FARMAKOLOGI

REVIEW FROM LAST SEMESTER

 Pharmacokinetics = The life cycle of the drug (Jadi bagaimana pengaruh tubuh
terhadap obat)
Pharmacodynamics = Efek obat terhadap tubuh
 Ingat bahwa ada 4 proses dalam disposisi obat, yaitu ADME :
1. Absorption from site administration (Inhalasi, Injeksi, Dubur, Oral, Subligual,
dkk)
2. Distribution
3. Metabolism
4. Excretion
 Sifat obat bersifat basa lemah dan asam lemah. Kenapa ? Biar tidak disosiasi semuanya.
Jadi yang jadi ion lewat ion channel (hidrofil) sementara senyawa yang tidak terion
melewati membram plasma (lipofil)
 Absorption ada 4 cara, yaitu :
1. Difusi melewati membran lipid
2. Solute Carrier transporter
3. Aquaporins
4. Pinocytosis
 Difusi dan berikatan dengan protein transporter (globulin, albumin, dkk). Bisa dalam
bentuk bound dan unbound. Obat akan dibawa ke tiap organ target dan akan dilepas.
Yang masih dalam keadaan ‘bound’ akan tetap berada di peredaran darah.
 Metabolisme ada 2 proses yaitu proses katabolisme dan konjugasi. Obat akan
dikatalisis (oxidasi, hidroxilasi, deaminasi, dkk) dan menjadi senyawa turunan dan
selanjutnya dikonjugasi. Senyawa deritatif biasanya sifatnya beracun karena ada gugus
(-OH)
 Enzim yang berpengaruh adalah enzim P450. Kalau diinduksi  akeh senyawa deritatif
toxic. Kalau diinhibisi  senyawa obat2 banyak di pembuluh darah. Overdosis.
 Proses Eliminasi ada 3 yaitu : Filtrasi di glomerulus, Ekskresi di renal tubul, difusi di
Tubulus coligens (senyawa lipofil diambil buat dipake lagi).
  Kerja obat ada yang agonis dan antagonis. Agonis sendiri dibedakan atas beberapa
jenis, yaitu :
- Full Agonist = Respons maksimal ketika obat yang berikatan dengan reseptor tidak
sampai 100%
- Partial Agonist = Respons kurang maksimal ketika obat yang berikatan dengan
reseptor sampai 100%
- Inverse Agonist = Bersikap negatif dari agonist.

BLOK 8

THE AUTONOMIC NERVOUS SYSTEM

 Saraf Otonom ada 2 macam yaitu Simpatis dan Parasimpatis.

 Simpatis = dikenal sebagai saraf thoracolumbar, berfungsi dalam fight or flight
response, preganglion dekat MedSpinal.
 Parasimpatis = dikenal sebagai saraf craniosakral, rest and digest, preganglion jauh dari
MedSpinal.
 Setiap tubuh diinervasi oleh tiap2 saraf otonom ini. Namun ada beberapa organ yang
spesifik diinervasi saraf2 tertentu.
Simpatis = Medulla Adrenal, Ginjal, Kelenjar Keringat, Pilomotor Muscle, Blood
Vessels di Skeletal Muscle, Splanchnic, dan Kulit
Parasimpatis = Cilliary Muscle, Otot polos Bronkus
 Pre-ganglionic dan Post-ganglionic dari Saraf Otonom, yaitu :
 Efek dari saraf simpatis dan parasimpatis terhadap organ efektor, yaitu :
Simpatis Parasimpatis
Target Effect Target Effect
α Gl. Salivary Thick secretion Gl. Salivary Thin Secretion
α M. Pupil radial Dilatation Lacrimal Gland Tear Secretion

Blood Vessel
M. Circular Iris Pupil Constriction
α Skin; Splanchnic Constriction
Ciliary Muscle Near vision
β2 Muslce Dilatation
acomodation
β1 Heart Heart Rate ↑ Heart Heart Rate↓
Gut Wall Motility ↑
β2 Gut Wall Motility ↓
Gut Sphincter Relaxation
α Gut Sphincter Constriction
Gut Secreations Secretion ↑
β2 Lung Airways Dilatation Lung Airways Constriction
Exocrine &
Epinephrine
Adrenal Medulla Pancreas endocrine
Secretion
secretion↑
Kidney Renin Secretion Rectum Defecation
β2 Bladder detrusor Relaxation Bladder detrusor Constriction
α Bladder Sphincter Constriction Bladder Sphincter Relaxation
α Male Genital Ejaculation Male Genital Erectiom
Gl. Sweat Sweating
α Pilomotor Muscle Piloerection

 Setiap pre-ganglionik fibre melepaskan NT Ach (Baik simpatis maupun parasimpatis).

Pada post-ganglionik fibre, setiap saraf baru mensekresikan Neurotransmitter masing-
masing. Pada post-ganglionik fibre simpatis mensekresikan Epinephrine namanya
adrenergic (Kecuali Kelenjar Keringat, ttp Ach). Pada post-ganglionik fibre
parasimpatis mensekresikan Acetyl-Choline sebagai NT utamanya disebut cholinergic.
 Presypnatic modulation ada untuk mengatur NT di pre-sinaps. Terminal presinaptik
yang mensintesis dan melepaskan neurotransmitter sebagai respons terhadap aktivitas
listrik pada serabut saraf sering kali sensitif terhadap zat neurotransmitter itu sendiri
dan terhadap zat lain yang dapat diproduksi secara lokal di jaringan. Efek presinaptik
 seperti itu paling umum bertindak untuk menghambat pelepasan pemancar, tetapi dapat
meningkatkannya.
 Ada heterotrophic interactions dan homotrophic interactions.
 Co-transmitter lainnya seperti :
- ATP
- Neuropeptide Y (NPY)
- Nitric Oxide (NO)
- Prostaglandin
- Adenosin
- Dopamin
- 5-hydroxytryptamine
- GABA
- Vasoactive Intestinal Peptide
- Endocannabinoid
CHOLINERGIC TRANSMISSION

 Ada pengaruh nicotinic dan muskarinik. Efek muskarinik sesuai dengan tabel diatas.
Sementara untuk efek nikotinik sendiri adalah Stimulasi dari gangglion otonom, sekresi
adrenaline, dan stimulasi dari otot volunter.
 Acetylcholine berasal dari AcetylCoa + Choline  Ach (Perlu enzim AchTransferase).
Depolarisasi pada terminal presinaps, exocytosis vesikel berisi Ach, binding dgn
reseptor, kalau sudah selesai di re-uptake dan di-degradasi.
 Untuk NICOTINIC RECEPTOR ada 3 kelas utama –otot, Central Nervous System,
Ganglionic (peripheral)—Bersifat ligand-gated ion channel (ionotropic). Selain itu
respons utama mereka sendiri menyebabkan terjadi excitatory (EPSP).

 Untuk MUSCARINIC RECEPTOR ada 5 yaitu M1, M2, M3, M4, dan M5.
Semuanya bersifat G-Protein Coupled Receptors (metabotropic receptor)
- Untuk angka ganjil (M1, M3, M5)  berhubungan dengan Gq  aktivasi
Phospolipase C  ↑ produksi IP3 dan DAG.
- Untuk angka genap (M2 dan M4)  Berhubungan dengan Gi  inhibisi adenyl
cyclase  ↓ C-AMP  ↑ K+
A. Cholinomimetic Drug
1. Direct-Acting Cholinergic Agonist
- Parasimpatomimetik, karena efek utama yang mereka hasilkan pada
menyerupai efek stimulasi parasimpatis.
- Diklasifikasi menjadi 2 kelas, yaitu :
a. Choline esters
Yang termasuk seperti ACh endogen dan ester-kolin sintesis, seperti
carbachol dan bethanechol.
b. Alkaloids
Nikotin dan Pilocarpine
- Structure Activity Relationship Fitur penting ACh untuk aktivitasnya
o Kelompok amonium kuaterner, yang menanggung muatan positif, dan
 o Gugus ester, yang memikul muatan negatif parsial dan rentan terhadap
hidrolisis cepat oleh cholinesterase
- Specifity yang kecil sehinggi limited of clinical uses.
 Effect of Muscarinic Agonist
- Cardiovascular Effect
o ↓ Heart Rate & Decreased Atria contraction  ↓ Cardiac Output
o Vasodilatation (dimediasi NO)
o Akibat Vasodilatasi & ↓ CO  ↓ Arterial Pressure
- Smooth Muscle Effect
o Kontraksi sebagai respons langsung terhadap agonis muskarinik,
berbeda dengan indirect effect pada otot polos pembuluh darah.
o Aktivitas peristaltik GI Tract ↑  nyeri kolik, dan otot polos
kandung kemih dan bronkial juga berkontraksi.
- Sweating, lacrimation, salivation and bronchial secretion
o Stimulation of exocrine glands and bronchial secretion and constriction.
- Eye Effect
o Kontraksi M. Constrictor pupillae & Regulate Intraocular Pressure
 Clinical Use of Muscarinic Agonist
- Bethanecol merangsang reseptor muskarinik, menyebabkan peningkatan
motilitas dan tonus usus. Merangsang otot detrusor kandung kemih,
sedangkan otot trigonum dan sfingter rileks. Efek ini merangsang buang air
kecil.
- Bethanecol digunakan untuk menstimulasi kandung kemih, terutama pada
retensi urin nonobstruktif postpartum atau postoperatif. Bethanechol juga dapat
digunakan untuk mengobati atonia neurogenik serta megakolon.
- Bethanechol atau distigmine (inhibitor cholinesterase) sekarang jarang
digunakan sebagai obat pencahar stimulan atau untuk merangsang pengosongan
kandung kemih.
- Tetes mata Pilocarpine menyebabkan penyempitan pupil (miosis) dan telah
digunakan untuk mengobati glaukoma (peningkatan tekanan di dalam mata).
- Pilocarpine (partial agonist) atau cevimeline (agonis M3 selektif) dapat
meningkatkan sekresi air liur dan lakrimal pada pasien dengan mulut kering
atau mata kering (mis. Setelah iradiasi, atau pada pasien dengan kerusakan
 autoimun pada kelenjar ludah atau kelenjar lakrimal seperti pada sindrom
Sjögren).

2. Indirect-Acting Cholinergic Agonist

- They inhibit enzyme cholinesterase.
- Cholinesterase enzymes
o Belong to family of serine hydrolase
o AChE & BuChE (pseudocholinesterase) enzymes, found in CSF &
plasma respectively
- Location : basement membrane of NMJ, neuronal synapses, erythrocyte
membrane, both pre- and postsynaptically in the nerve terminal where it
is membrane bound (Whalen&Panavelil,2015)
- Jenis-jenis Anti-ChE
1. Short-acting anticholinesterase
o Edrophonium  a quartenary amine, only for muscle strenght in
myastenia gravis, bind reversiblely to the active center of AChE
2. Medium-duration anticholinesterase
o Carbamyl group: Neostigmine, pyridostigmine, physostigmine
o Obat-obatan ini semuanya adalah karbamil, bukan asetil, ester dan
semuanya memiliki gugus dasar yang berikatan dengan situs
anionik.
o Pemindahan gugus karbamil ke gugus hidroksil serin dari situs
esterik terjadi seperti pada ACh, tetapi enzim karbamilasi sangat
jauh lebih lambat untuk dihidrolisis  obat-obat ini cukup tahan
lama.
3. Irreversibel anticholinesterase
o Pentavalent phosphorus (dyflos), organic group (parathion,
ecothiophate), sarin
 Effect Of Anticholinesterase Drugs
- Autonomic Cholinergic Synapses Effect :
o Effect: ↑ cholinergic transmission at cholinergic synapses & NMJ
o ↑ secretions from salivary, lacrimal, bronchial and gastrointestinal
glands; increased peristaltic activity; bronchoconstriction;
 bradycardia and hypotension; pupillary constriction; fixation of
accommodation for near vision; fall in intraocular pressure
o Large doses can stimulate later block autonomic ganglia 
depolarization block
o Acute antiChE poisoning (insecticides & nerve gases): severe
bradycardia, hypotension, difficulty of breathing
- Neuromuscular Effect :
o Neostigmine & pyridostigmine tend to affect neuromuscular
o Neuromuscular action causes muscle fasciculation & ↑ twitch
tension  depolarization block
- CNS Effect :
o Physostigmine & organophosphate can cross BBB  CNS effect
o The result is an initial excitation, which can result in convulsions,
followed by depression.
 Clinical Use of Muscarinic Agonist
- Physostigmine
o Muscarinic stimulation : contraction of GI smooth muscles, miosis,
bradycardia, and hypotension.
o Nicotinic stimulation can cause skeletal muscle twitches,
fasciculations, and skeletal muscle paralysis (at higher doses).
o Duration of action is about 30 minutes to 2 hours.
o Treatment of overdoses of drugs with anticholinergic actions, such
as atropine, and to reverse the effects of NMBs.
- Neostigmin
o More polar, absorbed poorly from GI tract & not enter CNS
o Internediate duration, DOA 30 mins – 2 hrs
o ↑ intestinal & bladder motility, antidote for competitive
neuromuscular-blocking drugs
o Manage symptoms of Myestema Gravis
- Phyridostigmine (mestinon®) & ambenonium
o Chronic management of Myestema Gravis
o Intermediate DOA (3-6 hrs & 6-8 hrs)
- Donepezil, rivastigmine & galantamine
 o Delay progression of Alzheimer disease
o Adverse Effect: GI distress

B. Anticholinergics Drugs
1. Muscarinic Antagonist
- Competitive antagonist
- SAR: same relationship as ACh but have a bulky aromatic group in place
of acetyl group
- Atropine & hyosine
o Alkaloids found in solanaceous plants
o Lipid soluble, absorbed from conjuctival sac, GI tract, able to
penetrate BBB
- Tertiary amines
o Cyclopentolate, tropicamide, oxybutynin, darifenacin (M3
selective) tolterodine
o Effects on the eye or the CNS (antihistaminic, antipsychotic,
antidepressant drugs)
o Drugs that act on the bladder to inhibit micturition, and are used
for treating urinary incontinence.
- Quaternary amines
o Ipratropium, tioproprium, propantheline, hyosine butylbromide
o More peripheral effects with reduced CNS effects.
o Ipratropium, another quaternary ammonium compound, is used by
inhalation as a bronchodilator
- Competitive (surmountable) pharmacological antagonists
o their blocking effects can be overcome by increased concentrations
of muscarinic agonists (jadi competitive mereka saling rebutan)
 Muscarinic Antagonist Effect :
- Peripheral Effect :
o Predictable – opposite to agonists of muscarinic receptor
o Their effectiveness varies with the tissue and with the source of
agonists
o Most sensitive tissue : salivary, bronchial and sweat glands
 o The least sensitive: acid secretion by the gastric parietal cells
o The effects include : inhibition of secretion (salivary, lacrimal,
bronchial, sweat gland), tachycardia, pupil dilated, IOP ↑, GI tract
motility ↓, bronchoconstriction.
- CNS Effects :
o less predictable
o At therapeutic concentrations include sedation, reduction of motion
sickness, and reduction of some signs of parkinsonism
o Atropine produces mainly excitatory effects on the CNS. At low
doses, this causes mild restlessness; higher doses cause agitation and
disorientation.
o Atropine poisoning is marked by excitement and irritability, the
result in hyperactivity and a considerable rise in body temperature,
which is accentuated by the loss of sweating.
 Clinical Use of Muscarinic Antagonist :
- CNS Disorders :
o Motion sickness
 Scopolamine is one of the most effective agents available for this
condition
 parenterally, orally, or as a transdermal patch .
 Useful doses usually cause dry mouth and sedation
o Parkinson ́s disease
 Treatment of extrapyramidal symptoms as side-effects of some
antipsychotics (chlorpromazine, haloperidol)
 Adjunctive therapy in some patients (biperiden, procyclidine,
benztropine)
 their use accompanied by all of the characteristic adverse effects
of antimuscarinic drugs
- Ophthalmological disorders
o Accurate measurements of refractive errors in uncooperative
patients
ciliary paralysis
 o Ophthalmoscopic examination of the retina
 diagnostic mydriasis
 topically as eye drops or ointment
 tertiary amine subgroup to ensure good penetration after
conjunctival application
 atropine (> 72 hours), homatropine (24 hours), cyclopentolate
(2-12 hours) and tropicamide (0.5-4 hours)
o Prevention of synechia (adhesion) formation in uveitis and iritis
 therapeutic mydriasis
 homatropine (longer-lasting drug, 24 hours)
- Cardiovascular disorders
o parenteral atropine (treatment of symptomatic bradycardia)
 In acute myocardial infarction (vasovagal attack) - preferable
over catecholamine
 and cardiac arrest resulting from vagal reflex activation
 overdose with digoxin or β blockers
o oral ipratropium
 treatment of bradycardia before implantation of pacemaker
- Respiratory disorders
o Bronchodilation in asthma
 Ipratropium  quaternary molecule which blocks of all
muscarinic receptors; administration by inhalation for
reduction of systemic effects; no negative effect on bronchial
epithelial cells and accumulation of bronchial secretion (does
not reduce the bronchodilation effect of β agonists); less likely
to cause tachycardia and cardiac arrhythmias in sensitive
patients (in comparison with β agonists)
o Chronic obstructive pulmonary disease
 ipratropium, tiotropium (longer duration of action, dominantly
blocks M1 and M3 receptors)
- Gastrointestinal disorders
o Peptic ulcer disease
 Pirenzepine, Gastrozepin (relative selective blocker of M1
receptors)
o Treatment of cramping, common traveler ́s diarrhea and other mild
and self-limited conditions of hypermotility
 Combination with an opioid antidiarrheal drug (atropine plus
diphenoxylate)
o further antispasmodic agent
 Predominantly quaternary amine for minimum CNS activity (to
limit penetration through the blood-brain barrier) and for
action at NN receptors in autonomic ganglia
 Otilonium (spastic painful conditions of the distal section of the
intestinal tract, including irritable bowel syndrome)
- Urinary disorders
o Treatment of overactive bladder
 Oxybutynin (selective for M3 receptor)  help in bladder
spasm after urological surgery (prostatectomy); reducing
involuntary voiding in patients with neurological disease;
improving blander capacity and continence and reducing
infection and renal damage; orally, transdermally
 trospium (non-selective antagonist)
 darifenacin (greater selectivity for M3 receptors than
oxybutynin)
 tolterodine (M3 selective antagonists, for use in urinary
incontinence)
o In urolithiasis to relive the painful ureteral smooth muscle spasm
caused by passage of the stone
- Cholinergic poisoning
o Poisoning  cholinesterase inhibitor insecticides, mushrooms with
muscarine, chemical warfare nerve gases
 o Antimuscarinic therapy
 No effective method for direct blocking the nicotine effects of
cholinesterase inhibition (nicotinic agonists and antagonists
cause blockade of transmission)
 To reverse the muscarinic effects (both CNS and peripheral
effects)  atropine (1-2 mg i.v. every 5-15 minutes until signs of
effect appear - dry mouth, reversal of miosis)
 Cholinesterase regenerator compounds  regeneration of
active enzyme from organophosphorus-ChE complex (
pralidoxime, diacetylmonoxime; oxime group has a very high
affinity for phosphorus → hydrolysis of complex before aging
 Pretreatment with reversible enzyme inhibitor (pyridostigmine)
to prevent binding of irreversible organophosphate inhibitors
(simultaneous us of atropine is required to control muscarinic
excess)

2. Ganglion-Blocking Drugs
- Acts on nicotinic receptor of both PNS & SNS autonomic ganglia
- Some also block the ion channel of the autonomic ganglia
- Non depolarizing competitive antagonist
- AE: marked venous pooling, postural hypotension, dry mouth, blurred
vision, constipation, severe sexual dysfunction
- Hexamethonium, mecamylamine, trimethaphan
- The clinical use is obsolete
 Neuromuscular Blocking Agent
- Block transmission: motor nerve ending & nicotinic receptor on skeletal
muscle
o Antagonist (Non-depolarizing agents: block ACh receptor or in
some cases ion channel)  Pancuronium, atracurium, vecuronium,
cisatracurium, mivacurium
o Agonist (depolarizing type: activates ACh receptor  persistent
depolarization)  Suxamethonium
- All drugs used clinically are non depolarizing agents
- Clinical useful for adjunct anesthesia: Tracheal intubation and Provide
complete muscle relaxation at lower anesthetic dose
ANDRENERGIC TRANSMISSION

 Cathecolamines
- Synthesis : Cathecol dan amine side chains
 Tyrosine Hydroxylase is specific enzyme that main control point for NA
synthesis
 Dopamine B-Hydroxylase is non selective enzymes but restricted to
catecholamine synthesising cells
 PNMT (methylation) : Located in adrenal medulla
- Noradrenaline (NE): transmitter released by sympathetic nerve terminal
- Adrenaline (E): hormone secreted by the adrenal medulla
- Dopamine: metabolic precursor of NA dan E, transmitter in the CNS
- Isoprenaline / isoproterenol: synthetic of NA, not present in the body