PHARMACOLOGY FOR

PAIN AND ANALGESIA

Kinanti Narulita Dewi

Pharmacology Department
Faculty of Medicine
UNISSULA
WHAT IS PAIN
An unpleasant sensory or emotional experience
associated with actual or potential tissue damage,
or described in terms of such damage.
Pain is always subjective.
Many people report pain in the absence of tissue
damage or any likely pathophysiological cause;
usually this happens for psychological reasons.

IASP
PHYSIOLOGY OF PAIN

Pain sensation
 First pain ： sharp, pricking, well
defined，A fibers
 Second pain ： dull, aching, poorly
localized, C fibers
PHYSIOLOGY OF PAIN
1. TRANSDUCTION OF PAIN
• Transduction begins when the free nerve
endings (nociceptors / pain-receptors) of non-
myelin C fibres and thin myelin A-delta fibres
of primary afferent neurones respond to
noxious stimuli.
• The nociceptors are distributed in the; somatic
structures (skin, muscles, connective tissue,
bones, joints); visceral structures (visceral
organs such as liver, gastro-intestinal tract).
PHYSIOLOGY OF PAIN
Nociceptors are exposed to noxious stimuli when
tissue damage and inflammation occurs as a result
of noxious stimuli :
• Mechanical (pressure, swelling, abscess,
incision, tumour growth)
• Thermal (burn, scald)
• Chemical (excitatory neurotransmitter, toxic
substance, ischaemia, infection)
This noxious stimulation causes a release of
chemical mediators from the damaged cells
including : prostaglandin, bradykinin, serotonin,
substance P, potassium, histamine, ACh, 5-HT,
glutamate, adenosine.
PHYSIOLOGY OF PAIN
• These chemical mediators activate and/or
sensitise the nociceptors to the noxious
stimuli. In order for a pain impulse to be
generated, an exchange of sodium and
potassium ions (de-polarisation and re-
polarisation) occurs at the cell membranes.
This results in an action potential and
generation of a pain impulse.
• Nociceptors transmit information by (A-
delta) and (C) fibers to the spinal cord and
brain.
PHYSIOLOGY OF PAIN
2. TRANSMISSION OF PAIN
• The C fibre and A-delta fibres terminate in the
dorsal horn of the spinal cord. There is a synaptic
cleft between the terminal ends of the C fibre and
A-delta fibres and the nociceptive dorsal horn
neurones (NDHN). In order for the pain impulses
to be transmitted across the synaptic cleft to the
NDHN, excitatory neurotransmitters are released,
which bind to specific receptors in the NDHN.
• These neurotransmitters are : adenosine
triphosphate, glutamate, calcitonin gene-related
peptide, bradykinin, nitric oxide, substance P,
endogenous opioids.
PHYSIOLOGY OF PAIN
2. TRANSMISSION OF PAIN
• The transmission process occurs in three stages.
The pain impulse is transmitted : (1) from the site
of transduction along the nociceptor fibres to the
dorsal horn in the spinal cord; (2) from the spinal
cord to the brain stem; (3) through connections
between the thalamus, cortex and higher levels of
the brain.
• The pain impulse is then transmitted from the
spinal cord to the brain stem and thalamus via
two main nociceptive ascending pathways. These
are the spinothalamic pathway and the
spinoparabrachial pathway.
PHYSIOLOGY OF PAIN
3. MODULATION OF PAIN
• The modulation of pain involves changing or
inhibiting transmission of pain impulses in the
spinal cord. The multiple, complex pathways
involved in the modulation of pain are referred
to as the descending modulatory pain
pathways (DMPP) and these can lead to either
an increase in the transmission of pain
impulses (excitatory) or a decrease in
transmission (inhibition).
PHYSIOLOGY OF PAIN
3. MODULATION OF PAIN
• Descending inhibition involves the release of
inhibitory neurotransmitters that block or
partially block the transmission of pain
impulses, and therefore produce analgesia.
Inhibitory neurotransmitters involved with the
modulation of pain include : endogenous
opioids (enkephalins and endorphins);
serotonin (5-HT); norepinephirine
(noradrenalin); gamma-aminobutyric acid
(GABA); neurotensin; acetylcholine; oxytocin.
PHYSIOLOGY OF PAIN
3. MODULATION OF PAIN
• Endogenous pain modulation helps to explain
the wide variations in the perception of pain in
different people as individuals produce
different amounts of inhibitory
neurotransmitters.
• Endogenous opioids are found throughout the
central nervous system (CNS) and prevent the
release of some excitatory neurotransmitters :
substance P, therefore, inhibiting the
transmission of pain impulses.
PHYSIOLOGY OF PAIN
4. PERCEPTION OF PAIN
• Perception of pain is the end result of the
neuronal activity of pain transmission and
where pain becomes a conscious
multidimensional experience.
• The multidimensional experience of pain has
affective-motivational, sensory-discriminative,
emotional and behavioural components.
When the painful stimuli are transmitted to the
brain stem and thalamus, multiple cortical
areas are activated and responses are elicited.
PHYSIOLOGY OF PAIN
4. PERCEPTION OF PAIN
• The reticular system : This is responsible for the
autonomic and motor response to pain and for
warning the individual to do something
(automatically removing a hand when it touches a
hot saucepan). It also has a role in the affective-
motivational response to pain such as looking at
and assessing the injury to the hand once it has
been removed form the hot saucepan.
PHYSIOLOGY OF PAIN
4. PERCEPTION OF PAIN
• Somatosensory cortex : This is involved with the
perception and interpretation of sensations. It
identifies the intensity, type and location of the
pain sensation and relates the sensation to past
experiences, memory and cognitive activities.
• Limbic system : This is responsible for the
emotional and behavioural responses to pain for
example, attention, mood, and motivation, and
also with processing pain and past experiences of
pain.
ANALGESICS (PAIN KILLER)

Different types of drugs are used for treatment of

pain. In general, they include :
1. Drugs, relieving pain due to multiple
causes (analgesics)
• Narcotic analgesics (morphine, fentanyl,
etc) : act chiefly in the CNS.
• Non-narcotic analgesics (paracetamol,
metamizole) : act chiefly peripherally.
ANALGESICS (PAIN KILLER)

2. Drugs relieving pain due to a single cause or

specific pain syndrome only
They are not classified as analgesics :
• Naratriptan (migraine)
• Carbamazepine (neuralgias)
• Glyceryl trinitrate (angina pectoris)
• Adrenal steroids (inflammatory pain)
• Butylscopolamine (spasm of visceral smooth
muscles)
• Baclofen (spasm of striated muscles), etc.
ANALGESICS (PAIN KILLER)

3. Adjuvant drugs
Anxiolytics, neuroleptics, antidepressants may
modify the perception of pain and remove the
concomitants of pain such as anxiety, fear,
depression. Placebo gives relief in 3%.

4. Anaesthetics
General and local are used during surgical
operations, some diagnostic, and other painful
procedures.
ANTIPYRETIC, ANALGESIC, AND
ANTI-INFLAMMATORY DRUGS

(Non-steroidal anti-inflammatory drugs, NSAIDs)

 Phospholipid

Bradykinin
Corticosteroids ⊕ Angiotensin
Phospholipase A2

Arachidonic acid

Cyclooxygenase (COX)
NSAIDs
5-lipoxygenase
PGG2
Prostacyclin(PGI2)
hydroperoxidase
PGE2
PGF2α PGH2
Leukotrienes
Thromboxane A2
Dipyridamole
 CHARACTERISTICS COMPARISON
BETWEEN COX-1 AND COX-2

COX-1 COX-2
Synthesis intrinsic induced
Functions physiological: physiological:
gastrointestinal production of PG
protection elevated during
platelet aggregation pregnancy
regulation pathological:
vascular resistance producing proteinase,
regulation PG, and other
renal blood flow inflammatory
regulation mediators
CLASSIFICATION OF NSAIDS

 Aspirin and other salicylates

 Aniline derivatives
 Indole derivatives
 Propionic acid derivatives
 Others
 OPIOID ANALGESICS
(NARCOTIC ANALGESICS)
AND
ANTAGONISTS
 Crude opium

Seeds of
Collecting resin opium poppy
Opium flowers of opium poppy
OPIOID RECEPTORS

Opioid receptors are a group of G-protein coupled

receptors with opioids as ligands
MECHANISM OF ACTION OF
OPIOID ANALGESICS
Effects are mediated via opioid
receptors :
• m (Mu) : mediate analgesia at the
supraspinal level.
• k (Kappa ): analgesia at the spinal
level.
•  (Delta) : analgesia in the periphery.
MU-RECEPTOR : TWO TYPES

• Mu-1 • Mu-2
– Located outside – Located
spinal cord throughout CNS
– Responsible for – Responsible for
central respiratory
interpretation of depression, spinal
pain analgesia, physical
dependence, and
euphoria
KAPPA RECEPTOR

• Only modest analgesia

• Little or no respiratory depression
• Little or no dependence
• Dysphoric effects
DELTA RECEPTOR

• It is unclear what delta’s responsible

for.
• Delta agonists show poor analgesia
and little addictive potential.
• May regulate Mu receptor activity.
ENDOGENOUS ANALGESIC

There are endogenous analgesic

substances with peptide structure and
morphine-like action.
They are called endogenous peptides and
were discovered during the investigation
of the mechanism of analgesic action of
morphine.
ENDOGENOUS ANALGESIC

Endogenous opioid peptides are :

a) enkephalins activate μ and δ-receptors;
b) endorphins activate μ, κ and δ-receptors;
c) dynorphins activate μ, κ and δ-receptors.
d) nociceptin – ORL1 (opioid like receptor) 
tolerance
Opioid peptides act in CNS as :
- neurotransmitters
- modulators of response (usually inhibitory)
OPIOID RECEPTORS
DISTRIBUTION AND PHYSIOLOGICAL
EFFECTS :
CERTAIN CELLS IN THE CNS
 Brainstem : mediate respiration, cough,
nausea and vomiting, maintain blood pressure,
pupillary diameter and control of stomach
secretions.
 Medial thalamus : modulate deep pain that is
poorly localized and emotionally influenced.
OPIOID RECEPTORS

CERTAIN CELLS IN THE CNS

 Spinal cord : involved in the reception and
integration of incoming sensory information
and attenuate painful afferent stimulation.
 Hypothalamus : affect neuroendocrine
secretion.
 Limbic system: influence emotional behavior.
OPIOID RECEPTORS
PERIPHERY
 Inhibit the release of excitatory,
proinflammatory substances from nerve
endings, which contribute to the anti-
inflammatory effect of opioids.

IMMUNE CELLS
 Immune depression
MU AND KAPPA RECEPTOR
ACTIVATION
Response Mu-1 Mu-2 Kappa

Analgesia

Respiratory
Depression
Euphoria

Dysphoria

Decrease GI
motility
Physical
Dependence
MECHANISM OF ACTION
 Activation of peripheral nociceptive fibers
causes release of substance P and other
pain-signaling neurotransmitters from
nerve terminals in the dorsal horn of the
spinal cord.
 Release of pain-signaling neuro-
transmitters is regulated by endogenous
endorphins or by exogenous opioid
agonists by acting presynaptically to inhibit
substance P release, causing analgesia.
MU AND KAPPA RECEPTORS

DRUGS MU KAPPA

Pure Agonists Agonist Agonist

Agonist- Antagonist Agonist

Antagonist
Pure Antagonist Antagonist
Antagonists
MECHANISM OF ACTION
• Pure Agonist : has affinity for binding plus
efficacy
• Pure Antagonist : has affinity for binding
but no efficacy; blocks action of
endogenous and exogenous ligands
• Mixed Agonist-Antagonist : produces an
agonist effect at one receptor and an
antagonist effect at another
• Partial Agonist : has affinity for binding but
low efficacy
OPIOID RECEPTORS
SUMMARY OF OPIOID ANALGESICS AND
ANTAGONISTS

 Strong agonists : fentanyl, heroin,

pethidine, methadone, morphine

 Moderate agonists : codeine

 Mixed agonist-antagonists : pentazocine

 Antagonists : naloxone, naltrexone

Mainly agonist action at μ receptors,
but some actions on other receptors
•Morphine Agonist action at κ receptors,
•Heroin with partial antagonist action
•Codeine at μ receptors
•Fentanyl •Pentazocine

⊕ ⊕ ⊕

μ opioid κ opioid  opioid

receptor receptor receptor
Analgesia Analgesia Analgesia
Respiratory depression Sedation/dysphoria
Euphoria/sedation Pupil constriction
Physical dependence
Decreased GI motility
Pupil constriction Antagonist act at μ, κ,  receptors
•Naloxone
•Naltrexone
CLASSIFICATION OF OPIATES
 NATURAL OPIATES : morphine (alcaloid), codeine,
papaverine and thebaine;
 SEMI-SYNTHETIC OPIATES : hydromorphone,
hydrocodone, oxycodone, oxymorphone, desomorphine,
diacetylmorphine (heroin), nicomorphine, dipropanoyl-
morphine, benzylmorphine and ethylmorphine;
 FULLY SYNTHETIC OPIOIDS : fentanyl, pethidine,
methadone, tramadol and propoxyphene;
 ENDOGENOUS OPIOID PEPTIDES : endorphins,
enkephalins, dynorphins, and endomorphins.
Semisynthetic derivative (opioid analogs)
Morphine derivatives
•Ethylmorphine, Heroin
Codeine derivatives
•Dextromethorphan (antitusive agent)
•Dihydrocodeine
•Hydrocodone
•Oxycodone: p.o.
Thebaine derivatives
•Buprenorphine, Etorphine
SYNTHETIC DERIVATIVES
PHENYLPIPERIDINES
pethidine, fentanyl
METHADONES
methadone, dextropropoxyphene
BENZOMORPHANS
pentazocine
TRAMADOL
GENERAL PHARMACOKINETICS
 LATENCY TO ONSET
 Oral (15 – 30 minutes)
 Intranasal (2 – 3 minutes)
 Intravenous (15 – 30 seconds)
 Pulmonary – inhalation (6 – 12 seconds)
 DURATION OF ACTION : anywhere between
4 and 72 hours depending on the substance
in question.
 METABOLISM : hepatic via phase 1 and
phase 2 biotransformations to form a diverse
array of metabolites (eg., morphine to
morphine-6-glucuronide).
MORPHINE
PHARMACOKINETICS
 Routes of administration (preferred)
 Oral latency to onset (15 – 60 minutes)

 It is also sniffed, swallowed and injected.

 Duration of action ( 3 – 6 hours)

 First-pass metabolism results in poor

availability from oral dosing.
 30% is plasma protein bound.
MORPHINE
PHARMACOLOGICAL EFFECTS
Agonist for mu, kappa, and delta receptors.
1. Analgesia :
 Raises the pain threshold at the spinal
cord level, alters nociception in the brain.
 Relieves anxiety and fear
 Symptomatic relief of moderate to severe
pain
MORPHINE
PHARMACOLOGICAL EFFECTS
2. Euphoria :
Produces a powerful sense of contentment
and well-being by stimulation of the ventral
tegmentum.
3. Miosis :
 The pinpoint pupil is the characteristic of
morphine use, little tolerance.
MORPHINE
4. Emesis :
Causes vomiting by stimulating the CTZ in
the medulla but with no unpleasant
sensations.
5. Respiration :
Causes respiration depression by
reduction of the sensitivity of respiratory
center neurons to carbon dioxide.
MORPHINE
6. Depression of Cough Reflex :
 Suppression of severe cough (rarely).
 May allow accumulation of secretions and
thus lead to airway obstruction and
atelectasis.
 Replaced by other safer antitussives.
7. Sedation :
Causes drowsiness and clouding of
mentation, even disrupting sleep.
MORPHINE
8. Gastrointestinal effect :
Suppression of severe diarrhea. Decreases
motility of smooth muscle and increases tone,
which causes constipation and increases
pressure in the biliary tract (worsens
abdominal colic, eg. Sphincter oddi
contraction).
MORPHINE
9. Cardiovascular :
 Has no major effects on the
cardiovascular system.
 Is usually contraindicated in individuals
with severe brain injury (because that
increased PCO2 induced by respiration
depression leads to cerebral vasodilation
and consequential increase in cerebral
blood flow and intracranial pressure).
 Causes postural hypotension sometimes.
MORPHINE
10. Histamine release :
Causes pruritus, urticaria, sweating, vasodilation
and bronchoconstriction.
11. Hormonal actions:
- Inhibits release of LH.
- Increases GRH, ADH, PRL.
12. Immune depression
MORPHINE
THERAPEUTIC USES :
A. ANALGESIA
 Used for various pain, especially acute,
obstinate constant pain (e.g. burn, cancer
pain);
 Fixed interval of administration reduces
tolerance and dependence;
 Severe pain of renal, etc
MORPHINE
B. CARDIAC ASTHMA
 Acute left ventricular heart failure induces
pulmonary edema.
 Reduces anxiety, cardiac preload and
afterload.
 Particularly useful for painful myocardial
ischemia with pulmonary edema.
C. TREATMENT OF DIARRHEA
Synthetic surrogates.
MORPHINE

D. RELIEF OF COUGH :
Synthetic antitussives.
E. PREMEDITATE DRUGS BEFORE
ANESTHESIA :
 Sedative, anxiolytic, and analgesic
properties. For high-risk surgery
administered systemically; for local
(epidural) anesthesia.
 Caution: respiratory suppression.
MORPHINE
ADVERSE EFFECTS :
 Respiratory depression
 Vomiting, constipation, biliary colic
 Dysphoria
 Allergy-enhanced or postural hypotensive
effects
 Urinary retention (prostatic hypertrophy)
 Elevation of intracranial pressure (head injury)
 Immune depression
MORPHINE
TOLERANCE AND PHYSICAL DEPENDENCE
 Repeated use produces tolerance to the
respiratory depression, analgesic, euphoric
and sedative effects, but not to pupil-
constricting and constipating effects.
 Physical and psychologic dependence
readily occur for strong μ agonists,
especially used on necessities.
MORPHINE
 Withdrawal symptoms : a series of
autonomic, motor and psychological
response that incapacitate the individual
(rhinorrhea, lacrimation, yawning, chills,
gooseflesh, hyperventilation, hyperthermia,
mydriasis, muscular aches, vomiting,
diarrhea, anxiety, and hostility).
MORPHINE
CONTRAINDICATIONS :
 Women during labor or lactation
 New-born infants
 Chronic obstructive pulmonary disease
(COPD)
 Asthma
Druggy Malformation
PETHIDINE (MEPERIDINE)
ACTIONS AND MECHANISMS :
 Binds to opioid receptors, particularly m
receptor.
 Actions similar to but less potent than
morphine.
----Transient decrease of gastro-intestinal
motility and increase of the tone
---- Indistinctly central depression of cough
reflex.
PETHIDINE (MEPERIDINE)

THERAPEUTIC USES :
 Analgesia : various severe pain, including
during obstetric labor (less depression of
respiration in newborn infants).
 Cardiac asthma.
 Administration before anesthesia and artificial
hibernation, combined with chlorpromazine
and promethazine.
PETHIDINE (MEPERIDINE)
 Almost identical to morphine
(potency : 1/7 – 1/10 of morphine)
 Tends to cause restlessness
rather than sedation
 Antimuscarinic effects : dry
mouth & blurred vision
 Less antitussive
 Shorter duration of action (4-6 h)
– preferred in labour
 Sol. 5% 2 ml (= 100 mg/2 ml)
s.c./i.m
FENTANYL
 Actions similar to morphine, high efficacy for mu
1 receptors.
 75 – 125 (±80) times the analgesic potency of
morphine and 10 times the analgesic potency of
hydromorphone  most effective opiate
analgesic.
 Main use : is in anaesthesia, used in conjunction
with droperidol, a neuroleptic, producing
neuroleptanalgesia, ↓ O2 consumption (AMI).
 Side effects : dependence, euphoria, miosis,
nause vomitus, vagal reflex (↓ HR), respiratory
depression.
FENTANYL
PHARMACOKINETICS
 Routes of administration
 Oral, and transdermal (possibly
intravenous)
 Highly lipophilic
 Latency to onset (7-15 minutes
oral; 12-17 hours transdermal
 Duration of action (1-2 hours
oral; 72 transdermal)
 80 – 85% plasma protein bound
 90 % metabolized in the liver to
inactive metabolites
 PENTAZOCINE
 An agonist on k receptor, but partial
agonist on  receptors and a weak
antagonist at m receptor.
 Actions (less potent compared with
morphine) : analgesia and
respiratory depression, indistinct
euphoria and dependence.
Dysphoria, hallucinations and
hypertension in high dose.
 Used for moderate or chronic pain.
BUPRENORPHINE
 Partly agonist of mu-opioid receptors
 Acts longer than morphine (approximately 6
hours)
 Analgesic activity is higher than of morphine,
that’s why it’s used in doses of 0,3-0,6 mg
 In case of breathing depression, which it
causes, naloxon is less effective since
buprenorphine is slowly released from the
connection with mu-receptors
 Indicated for pain decreasing in the same
situations as other narcotic analgesics
BUPRENORPHINE
 May be used for detoxication and supporting
treatment of individuals who is addicted to
heroine
TRAMADOL
 Tramadol provides moderate pain relief
because of its dual actions as a weak µ-
agonist and inhibits uptake of
monoamine transporters (NA and 5-HT),
which is thought to produce analgesia
synergistically  effective on moderate
to severe acute and chronic pain.
 It produces less respiratory depression for
a given analgesic effect.
CODEIN
 Selectively suppress cough center in medulla
oblongata.
 Potency :
 Analgesia : 1/7 of morphine

 Suppression of cough : 1/10 of morphine

 Respiratory depression, constipation,

tolerance, dependence ＜ that of morphine
 Clinical Uses :
 Dry cough

 Moderate pain  neuralgia ec herpes

zooster
CODEIN
 Pharmacokinetics:
 Well absorbed from oral and injection.

 10% converted to morphine through

demethyl.
 Adverse Reactions:
 Respiratory suppression in high dose;

 Tolerance and physical dependence with

frequently repeated administration;

 Suppress secretion of bronchial gland and

movement of cilia.
 LOW EFFICACY FOR MILD AND
MODERATE PAIN
codeine, dihydrocodeine, dextropropoxiphene,
oxycodone, pentazocine, tramadol

HIGH EFFICACY FOR SEVERE PAIN

alfentanil, buprenorphine, heroin,
fentanyl, methadone, morphine,
pethidine, sufentanil
 Efficacy
high
Addiction/abuse

low
Morphine Pethidine Methadone Fentanyl Codeine

A comparison of the maximum efficacy and

addiction/abuse liability of commonly used
narcotic analgesics
 Time to peak effect (oncet)
Duration of action

20min
Morphine
4 hours

15min
Pethidine 2 hours
5min
Fentanyl 45min

Time to peak effect and duration of action of

several opioids administered intravenously
TOLERANCE & DEPENDENCE
• Tolerance – it is increasing of the dose
of a drug required to produce the same
effect.
• It occurs rapidly with opioids (with
morphine 12–24 hours, e.g. the hot
plate test – in mice, after 3 days the
dose of morphine required for analgesia
increases 5-fold).
• Important in drug addiction – may need
to increase dose 50-fold.
TOLERANCE & DEPENDENCE
Why does tolerance occur?
There are several potential reasons :
• Increased metabolism of the drug
• Decreased receptor affinity

Dependence takes two forms :

• Physical
• Psychological
TRIAD IN CASE POISONING
WITH MORPHINE
 Acute miosis
(pinpoint pupils)

 Cheyne Stokes
respiration

 Deep tendon
reflexes increased
TREATMENT OF ACUTE POISONING :
OPIOID COMPETITIVE ANTAGONISTS
 Naloxone (μ, κ and δ-antagonist)
 Naltrexone (μ, κ and δ-antagonist)
 Nalorphine / Allylnormorphine (μ-
antagonist / κ-agonist)
 NALOXONE
 Competitive blocker of opioid receptor, with 10x
higher affinity for m receptor than for k.
 Actions :
 Precipitates withdrawal symptoms
 Reverses the coma and respiratory depression
of opioid overdose (short action duration
(naltrexone with much longer action duration)
 Eliminates some adverse effects with opioids
 Dose : 0,1 – 0,2 mg (max 10 mg) iv (adult) & 0,0(05 –
0,1 mg (anak)
 WHO
GUIDELINES
 FARMAKOLOGI
OBAT ANESTESI LOKAL
Pharmacology Department
Faculty of Medicine UNISSULA
PENGGOLONGAN OBAT
ANESTESI LOKAL
GOLONGAN POTENSI DURASI
ESTER AMIDE :
PROKAIN 1 SINGKAT
KOKAIN 2 MENENGAH
TETRAKAIN 26 PANJANG
(PANTOCAINE)
AMIDE – AMIDE :
MEPIVAKAIN 2 MENENGAH
PRILOKAIN 3 MENENGAH
LIDOKAIN 4 MENENGAH
ETIDOKAIN 16 PANJANG
BUPIVAKAIN 16 PANJANG
ROPIVAKAIN 16 PANJANG
LEVOBUPIVAKAIN 16 PANJANG
MEKANISME KERJA
 Infiltrasi anestetik lokal di sekitar saraf,
menyebabkan keluarnya Ca2+ dari reseptor dan
anestetik lokal akan menmpati reseptor
tersebut sehingga terjadi blokade pada ion
kanal Na+  hambatan konduksi Na+ dan
depresi induksi sehingga tidak mencapai nilai
potensial  tidak terjadi potensial aksi.
FARMAKOKINETIK
 < 50% anestetik lokal berbentuk lipid soluble
non-ionized pada pH 7,4.
 Hampir semua anestetik lokal mempunyai pKa
yang alkalis (basa lemah). Konstanta disosiasi
(pKa) adalah nilai pH dimana bentuk ionisasi
dan non ionisasi berada dalam jumlah yang
seimbang. Bentuk non-ionized menentukan
terjadinya difusi.
 Kelarutan dalam lemak menunjukkan potensi
intrinsik anestetik lokal karena 90% dari
membran saraf adalah lemak.
FARMAKOKINETIK
 Larutan anestetik lokal yang tersedia di pasaran
mempunyai pH 6  dimaksudkan untuk
memperkuat stabilitas kimia.
 Penambahan vasokonstriktor  pH diturunkan
menjadi 4 karena molekul katekolamin labil pada
pH alkalin. Pada pH yang lebih rendah akan
menghasilkan onset yang lebih lambat.
 Infiltasi ke daerah inflamasi tidak menghasilkan
efek anestetik yang optimal, karena keasaman
meningkat pada jaringan yang mengalami
inflamasi (pH = 5).
FARMAKOKINETIK
 Absorbsi : dipengaruhi oleh tempat penyuntikan
dan dosis, penggunaan epinefrin, karakteristik
farmakologik.
 Distribusi : golongan amide – amide lebih luas
didistribusikan ke dalam jaringan daripada
golongan ester – amide.
 Eliminasi : metabolisme amide – amide terutama
di hepar & ekskresi di ginjal. Eliminasi & waktu
paruh ester – amide sangat cepat (cepat
terhidrolisis dalam plasma dan hepar).
TEKNIK / CARA PEMBERIAN
 TOPIKAL = disemprotkan pada mukosa / kulit
 INFILTRASI = diinfiltrasikan di bawah kulit
 BLOK SARAF = diinjeksikan sekitar saraf perifer
 BLOK EPIDURAL = diinjeksikan pada ruang
epidural
 BLOK SUBDURAL / SPINAL = diinjeksikan pada
ruang subdural
 INTRAVENA REGIONAL
FARMAKOKINETIK
DOSIS ANESTESI LOKAL UNTUK TOPIKAL
OBAT KONSENTRASI DURASI DOSIS MAKSIMAL
1. KOKAIN 4% 30 menit 200 mg
2. LIDOKAIN 2–4% 15 menit 200 mg
3. TETRAKAIN 0,5 % 45 menit 50 mg
4. BENZOKAIN 2 – 10% Beberapa jam
DOSIS ANESTESI LOKAL UNTUK INFILTRASI DAN BLOK SARAF
OBAT KONSENTRASI DURASI DOSIS MAKSIMAL
1. Prokain 2–4% 0,5 jam 1000 mg
2. Lidokain 1–2% 1 – 2 jam 500 mg
3. Mepivakain 1–2% 1 – 2 jam 500 mg
4. Tetrakain 0,1 – 0,25 % 2 – 3 jam 75 mg
5. Kloroprokain 1–2% 1000 mg
6. Piperokain 1–2% 750 mg
7. Heksilkain 1–2% 500 mg
8. Prilokain 1–2% 500 mg
9. Bupivakain 0,5 % 5 – 7 jam 200 mg
10. Etidokain 0,5 – 1 % 4 – 6 jam 200 mg
FARMAKOLOGI OBAT
ANESTESI INTRAVENA
NON NARKOTIK
Pharmacology Department
Faculty of Medicine UNISSULA
PREPARAT ANESTESI
INTRAVENA NON NARKOTIK
 GOLONGAN BARBITURAT
 GOLONGAN BENZODIAZEPIN
 PROPOFOL
 KETAMIN
GOLONGAN BARBITURAT
 Hipnotik sedatif derivat asam barbiturat.
 Berdasarkan lama kerjanya :
 Long acting (6 jam) : barbital, phenobarbital,
mephobarbital
 Intermediate acting (3 – 6 jam) : probarbital,
amobarbital, buthetal
 Short acting (< 3 jam) : pentobarbital,
cyclobarbital
 Ultra short acting : thiopental, hexobarbital
GOLONGAN BENZODIAZEPIN
 Transquiliser minor  transquiliser, sedatif atau
hipnotik
 Penggunaan intra vena paling sering : diazepam,
midazolam.
 Mekanisme kerja : mempengaruhi transmisi
interneural pada medulla spinalis  relaksasi otot
skelet yang mengalami spasme. Benzodiazepin
mempengaruhi reticular facilitatory system dan
mendepresi sistem limbik (hipokampus, amigdala,
talamus fornik & girus angulatus).
 Penggunaan : antikonvulsi dan efek amnesia.
DIAZEPAM VS MIDAZOLAM
DIAZEPAM :
 Bersifat agak asam  menimbulkan nyeri di
tempat suntikan (im atau iv).
 Tingginya kelarutan dalam lemak  mudah
menembus barier plasenta.
 Pada sistem respirasi : menimbulkan depresi
ringan bila diberikan melalui intra vena.
Hipoventilasi terjadi akibat berkurangnya volume
tidal meskipun terjadi peningkatan frekuensi
napas. PCO2 sedikit meningkat dan PaO2 sedikit
turun.
DIAZEPAM VS MIDAZOLAM
DIAZEPAM :
 Pengaruh pada sistem KV : menurunkan
tekanan darah arteri, resistensi arteri perifer
dan curah jantung < 20%.
 Diazepam + narkotik  depresi respirasi
semakin berat dan depresis sistem KV  efek
simpatolitik.
DIAZEPAM VS MIDAZOLAM
MIDAZOLAM :
 Larut dan stabil dalam air
 Tidak menimbulkan nyeri di tempat
suntikan
 Bersifat anxiolitik, anti konvulsif,
anterograde amnesia.
 Onsetnya lebih cepat, durasi kerja lebih
pendek dan kekuatannya 1,5 – 3 kali lipat
dibandingkan diazepam.
ANTAGONIST BENZODIAZEPIN
1. AMINOPHILIN :
 Aminophilin bersifat antagonis terhadap
ikatan reseptor adenosine terhadap obat –
obat golongan benzodiazepine 
menyebabkan re-uptake adenosine dan asetil
kolin akan dilepaskan kembali sehingga
pengaruh benzodiazepine terhadap SSP
dapat dihilangkan.
 Dosis : 1 – 2 mg/kgBB (dosis efektif untuk
menghilangkan efek sedasi dari midazolam).
ANTAGONIST BENZODIAZEPIN
2. FLUMAZENIL :
 Flumazenil mempunyai afinitas terhadap
reseptor benzodiazepine lebih tinggi
dibandingkan golongan benzodiazepine
sehingga bekerja dengan menempati reseptor
tersebut.
 Flumazenil dapat menghilangkan efek sedasi,
amnesia, depresi nafas, depresi kardiovaskular
dari benzodiazepine.
 Onset : 1 – 2 menit (iv). Dosis : 0,1 – 1 mg/kgBB.
PROPOFOL
 Obat anestesi umum (2,6 diidoprophyl phenol).
 Cairan emulsi isotonik berwarna putih, terdiri dari
gliserol, phospatid dari telur, sodium hidroksida,
minyak kedelai dan air
 Onset cepat (30 – 60 detik) dan durasi kerjanya
singkat
 Larut dalam lemak, sesudah diberikan melalui intra
vena  cepat berdistribusi ke jaringan  mudah
menembus BBB dan berdistribusi ke jaringan otak
 Mekanisme kerja : peningkatan aktifitas GABA
dalam menghambat neurotransmitter di SSP
PROPOFOL
 Sistem KV : penurunan tekanan darah,
bradikardi sampai asistol
 Sistem respirasi : depresi napas  apneu,
pemberian kontinu mengurangi tidal volume
dan laju napas, mengurangi reflek jalan napas
atas
 SSP : menurunkan aliran darah ke otak, tekanan
intra kranial dan metabolisme otak
 Imunologi : memicu pelepasan histamin <<
 Indikasi : induksi anestesi dan sedasi
KETAMIN
 Kristal putih yang larut dalam air
 Onset cepat (10 – 60 detik setelah diberikan
melalui intra vena). Durasi 10 – 15 menit.
 Reflek bulu mata, korneal dan laringeal agak
terdepresi. Tonus otot meningkat, gerakan
involunter.
 Sistem KV : eksitasi saraf simpatis 
peningkatan kadar epinefrin dan nor epinefrin 
meningkatkan tekanan darah, laju jantung dan
curah jantung  bermanfaat pada penderita
shock.
KETAMIN
 Pada SSP : ketamin menimbulkan gangguan
fungsi dan gangguan elektrofisiologi antara
thalamokortikal dan sistem libik  anestesi
disosiasi  rangsang yang diterima akan
diinterpretasikan berbeda. Timbul katalepsi,
analgesi yang kuat dan amnesia, tapi efek sedasi
ringan. Pasien dapat mengalami halusinasi dan
mimpi buruk. Meningkatkan aliran darah ke otak,
konsumsi oksigen di otak dan tekanan intra
kranial  bahaya pada TIK yang tinggi
KETAMIN
 Sistem respirasi :
 Sedikit mengurangi laju napas, pada
penyuntikan cepat  apneu.
 Melebarkan bronkus dan merupakan agen
antagonis bronkokonstriktor akibat histamin
(bermanfaat pada penderita asma bronkial).
 Meningkatkan sekresi kelenjar trakeo-
bronkial & saliva
 Mata : meningkatkan TIO, gerakan bola mata
dan nistagmus
KETAMIN
 Pada dosis kecil (0,15 mg/kgBB) berpotensi
sebagai preemptif analgesi : pemberian obat
sebelum terjadinya nyeri dengan pencegahan
plastisitas susunan saraf pusat (anti reseptor
NMDA)
 Precaution :
 Pasca pemberian ketamin dapat terjadi
emergency delirium (visual, auditorik,
proprioseptif, ilusi, konfusi  delirium).
 Emergency delirium dapat dikurangi dengan
pemberian benzodiazepin (midazolam).
PHARMACOLOGY OF
MUSCLE RELAXANT

Pharmacology Department
Faculty of Medicine UNISSULA
FISIOLOGI TRANSMISI NEUROMUSCULAR
& CARA KERJA HAMBATAN SARAF OTOT
 Transmisi rangsang saraf motorik ke otot
terjadi di neuromuscular junction oleh
neurotransmitter asetil kolin (Ach).
 Neurumuscular junction terdiri dari ujung saraf
motorik tak bermielin yang berhadapan
dengan membran otot. Keduanya dipisahkan
oleh celah sinaptik.
 Pada ujung saraf terdapat vesikel – vesikel
yang berisi asetil kolin, sedangkan pada
membran otot terdapat reseptor asetil kolin.
FISIOLOGI TRANSMISI NEUROMUSCULAR
& CARA KERJA HAMBATAN SARAF OTOT
 Ketika impuls sampai ke ujung saraf motorik,
maka terjadi influks kalsium dan pelepasan
asetil kolin ke celah sinaptik.
 Bila asetil kolin dilepaskan dari ujung saraf dan
ditangkap reseptor, maka terjadilah aksi
potensial / depolarisasi  depolarisasi cukup
kuat  kontraksi otot.
 Asetil kolin merupakan zat yang mudah sekali
dihidrolisis oleh kolin esterase.
 Apabila asetil kolin dihidrolisis  depolarisasi
berakhir  terjadi repolarisasi.
FISIOLOGI TRANSMISI NEUROMUSCULAR
& CARA KERJA HAMBATAN SARAF OTOT
 Kerja transmisi neuromuscular dapat dihambat
dengan beberapa cara, antara lain :
1. Menghambat sintesis atau pelepasan asetil
kolin. Contoh : toksin botulinum, prokain,
antibiotik golongan aminoglikosida,
hipokalsemia, hipermagnesemia
2. Mengurangi kepekaan membran otot. Contoh :
NMBA golongan depolarizing.
3. Mencegah bergabungnya asetil kolin dengan
reseptor membran secara competitive inhibition.
Contoh : NMBA golongan non depolarizing.
PENGGOLONGAN MUSCLE
RELAXANT
 Berdasarkan cara kerjanya, NMBA dibagi
menjadi 2 golongan :
1. Golongan depolarizing : succinyl choline /
suxamethonium
2. Golongan non depolarizing : D
tubocurarine, pancuronium bromide,
galamin, alcuronium, atracurium,
vecuronium, mivacurium.
PENGGOLONGAN MUSCLE
RELAXANT
 Berdasarkan lama kerjanya (duration of action),
NMBA dibagi menjadi 2 golongan :
1. Ultra short acting (3 – 8 menit) : succinyl
choline
2. Short acting : mivacurium
3. Intermediate acting (30 – 45 menit) : atracurium,
cisatracurium, rocuronium, vecuronium
4. Long acting (60 – 120 menit) : pancuronium,
doxacurium, D-tubocurarine, galamin dan
alcuronium
NMBA INDICATIONS

 First sensation felt is weakness.

 Followed by total flaccid paralysis.
 Small, rapidly moving muscles are
affected first (fingers, eyes), then limbs,
neck, trunk.
 Finally, intercostal muscles and the
diaphragm are affected, resulting in
cessation of respirations.
 Recovery of muscles usually occurs in
reverse order.
NMBA INDICATIONS

 Main use : maintaining controlled

ventilation during surgical procedures.
 Endotracheal intubation (short acting).
 To reduce muscle contraction in an
area that needs surgery.
 Diagnostic agents for myasthenia
gravis.
NMBA SIDE / ADVERSE
EFFECTS
 Hypotension (due to blockade of
autonomic ganglia & release of
histamine).
 Tachycardia (blockade of muscarinic
receptors).
SUCCINYL CHOLINE
 NMBA golongan depolarizing  onsetnya cepat dan
durasinya singkat  dipakai untuk mempermudah
intubasi.
 Pemberian secara intra vena / intra muskular.
 Menimbulkan depolarisasi pada motor end plate, akan
tetapi succinyl choline tidak mengalami hidrolisis
secepat acetyl choline  depolarisasi lebih lama  otot
kehilangan respon berkontraksi  terjadi fasikulasi 
kelumpuhan (flaccid muscle paralysis).
 Obat ini dihidrolisis oleh kolin esterase yang diproduksi
di hepar. Oleh karena itu pada penyakit hepar  aksi
obat dapat memanjang.
ANTI CHOLINE ESTERASE
Ada 2 golongan anti choline esterase :
 Bekerja secara irreversible :
1. Diisoprofil fluoro phosphate
2. Gas perang : sarin, tabun
3. Insektisida fosfat ester malathion, parathion, Tetra
Ethyl Pyro Phosphate (TEPP), Hexa Ethyl Pyro
Phosphate (HEPP)
 Bekerja secara reversible :
1. Edrophonium
2. Physostigmin
3. Neostigmin / Prostigmin
ANTI CHOLINE ESTERASE
 Obat yang menghambat kerja choline esterase
sehingga hidrolisis acetyl choline dihambat  kadar
acetyl choline meningkat  menimbulkan efek
muskarinik dan nikotinik.
 Efek muskarinik : efek terhadap otot polos dan
kelenjar.
 Otot polos :
 Bronkus  bronkokonstriksi dan
bronkospasme
 Usus dan ureter  hiperperistaltik
 Vesica urinaria  kontraksi
ANTI CHOLINE ESTERASE
 Pembuluh darah perifer  vasodilatasi
 Jantung  bradikardi
 Mata  miosis
 Kelenjar : meningkatnya sekresi kelenjar eksokrin
(keringat, bronkus, air mata, lambung dan usus)
 Efek nikotinik : efek terhadap otot rangka dan
ganglion
Thank you!
QUESTIONS?!
QUIZ
 1
Manakah analgetik opioid di bawah ini
yang mempunyai potensi kuat terhadap
reseptor μ?
A. Morfin
B. Codein
C. Fentanyl
D. Pethidine
E. Pentazocin
 2
Manakah di bawah ini yang berpotensi
sebagai kolin esterase inhibitor yang
irreversible?
A. Edrophonium
B. Physostigmin
C. Neostigmin
D. Prostigmin
E. TEPP
 3
Manakah obat anestesi intra vena di
bawah ini yang menyebabkan emergency
delirium?
A. Morfin
B. Propofol
C. Ketamin
D. Midazolam
E. Succinyl choline
 4
Manakah obat anestesi intra vena di
bawah ini meningkatkan tekanan intra
kranial?
A. Morfin
B. Propofol
C. Ketamin
D. Midazolam
E. Succinyl choline
 5
Manakah faktor di bawah ini yang dapat
menggangu potensi lidokain untuk
anestesi infiltrasi?
A. pH tinggi
B. pH rendah
C. Non-ionized
D. Derajat kelarutan dalam lemak