
 Drugs:
◦ Hyoscine Butylbromide: Oesophageal and GIT spastic
conditions – Buscopan
◦ Atropine methonitrate: Abdominal colics and hypercidity
◦ Ipratropium Bromide: Selective action on Bronchial SM
 Enhanced mucocilliary clearance (contrast to Atropine)
 Slowly acting Bronchodilator - 1-2 Hrs (prophylactic use)
 Acts mainly on larger Central airways (contrast to
sympoathomimetics)
 More effective in COPD than Asthma
 Other Drugs – Tiotropium bromide, Propantheline, Oxyphenonium,
Clidinium and Glycopyrrolate

Atropine Substitutes - Quarternary

compounds
 Dicyclomine and valethamate
 Dicyclomine: Direct SM relaxant and weak antispasmodic
◦ Lesser side effects than Atropine
◦ Atropine toxicity in infants (not recommended below 6
months)
 Valethmate: Dilatation of Cervix in delayed labour

Tertiary Amines
 Oxybutynin:
◦ Specific selectivity for receptors in Urinary bladder and salivary
gland (M1/M3)
◦ Additional smooth muscle relaxation property
◦ Uses:
 Bladder surgery after urologic surgery
 Spina bifida and nocturnal enuresis
 Involuntary voiding in patients with neurologic disease -
children with meningomyelocele
 Dose: 5 mg BD/tds or local instillation
 Tolterodine – M3 selective
 Flavoxate – similar to Oxybutynin
 Drotaverine: Newer Drug - Non anticholinergic smooth
muscle relaxant – elevation of cAMP/cGMP
◦ Renal colic, biliary colic, IBS, uterine spasms etc.
◦ Dose: 40 – 80 mg tds

Individual Drugs – Vasicoselective

Mydriatics
Homatropine,
Cyclopentolate and
Tropicamide –
various
ophthalmological
procedures as
substitutes of
Atropine
 Ganglion stimulants:
◦ Selective agonists: Nicotine, Lobeline, DMPP and TMA
◦ Non-selective: Acetylcholine, carbachol, Pilocarpine,
Anticholinesterases
 Ganglion Blockers:
◦ Competitive blockers:
 Quaternary compounds: Hexamethonium,
Pentolinium
 Secondary/tertiary: Mecamylamine, Pempidine
◦ Persistent depolarizers: Nicotine (large dose) and
Anticholinesterases

Drugs acting in Autonomic ganglia

 THANK YOU
ALHAMDULILLAH