Pharmacology of Analgesics
Datten Bangun M.Ichwan Bagian Farmakologi & Terapeutik Fakultas Kedokteran USU
• Everyone
has experienced mild pain pain in response in response to antointense an or intense noxiousor stimuli noxious ⇒ stimuli This pain ⇒ helps This pain us tohelps avoidus potential to avoid potential damage by damage actingby asacting an early as warning an early signal warning signal • In Inthis thisrespect, respect, pain can pain be can an early be diagnostic an earlysymptom diagnostic for thesymptom onset of many for illnesses 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) • • • •
Central Modulation Perception & Interpretation Emotional State (Suffering) Reaction or pain behavior
• Acute
• Neuropathic • Chronic
PATOFISIOLOGI NYERI Impuls Nyeri dari perifer
Substantia Gelatinosa Rolandi
Tractus Spinothalamicus lateral
Nuclaeus Posterolateral Ventral Thalamus Gyrus Post Centralis
Pusat “relay” di Batang Otak
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 pain • Anticipate, prevent and manage side effects • Consider sequential and alternative drug trials • Use appropriate adjuvant
Analgesic drug • A drug that relieves pain due to multiple causes = e.g. paracetamol, morphine • Drugs that relieve pain due to a single cause or spesific syndrome 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 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 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
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.
• • • •
Acetaminophen & Aspirin NSAID’s Opioids (Narcotic analgesics) Tricyclic and heterocyclic antidepressants • SSRI’s • Serotonin (5-HT) receptor agents
• • • • • •
Anticonvulsants Psychotropics Adrenergic agents Topical agents Injection therapy Intravenous agents
WHO ANALGESIC LADDER Choosing pain killer and its combinations
Strong opioid ± NSAID ± adjuvant analgesic NSAID ± adjuvant analgesic ± weak opioid (codeine) paracetamol or NSAID ± adjuvant analgesic Pain Painthreshold threshold
0
1
2
mild
Pain tolerance
3
4
5
6
moderate
7
8
9
severe
10
Narcotic analgetics (Opioid analgetics) = opioid---- similar or produce effects like opium = opiate--- a product of Opium
Afgan-opium
OPIUM Berasal
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 activators,classified as strong,partial or weak agonist,based on its analgesic efficacy = Mixed agonist-antagonist (nalbuphine or pentozocine) 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)
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
κ (kappa) δ (delta) σ (sigma)
ANALGETIKA OPIOID DI DALAM KLINIK Agonis Opioid
Agonis Kuat
Agonis Lemah-Sedang
• Morfin
• Propoxyphene
Agonis Kerja Campuran
• Pethidine
• Hydrocodone
• Nalbuphine
• Fentanyl
• Oxycodone
• Buprenorphine
• Methadone
• Codeine
• Butorphanol
• Levorphanol
• Pentazocine • Dezocine
Subclasses: = Strong agonist -- strong analgesics - morphine,meperidine,methadone =
Moderate agonist- moderate analget. - oxycodone,codeine,nalbuphine,pentzocine
= 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 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 PCO2 causes cerebral vasodilation; decreased respiratory drive is the cause of death in overdose 4. Cerebro/Cardiovascular: cerebral vasodilation may increase intracranial pressure, morphine causes vasodilation via 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 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 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
Dipergunakan dibidang medis (dulu)
- menenangkan - timbul rasa enak
Disalah gunakan
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 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.
