Pharmacology of AnalgesicsPharmacology of AnalgesicsPharmacology of Analgesics

Datten Bangun Datten Bangun

M.IchwanM.Ichwan

Bagian Farmakologi & Terapeutik Bagian Farmakologi & Terapeutik

Fakultas KedokteranFakultas Kedokteran

USUUSU

• Everyone has experienced mild pain in response to an

intense or noxious stimuli ⇒ This pain helps us to avoid

potential damage by acting as an early warning signal

• In this respect, pain can be an early diagnostic symptom for the onset of many

illnesses

• Everyone has experienced pain in response to an intense or

noxious stimuli ⇒ This pain helps us to avoid potential

damage by acting as an early warning signal

• In this respect, pain can be an early diagnostic symptom for

the onset of many illnesses

• Pain can also be severe and incapacitating, as after an

injury, during recovery from surgery, or in association with

medical conditions such as rheumatoid arthritis

• Under this circumstances, noxious stimuli can elicit severe

pain because of increases in the excitability of the

somatosensory system, and stimuli that would not normally

cause pain can become painful

Pain is the most common symptom for

which patients see a doctor.

The complaint doesn’t mean that an

analgesic is needed.

To manage the pain,the doctor needs to

know what is happening to the patient in

mind and body.

“an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage” *IASP, 1986

• Noxious Stimulus (Nociception)(Nociception)

• Central Modulation

• Perception & Interpretation

• Emotional State (Suffering)

• Reaction or pain behavior

•• AcuteAcute•• NeuropathicNeuropathic•• ChronicChronic

PATOFISIOLOGI NYERI

Impuls Nyeri dari perifer

Substantia Gelatinosa

Rolandi

Tractus Spinothalamicus lateral

Nuclaeus Posterolateral

Ventral Thalamus

Pusat “relay”

di Batang Otak

Gyrus Post

Centralis

Thalamus

• Select the appropriate analgesic drug

• Prescribe the appropriate dose

• Administered through the appropriate route

• Schedule the appropriate dosing interval

• Prevent persistent pain and eliminate breakthrough painpain

• Anticipate, prevent and manage side effects

• Consider sequential and alternative drug trials

• Use appropriate adjuvant

Analgesic drugAnalgesic drug

• A drug that relieves pain due to multiple causes= e.g. paracetamol, morphine

• Drugs that relieve pain due to a single cause or spesificsyndrome only, e.g. ergotamine (migraine), carbamazepine

(neuralgias), glyceryl trinitrate (angina pectoris), are not

classed as analgesics; nor are adrenocortical steroids

that supppress pain of inflammation of any cause.

• are classed as;• NARCOTIC (which act in the CNS and cause drowsiness, i.e. • =opioid• NON-NARCOTIC (which act chiefly peripherally, e.g. diclofenac)

Adjuvant drugsAdjuvant drugs

• are those used alongside analgesics in the management

of pain

• They are not themselves analgesics, though they may

modify the perception or the concomitants of pain thatmodify the perception or the concomitants of pain that

make it worse (anxiety, fear, depression),

e.g. psychotropic drugs,

or they modify underlying causes, e.g. spasm of smooth

or of voluntary muscle

• Acetaminophen & Aspirin

• NSAID’s

• Opioids (Narcotic analgesics)

• Anticonvulsants

• Psychotropics

• Adrenergic agents

Pain is the most common symptom for which patients see a doctor. The

complaint doesn’t mean that an analgesic is needed. To manage the pain,the

doctor needs to know what is happening to the patient in mind and body.

• Opioids (Narcotic analgesics)

• Tricyclic and heterocyclic antidepressants

• SSRI’s

• Serotonin (5-HT) receptor agents

• Adrenergic agents

• Topical agents

• Injection therapy

• Intravenous agents

NSAID ±adjuvant analgesic

± weak opioid

Strong opioid

± NSAID ±adjuvant analgesic

WHO ANALGESIC LADDER

Choosing pain killer and its combinations

± weak opioid(codeine)

paracetamolor NSAID ±

adjuvant analgesic

0 1 2 3 4 5 6 7 8 9 10

Pain tolerancePain threshold

mildmild moderatemoderate severesevere

Pain thresholdPain thresholdPain thresholdPain thresholdPain threshold

Narcotic analgetics (Opioid analgetics)

= opioid----���� similar or produce effects like opium

= opiate---���� a product of Opium= opiate---���� a product of Opium

Afgan-opium

OPIUMBerasal dari tanaman Papaver somnifera.

Opium →→→→ candu →→→→ morfin →→→→ heroin (putaw)

Concepts=Receptors for endogenous opioid peptides

(enkephalins and endorphines),i.e;µ,ĸ and δ

are targets for opioid analgesics

= Most opioids are nonselective receptors = Most opioids are nonselective receptors

activators,classified as strong,partial or weak

agonist,based on its analgesic efficacy

= Mixed agonist-antagonist (nalbuphine or pen-

tozocine) activate ĸ, but block µ receptor

RESEPTOR OPIOID DI DALAM TUBUH

Ada 4 jenis yang telah diketahui :

� Reseptor µ : µ1 dan µ2

� Reseptor κ : κ1,κ2 dan κ3

� Reseptor δ : δ1 dan δ2

� Reseptor σ : σ1 dan σ2

Reseptor Efek Agonis

µ (mu)

κ (kappa)

δ (delta)

σ (sigma)

Analgesia supraspinal, euforia, myosis,

depresi pernapasan, sedasi, konstipasi

Analgesia spinal, disforia, depresi pernapasan,

sedasi, myosis

Belum diketahui pada manusia, tetapi

analgesia pada hewan

Disforia, halusinasi, efek psikomimetik,

midriasis

ANALGETIKA OPIOID DI DALAM KLINIK

Agonis Kuat Agonis Kerja

Agonis Opioid

Agonis Lemah-Sedang Agonis Kuat

• Morfin

• Pethidine

• Fentanyl

• Methadone

• Levorphanol

Agonis Kerja Campuran

• Nalbuphine

• Buprenorphine

• Butorphanol

• Pentazocine

• Dezocine

Agonis Lemah-Sedang

• Propoxyphene

• Hydrocodone

• Oxycodone

• CodeineCodeine

Subclasses:

= Strong agonist --����strong analgesics

- morphine,meperidine,methadone

= Moderate agonist-���� moderate analget.

- oxycodone,codeine,nalbuphine,pentzocine

= weak agonist -���� mild analgesic= weak agonist -���� mild analgesic

- propoxyophene,

Mechanism of action

In terms of analgesia, opioids exert both spinal

and supraspinal actions:

1.Spinal analgesia occurs by activation of

presynaptic opioid receptors--���� decreased

calcium influx -----���� decreased release of calcium influx -----���� decreased release of

neurotransmitter involved in nociception

2.Supraspinal analgesia, occurs by activation

of postsynaptic opioid receptors in the medulla

midbrain,---���� inhibition of neurons involved in

pain pathways via increased flux of potassium

ions

Pharmacokinetic:

-most opioid are well absorbed by s.c, i.m, or

oral route, but due to first-pass effect-----����

oral route need higher dose

is very difficult to predict in different patient.

- Codein and oxycodone : less first-pass effect

Pharmacodynamics:1.Analgesia : - efficacy is variable,depending

on the drug

2. Sedation : - strong agonists cause more

sedation (euphoria)

3. Respiratory depression:

Increased PCO2Increased PCO2

causes cerebral vasodilation;

decreased respiratory drive is

the cause of death in overdose

4. Cerebro/Cardiovascular:cerebral vasodilation mayincrease intracranial pressure,morphine causes vasodilationvia histamin release.

5.Gastro-intestinal;- decrease peristalsis-----���� constipation

6.Other smooth muscle:- relaxation of uterine smooth muscle,

- contraction of biliary, bladder and

ureteral smooth muscle ( except ureteral smooth muscle ( except

meperidine)

7. Pupils : opioids (except meperidine)----���� miosis

8. Cough suppression----���� antitussive

9. Emesis------ via CTZ

10. Tolerance:

- chronic use leads to marked tolerance to

most actions except constipation and

miosis

11.Dependence

-psychological and physical dependence

- abuse liability is greatest with strong

agonist

- on abrupt discontinuance-----���� withdrawal

(abstinence) syndrome ---�SAKAW

Clinical Use:

1.Analgesia

2.Cough suppression---�-codein

- dextromethorphan

3.Diarrheal states -----� - loperamide

- diphenoxylate- diphenoxylate

4.Anesthesia------------� - fentanyl

- morphine

5.Withdrawal states---� - methadone

6.Pulmonary edema--���� due to its vasodilating

effect--����reduce preload

Toxicities:

Overdose:

- hypotension

- respiratory depression--���� coma

Chronic use------���� tolerance and dependence

Efek dari heroin (diacetyl morphine

- hilang rasa takut

- hilang rasa sakit

- menenangkan

- timbul rasa enak

Dipergunakan dibidang

medis (dulu)

Disalah gunakan

Efek heroin pada penggunaan khronis:Efek heroin pada penggunaan khronis:- toleransi ���� dosis yang diperlukan makin

besar / tinggi.

- ketergantungan ���� psikis ���� “sugesti”

���� fisik

Sakaw = sakit oleh karena putaw

Gejala sakaw

�Timbul setelah ± 6 jam penggunaan terakhir dengan

gejala sebagai berikut.

� Rasa sakit yang hebat diseluruh badan istimewa di

perut.

� Bulu roma berdiri (goose-flesh reflex)

� Air liur, ingus, air mata bercucuran���� flu-like � Air liur, ingus, air mata bercucuran���� flu-like

syndrome

�Setelah beberapa jam, gejala ini menurun / menghilang,

NAMUN esoknya gejala ini muncul lagi tapi dengan

intensitas berkurang.

TIDAK ADA YANG MATI OLEH KARENA SAKAW.