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Farmakologi

OBAT ANTI NYERI


Fathiyah Safithri
Laboratorium Farmakologi
Fakultas Kedokteran Universitas Muhammadiyah Malang

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DEFINISI NYERI
= Pengalaman sensorik dan emosional yang tidak

menyenangkan akibat kerusakan jaringan,


jaringan baik
aktual maupun potensial, atau yang digambarkan
dalam bentuk kerusakan tersebut

MEKANISME PROTEKSI TUBUH


(berfungsi melindungi & memberi tanda bahaya)

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JENIS NYERI
Menurut Sumber Nyeri :
NYERI NOSISEPTIF / NYERI INFLAMASI
- adanya kerusakan / inflamasi jaringan ujung saraf menerima rangsang
nyeri

NYERI NEUROPATIK
- berhub dg lesi sist syaraf perifer / sentral
- mis. Neuropatik DM, kompresi serabut saraf, neuroma

NYERI NOSISEPTIF-NEUROPATIK
NEUROPATIK
Menurut lamanya,
AKUT
- terjadi segera setelah trauma, operasi, atau lesi saraf
KRONIK
- terjadi kontinu (minimal 3 bulan)

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PROSES TIMBULNYA NYERI


STIMULUS
KERUSAKAN JARINGAN
MEDIATOR NYERI
(HISTAMIN, PG, BRADIKININ, LEOKOTRIEN, SEROTONIN DLL)

Transduksi
Transmisi

Modulasi
Persepsi

RESEPTOR NYERI (nociceptor)


SARAF SENSORIS
MEDULA SPINAL
THALAMUS / KORTEKS
KORTEKS PUSAT NYERI

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TRANSDUKSI

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JALUR TRANSmisi NYERI

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FAST & SLOW PAIN PATHWAY

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JALUR TRANSMISI NYERI

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INFLAMASI / RADANG
Stimuli : panas, bhn kimia, mekanik
Tujuan tubuh menimbulkan reaksi radang :
1.

Menetralkan dan menghancurkan bahan


berbahaya

Tanda radang
cardinal signs :

2. Mencegah penyebaran bahan berbahaya

rubor

3. Memperbaiki kondisi yang rusak

calor

Proses yang terjadi :

tumor,

kerusakan mikrovaskular

peningkt permeabilitas kapiler

migrasi lekosit ke jar radang.

Mediator kimiawi yang dilepas secara lokal


histamin, 5 HT, bradikinin,PAF,
PAF, substance
P, tromboksan, proton, radikal bebas,
leukotrien, prostaglandin
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dolor
functiolaesa

DEMAM / PANAS

Suhu tubuh diatur oleh keseimbangan produksi dan hilangnya panas


oleh hipotalamus (normal termostat mengatur pd setpoint 37o C )

termoregulator
Demam : Ada gangguan keseimbangan pengaturan panas akibat
pelepasan zat pirogen (sitokin
IL-1 , memicu peningkatan PG di
hipotalamus)

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FEBRIS

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Terapi NYERI
A. TERAPI FARMAKOLOGI
1. Menghambat mediator nyeri
(transduksi):
analgesik non narkotik
NSAID
Antiinflamasi steroid

2.

Menghambat transmisi nyeri


anestesi lokal

3.

Blokade pusat nyeri di SSP (Persepsi)


Analgesik narkotik
Anestesi umum

B.

TERAPI NON FARMAKOLOGI

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(Golan et al., 2008)

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Terapi
Terapi

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Terapi Nyeri Non-farmakologik


farmakologik
Cognitive-Behavioral
Relaxation
Preparatory information
Hypnosis
Physical Agents
Application of superficial heat and cold
Massage
Exercise
Immobilization
Electroanalgesia (eg, TENS= transcutaneous
t
electrical nerve
stimulation )
Acupuncture

Carr DB, et al. AHCPR Pub. No. 92-0032. 1992.

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Pain Rating Scales

Mild

Moderate

Pain threshold
Pain tolerance
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Severe

10

Choosing pain killer and its combinations


10 Pain Intensity Scale

Mild

Moderate

paracetamol
NSAID
or/+

NSAID
weak opioid

adjuvant
adjuvant
analgesic
analgesic

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10

Severe
Strong opioid

NSAID

adjuvant
analgesic

Current view in selecting analgesic and antianti


inflammatory drugs
Efficacy (indication)
Safety (side effect)
Not only GI toxicity
Cardiovascular toxicity
Renal toxicity
Bleeding
Bone healing impairment etc
Suitability (contra-indication)
indication)
Availability
Pharmacokinetics and drug interaction
Daily cost
Evidence based medicine
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ANALGESIK NON OPIOID

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Analgesic Non Opioid Drugs


Acetaminophen
NSAID
Non selective COX inhibitor
Salicylic
Salicylic acid (aspirin)
Asetic
Asetic acid (indomethacine, ketorolac,
diclofenac)
Propionic
Propionic acid (ketoprofen)
Anthranic
Anthranic acid (mefenamat)
Enolic
Enolic acid (piroxicam)
Selective COX 2 Inhibitor
Rofecoxib
Celecoxib
Etedolac
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Analgesik Non-opioid
opioid
Acetaminophen

Tramadol

Mekanisme kerja hamb sintesa PG


hipotalamus,

sintetik weak -opioid


inhibisi re-uptake
norepinephrine dan
serotonin (5-HT3)

Efek samping

Opioid-like effects

Hepatotoksik

Sisson CB. In: Benzon HT, et al, eds. Essentials of Pain Medicine and Regional Anesthesia;
Anesthesia
1999:5962.

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Acetaminophen
A c e to m in o p h e n M e
ta b o lis m
eta
A c - g lu cu ro n id e

Ac

A c - su lfate
C yto ch ro m e P - 4 5 0

R ea ctive ele ctro p h ilic


c o m p o u n d (A c *)

G ood

GSH
G S -A c *

A c * - p ro tein

A c - m erc a p tu rate

B ad

H e p atic c ell d eath

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NSAID
(NON STEROIDAL ANTI INFLAMMATORY DRUG)

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phospholipids
arachidonic acid
COX-2

COX

COX-1
1

cyclic
endoperoxides
PGI2

stimulates platelet
aggregation,
vasoconstriction

hyperalgesia
PGD2
inhibits platelet
aggregation,
vasodilator

5-HPETE
TXA2

inhibits platelet
aggregation,
vasodilator,

PGE2
vasodilator,

hyperalgesia

LOX

PGF2
PGF2alfa

LTA4
LTB4
chemotaxis

LTC4

bronchoconstriction
myometrial contr.

LTD4

hyperalgesia

LTE4

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brochoconstriction
increase
vascular
permeability

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zilueton

zafirlukast
montelukast

10/02/2010

Ngatidjan, NSAIDs - GOUT

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32

(Nijkamp et al., 20

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NSAID
Effects :
Analgesics
Antiiflammation (most)
Antipyretics (most)
Uricosuria (some)

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NSAID
Mekanisme kerja :
Menghambat sintesa PG melalui penghambatan enzim
COX 1 dan atau COX 2
NSAID konvensional menghambat COX-1
COX dan COX-2
Inhibisi COX-1 gastrotoksik, agregasi platelet
Obat baru hanya menghambat COX-2
COX pada dosis terapi

Efek : secara umum = analgetik, antiinflamasi, antipiretik


Dosis antipiretik >>> dosis analgetik, antiinflamasi
Efek terapi atau efek samping NSAID tergantung pada
penghambatan biosintesis prostaglandin. Inhibisi PG
synthetase menurunkan inflamasi dan selanjutnya
mengurangi nyeri.

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PROSTAGLANDIN (PG)
Merup autakoid, terdapat di semua jaringan dg spektrum
aktivitas yg bervariasi
Fungsi :
Inflamasi sebagai mediator COX 2
Homeostatic COX 1, terdapat di lambung, usus, platelet,
mucosa bronkus dan ginjal

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ASA
COX1
(cyclooxygenase
(cyclooxygenase-1)
blocks

ASA
COX1-thrombocyte

COX1-endothel

TX-A2 synthesis
(stimulate thrombocyte aggregation)
COX1 can not be synthesized instantly

- prostacyclin synthesis
inhibit thrombocyte aggregation
(antithrombotic properties)

- new COX-1 can be synthesized

low dose acetosal


effectively inhibit COX1 thrombocyte

low dose acetosal


ineffective in COX1 endothel inhibition

thrombocyte aggregation
10/02/2010

Ngatidjan, NSAIDs - GOUT

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Antithrombotic effect

37

Summary of analgesic, anti-inflammatory


inflammatory and
antipyretic activity of NSAIDs (ED50 in mg/kg)
ketorolac

indomethacin

diclofenac

ketorolac

indomethacin

diclofenac

naproxen

ibuprofen

piroxicam

naproxen

ibuprofen

piroxicam

120

60

100

50

80

40

ketorolac

indomethacin

diclofenac

naproxen

ibuprofen

piroxicam

60

30

40

20

5
4
3
2

20

10

1
0

0
analgesic

antipyretic

anti-inflammatory

NSAID

Analgesic

Anti-inflammatory

Antipyretic

ketorolac

0.7

0.9

indomethacin

2.1

diclofenac

0.4

naproxen

13

56

0.5

ibuprofen

45

10

piroxicam

100

1.7

tenoxicam

100

1.7

aspirin

228

162

18

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Less GI side effects


More GI side effects
Acetosal
Ketorolac

Indomethacin Ibuprofen
Piroxicam Ketoprofen

Diclofenac
Meloxicam
Nimesulide

Celecoxib
Rofecoxib
Valdecoxib

COXIB

preferentially
nonnon
COX-1
COX-2
COX-1
COX-2
selective
selective selective
selective
selective
COX
inhibitor inhibitor
inhibitor
inhibitor inhibitor
preferentially

anti-inflammatory
anti
analgesic
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(Rang et al., 2003)

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(Finkel et al., 2009)


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ANALGETIK OPIOID

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opioid is a natural or
synthetic drug that binds
to opioid receptors
producing agonist effects
RESEPTOR OPIOID : Mu
(), Kappa () & Delta ()
Resept delta : regulasi
aktifitas resept Mu
Sangat efektif
Efek samping sering

Response

Analgesia

Respiratory
Depression
Euphoria
Dysphoria
Decrease GI
motility
Physical
Dependenc
e

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Mu-1

Mu-2

Kappa

Aktivasi Reseptor Opioid


menyebabkan :
- Me konduktansi ion K
- Hiperpolarisasi
- Aksi potensial
terhambat
- Release
neurotransmitter
terhambat

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Efek Farmakologis Analgetik Opioid


Sedation and anxiolysis
Drowsiness and lethargy
Apathy
Cognitive impairment
Sense of tranquility
Depression of respiration
Main cause of death from opioid overdose
Combination of opioids and alcohol is especially
dangerous
Cough suppression
Opioids suppress the cough center in the brain
Pupillary constriction
pupillary constriction in the presence of analgesics is
characteristic of opioid use

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Efek Farmakologis Analgetik Opioid


Nausea and vomiting
Stimulation of receptors in an area of the medulla called
the chemoreceptor trigger zone causes nausea and
vomiting
Unpleasant side effect, but not life threatening
Gastrointestinal symptoms (constipation)
Opioids relieve diarrhea as a result of their direct actions
on the intestines
Urine Retention
Other effects
Opioids can release histamines causing itching or more
severe allergic reactions including bronchoconstriction
Opioids can affect white blood cell function and immune
function

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Analgetik Opioid
Indicated for musculoskeletal pain :
-

Severe injury

Oncogenic pain

Pain that is not alleviated by NSAIDs or other analgesics

Contraindicated for :
-

Patients with respiratory problems

Chronis usage of the drugs may cause :


-

Tolerance decrease of the effect

Addiction need to a compulsive use

Dependency (physically or psychologically)


psychologically

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Multimodal Analgesia

Morfin

Potensiasi

Pengurangan dosis
tiap analgesik
Meningkatkan
antinociception karena
efek sinergistik
Mengurangi efek
samping tiap obat

NSAIDs,
acetaminophen,
blok saraf

Kehlet H, Dahl JB. Anesth Analg.. 1993;77:10481056.


1993;77:1048
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ANALGETIK ADJUVANt

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= Obat yang dikombinasikan pada obat analgetik utama (non


opioid / opioid) untuk me efek analgetik,
menyeimbangkan efek & efek samping
- Sering dipakai untuk terapi nyeri neuropatik
Yang termasuk adjuvant :
Kortikosteroid
Neuroleptik
Benzodiazepin
Antidepressan (TCA : amitriptilin, doxepin, imipramin,
desipramin, nortryptilin )
Antikonvulsan (karbamazepin, Phenitoin, Sodium
valproate, Gabapentin)
Klonidin
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OBAT ANESTESI LOKAL

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OBAT LOKAL ANESTESI


Obat Lokal Anestesi ---> obat yg menyebabkan blokade konduksi impuls di sepanjang
jalur saraf pusat maupun perifer secara reversibel setelah anestesi regional
Dibedakan 2 golongan :
1. Amida (Bupivacaine, Nupercaine, Etidocaine, Lidocaine,
Mepivacaine, Prilocaine, Ropivacaine)
2. Ester (Chloroprocaine, Cocaine, Procaine, Tetracaine)

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Mekanisme kerja obat anestesi lokal

Obat lokal anestesi mencegah proses depolarisasi membran saraf dengan


memblok aliran ion Na hambatan transmisi impuls saraf (blokade konduksi)
Kualitas hambatan terjadi setelah pemberian sangat tergantung pada :
karakteristik obat yaitu potensi (ditentukan oleh kelarutan dalam lemak); onset (ditentukan
oleh pKa) dan durasi (ditentukan oleh ikatan protein), volume konsentrasi yang dipakai
penambahan vasokonstrikor (epinephrin) : memperlambat penyerapan dan
memperpanjang efek durasi anestesi 60%.
lokasi penyuntikan
kecepatan penyuntikan
posisi dan kondisi pasien

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Cara Penyuntikan
Infiltrasi anestesi :
Penyuntikan
Penyuntikan lokal anestesi ke lokasi yg akan
dianestesi.
Blok anestesi:
Menyuntikkan
Menyuntikkan lokal anestesi di sekitar saraf utama
yg jaraknya jauh dari lokasi yg akan dianestesi.

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Kriteria ideal obat anestesi lokal


1. Onset cepat

2. Durasi panjang
3. Dapat dititrasi
4. Toksisitas rendah
5. Tempat kerja terlokalisir
6. Khusus menghambat nyeri,
tidak berefek pada fungsi motorik
7. Dosis relatif kecil
8. Efek samping minimal
9. Reversibel

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OBAT ANESTESI LOKAL


OBAT

Prokain
Lidokain
Mepivacaine
Prilokain
Bupivakain
Ropivakain (Naropin)
(Levobupivakain) Chirokain

DURASI

MAX

2-4%
1-2%
1-2%
1-2%
0,5%
2,5
2,5-7,5%

1 jam
1-2 jam
1-2 jam
1-2 jam
5-7 jam
6-8 jam

1000 mg
500 mg
500 mg
500mg
200 mg

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LIDOKAIN
Mekanisme Kerja :
cegah transmisi impuls saraf atau blokade konduksi mel
hambat lintasan ion sodium melalui kanal Na di membran
saraf
Farmakokinetik :
Absorbsi & distribusi dipengaruhi tempat injeksi, dosis,
epinephrine dan sifat farmakologi.
Faktor terkait : usia, status kardiovaskuler dan fungsi hepar.
Eliminasi metabolisme hepar

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ANESTESI UMUM

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GENERAL ANAESTHETICS
THE FIRST GENERAL
ANAESTHETICS
Nitrous oxide, 1880,
Laughing gas
Ether, 1846, explosive
Chloroform, 1847,
Toxic to the liver

THEORIES OF ANAESTHETIC
ACTION
LIPID THEORY Anaesthetics
dissolve in lipid part of cell
membranes and depress
membrane activity
PROTEIN THEORY Anaesthetics
bind to hydrophobic protein site
in membranes and depress
activity
Depression of transmitter release
rather than nerve conduction.
Not via receptors
We dont really know how they

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FOUR STAGES OF ANAESTHESIA


1.Analgesia
2. Delirium
loss of consciousness,
delirious excitement
reflex activity
3. Surgical anaesthesia
deep unconsciousness,
respiratory depression
muscle relaxation
4. Medullary paralysis
respiratory & cardiovascular, depression, death
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ADVERSE EFFECTS
Respiratory & cardiac depression
Sensitisation of heart to catecholamines
Malignant hyperthermia
Aspiration of gastric contents use endotracheal tube
Hepatotoxicity
Renal toxicity

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ADJUNCTS TO ANAESTHESIA
(Preanaesthetic medications)
Benzodiazepines/ Barbiturates
Reduce anxiety & produce sedation
Opioids
Analgesia,
Depression of cough
Anticholinergic drugs
Decrease risk of bradycardia
Neuromuscular blocking agents
Paralysis

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ANESTESI INHALASI

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Enflurane ( Ethrane ).
Halothan ( Fluothane )
Isoflurane (Forane ).
Desflurane.
Sevoflurane.

OBAT ANTI GOUT

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(Golan et al., 2008)(Golan et al., 2008)


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(Finkel et al., 2009)

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Drugs used in Gout and


Hyperuricemia
Allopurinol : prevents or treats hyperuricemia
Uric acid is formed by purine metabolism and an
enzyme xanthine oxidase. Allopurinol prevents
formation by inhibiting xanthine oxidase.
Colchicine : used to treat or prevent acute attacks of
gout. Drug of choice for acute attacks. Decreases
inflammation by affecting leukocytes.
Probenecid : increases urinary excretion of uric acid.
Not effective in acute attacks.
Sulfinpyrazone : uricosuric similar to Probenecid. Not
for acute attacks.

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Guidelines for Treating Gout

in accute attack

analgesic NSAIDs
uricosuric agent
colchicin
glucocorticoids (if necessary)

Maintenance drugs are Allopurinol, Probenecid, and


Sulfinpyrazone
Colchicine needed for several weeks to prevent acute attacks
while serum levels are being lowered
Need high fluid intake, alkaline urine to prevent renal calculi

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Migraine
Migraine:: a neurological disease characterized by attacks
of headache, photophobia, phonophobia, and nausea.
3 times more common in women than men
Up to 28 million people in the US are affected

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The 4 phases of a migraine


Prodrome
Occurs hours to days before
migraine without headache
Aura
Neurological phenomena such as
disturbance of vision just before
headache
Pain phase
Headache on one side of head
with nausea, photophobia and
other classic migraine symptoms
Postdrome
Exhaustion, irritability, depression

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Causes of Migraine
Increased excitability of CNS
Meningeal blood vessel dilation
Activation of perivascular sensory trigeminal
nerves
Pain impulses
Vasoactive neuropeptides contain:
substance P
calcitonin gene-related
related peptide (CGRP)
neurokinin A
combination of increased pain sensitivity,
tissue and vessel swelling, and inflammation

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Evidence for neural


causes :

Evidence for vascular


cause:
1. During the aura phase,
there is a decrease in
cerebral blood flow
(indicating that ischaemia
maybe causing the aura)
2. During a throbbing
headache, there is
cerebral vascular dilation
(the stretch of the vessels
triggers nerve endings
around the vessels)
3. Headache can be triggered
by vasodilators (e.g.. GTN)
and reversed by
vasoconstrictions

1. Pain sensitive trigeminal


nerves innervate cerebral
vessels
2. Trigeminal nerves release
a peptide CGRP (calcium
gene related peptide)
3. CGRP is elevated during a
migraine
4. Sumatriptan inhibits the
release of CGRP (also acts
as a 5HT1D agonist)

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Pathophysiology:Triggers
Triggers

Emotional
Physical

Chemical

Locus Cerulus
Sympathetic System

Dorsal Raphe

Release of NE

Release of 5-HT

Vasoconstriction

stimluation of 5-HT 2B or 5Ht 7

stimulates chemo center

Vasoconstriction

Nausea & vomiting

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Acute Treatment: Drug Therapy

Analgesics/combination analgesics
NSAIDs
Opioids
Neuroleptics/antiemetics
Migraine specific
Triptans
Ergotamines

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Prophylaxis Therapy
Anticonvulsants: topiramate, valproate,
Keppra, gabapentin
Tricyclics
Amitriptylene, nortriptylene, trazodone

Beta Blockers
Timolol, propranolol, nadolol

Calcium channel blocker verapamil


ACE inhibitors
SSRIs
Atypicals

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Severity Migraine
severity

last

TTT

mild Migraine

<2 hours

analgesics (Aspirin,
Acetaminophen , NSAIDS ) ,
Antiemetic

<4 hours

refractory to above
give Antiemetic , analgesics ,
Triptan agents .

4-6 hours

refractory to above
give Other Antiemetic ,
Serotonin Agonist
(Dihydroergotamine , Triptans)

6 to 72 hours

refractory to above
Emergency ttt

Headache
Moderate Migraine
Headache
Severe Migraine
Headache

Severe Refractory
Migraine Headache
status migrainosus

over 72 hours

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Mild migraine
Simple analgesics
NSAIDs
Isometheptene (Midrin, etc.)
Metoclopramide (Reglan) may be added to reduce nausea
and enhance drug absorption
Moderately severe migraine
NSAIDs
Isometheptene
Ergotamine, oral or intranasal
Sumpatriptan (Imitrex), oral or intranasal
Zolmitriptan (Zomig), oral
Naratriptan (Amerge), oral
Rizatriptan (Maxalt), oral
DHE, intranasal
With oral agents, metoclopramide may be added to reduce
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Severe migraine
Ergotamine plus an antiemetic, both administered by
suppository
Sumatriptan, subcutaneous injection, intranasal or
oral
Zolmitriptan, oral
Naratriptan, oral
Rizatriptan, oral
DHE, intramuscular or intranasal
Extremely severe migraine
Ketorolac (Toradol), 60 mg intramuscularly
DHE, intravenous, plus metoclopramide
Dopamine antagonist
Opioids
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