Anti Nyeri

7/22/2019 Anti Nyeri

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ANALGESICS


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PENDAHULUAN

Analgesik: senyawa yang pada dosis

terapetik meringankan atau menekan rasa

nyeri tanpa memiliki kerja anastesi umum.analgesik berasal dari kata Yunani an-

(tanpa) dan -algia (nyeri).


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NYERI

Nyeri adalah suatu gejala yang berfungsi

untuk melindungi dan memberikan tanda

bahaya tentang adanya gangguan-gangguanpada tubuh; seperti peradangan, infeksi-

infeksi kuman, dan kejang otot.

ALARM


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Penyebab Nyeri

Adanya rangsangan-rangsangan

mekanis/kimiawi ( kalor/listrik )

mediator-mediator nyeri.

Mediator nyeri antara lain : histamin,

serotonin, plasmakinin-

plasmakinin, prostaglandin-prostaglandin,ion-ion kalium.


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Mediator-mediator tersebut merangsang

reseptor- reseptor nyeri pada ujung sarafbebas di kulit, selaput lendir,dan jaringan,

lalu dialirkan melalui saraf sensoris ke

susunan syaraf pusat ( SSP ) melaluisumsum tulang belakang ke talamus dan

ke pusat nyeri di otak besar ( rangsangan

sebagai nyeri ).


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Pain sensation can be influenced

or modified as follows:

elimination of the cause of pain

lowering of the sensitivity of nociceptors

(antipyretic analgesics, local anesthetics)

interrupting nociceptive conduction in sensorynerves (local anesthetics)

suppression of transmission of nociceptive

impulses in the spinal medulla (opioids)

inhibition of pain perception(opioids,general

anesthetics)

altering emotional responses topain


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Penggolongan Nyeri

1. Nyeri akut : nyeri yang tidak berlangsunglama. Berdasarkan sumber nyeri , dibagi :

Nyeri permukaan: luka luar, iritasi bahan

kimia, dan rangsangan termal di permukaan Nyeri somatis dalam: dari luka/iritasi dari

dalam tubuh, seperti karena injeksi atau dari

ischemia Nyeri viseral: nyeri ini berasal dari organ-

organ besar dalam tubuh, seperti hati, paru-

paru, usus, dll


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Acute pain of visceral origin ismost often associated with

inflammation.


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2. Nyeri kronis: nyeri ini berlangsung sangat

lama, bisa menahun, yang kadang

sumbernya tidak diketahui. Nyeri kronis

sering diasosiasikan dengan penyakit

kanker dan arthritis. Ex : neuropathic pain


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PENGGOLONGAN

ANALGETIK

Berdasarkan aksinya, obat-abat analgetik dibagi

menjadi 2 golongan :

1. Analgesik nonopioid / perifer

2. Analgesik opioid.

Kedua jenis analgetik ini berbeda dalam hal

mekanisme dan target aksinya.


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NON-OPIOID ANALGESICS

target aksi pada enzim, yaitu enzimsiklooksigenase (COX). COX berperan dalam

sintesis mediator nyeri, salah satunya adalah

prostaglandin.

Mekanisme umum : mengeblok pembentukan

prostaglandin dengan jalan menginhibisi enzim

COX pada daerah yang terlukamengurangi

pembentukan mediator nyeri .

Mekanismenya tidak berbeda dengan NSAID dan

COX-2 inhibitors.


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Efek samping yang paling umum darigolongan obat ini adalah gangguan lambung

usus, kerusakan darah, kerusakan hati dan

ginjal serta reaksi alergi di kulit. Efek samping biasanya disebabkan oleh

penggunaan dalam jangka waktu lama dan

dosis besar.


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Penghambatan oleh obat-obat Analgesik Nonopioid


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Phospholipase

Arachidonic acid

Cyclooxygenase Lipoxygenases

Steroids-----

NSAIDs -----

Prostaglandins

PGE2PGF2 PGI2

pyrexia vasodilationalgesic

PMNs

Lymphokines

-----Lipoxygenase inhititors

The events of the inflammtory response and mechanisms of anti-flammatory


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Non-steroidal anti-inflammatory

drugs (NSAIDs)NSAIDs have three major actions, all of

which are due mainly to the inhibition of

arachidonic acid cyclo-oxygenase ininflammatory cells (the COX-2 isoenzyme),

and the resultant decrease in prostanoid

synthesis.


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drugs (NSAIDs)

An anti-inflammatory action:

(1) The decrease in vasodilator prostaglandins(PGE2, PGI2) means less vasodilatationand, indirectly, less oedema.

(2) The inhibition of activity of adhesion

molecule.

(3) Accumulation of inflammatory cells isalso reduced.


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COX: COX-1:constitutive enzyme: is involved in

tissue homeostasis.

COX-2:inducible enzyme: is responsiblefor the production of the prostanoid

mediators of inflammation.

return


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drugs (NSAIDs) An analgesic effect:decreased

prostaglandin generation means less

sensitisation of nociceptive nerve endings toinflammatory mediators such as bradykinin

and 5-hydroxytryptamine.

Relief of headache is probably due todecreased prostaglandin-mediated

vasodilatation.


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drugs (NSAIDs)

An antipyretic effect:this is partly due to a

decrease in the mediator prostaglandin that is

responsible for elevating the hypothalamic set-point for temperature control in fever.

Endogenous pyogen(IL-1,TNF,IFN, IL-6)

BBB CNS(PEG, Na+/Ca2+, cAMP,CRH)

fever


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Classification

Non-selective COX inhibitor

Selective COX inhibitor

Salicylates

Acetaminophen

Indomethacin

et al

selection

chemcialconstitution


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drugs (NSAIDs) Some important examples are aspirin,

ibuprofen, naproxen, indomethacin,

paracetamol. (The last agent has analgesicand antipyretic effects but little anti-

inflammatory action).


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1. The Salicylates: Aspirin

Aspirin (acetylsalicylic acid) was first isolated in1829 by Leroux from willow bark.

It can cause irreversible inactivation of cyclo-oxygenase, acting on both COX-1 and COX-2.


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Aspirin

Salicylates are given orally and are rapidlyabsorbed; 75% metabolized in the liver.

Excretion:85% in alkaline urine

5% in acid urine


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Pharmacologic effects

(1) Antipyretic action: is rapidly effective in

febrile patients, yet has little effect on

normal body temperature.(2) Anti-inflammatory effects: the primary

clinical application is in the treatment of

musculoskeletal disorders, such asrheumatoid arthritis, osteoarthritis and

ankylosing spondylitis.


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(3) Analgesic effects:

(a) is usually effective for low- to moderate-intensity pain. Integumental pain is relieved betterthan the pain from hollow visceral areas.


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(b) relief of pain occurs through both peripheraland central mechanisms.

----Peripherally, it inhibits the synthesis of PGs in

inflamed tissues, thus preventing the sensitizationof pain receptors to both mechanical and chemicalstimuli.

----Centrally, the analgesic site exists in close

proximity to the antipyretic region in thehypothalamus. Its analgesia action is notassociated with mental altertions, such as hypnosisor changes in sensation other than pain.


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(4) Respiratory effects:

(a) High doses result in medullary stimulation,leading to hyperventilation and a respiratoryalkalosis. Compensation rapidly occurs becausethe kidney is able to increase the excretion of

bicarbonate, producing a compensated respiratoryalkalosis.

(b) Toxic doses or very prolonged administrationcan depress the medullary resulting in anuncompensated respiratory acidosis.


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(5) Cardiovascular effects:

(a)Therapeutic doses have no significant

cardiovascular effect. However, the prophylacticuse of aspirin to reduce thromboembolic events in

coronary and cerebral circulation has increased.

Studies have demonstrated that such use results in

long-term survival and reduced frequency ofsecond myocardial infarctions.


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(5) Cardiovascular effects:

(b) High doses may cause peripheral vasodilation

by exerting a direct effect on smooth muscle.(c) Toxic doses depress circulation directly and by

central vasomotor paralysis. Noncardiogenic

pulmonary edema may occur in older patients on

long-term salicylate therapy.


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(5) Gastrointestinal effects:

(a) It can cause epigastric distress, nausea, and vomiting by

irritating the gastric mucosal lining and stimulating thechemoreceptor trigger zone in the CNS.

(b) It may cause a dose-related gastric ulceration, bleeding,

and erosive gastritis because of inhibiting the formation ofPGE2, which inhibits gastric acid secretion and has acytoprotective effect. Salicylate-induced gastric bleeding is

painless and may lead to an iron deficiency anemia.


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(6) Hepatic effects:

(a) dose-dependent hepatic damage. Usually,asymptomatic, elevated plasma transaminaselevels are the key indication of hepatic insult.

(b) more severe and associated with encephalopathy

seen in Reyes syndrome.Use of salicylates in children with chickenpox or

influenze is contraindicated.


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(7) Hematologic effects:

(1) It inhibits the platelet aggregation by

decreasing the production of TXA2.

(2) In doses greater than 6g/d, aspirin may

reduce plasma prothrombin levels.


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(8)Renal effects: It can result in salt and waterretention because of decreasing renal blood

flow.(9) Metabolic effects: It can produce

hyperglycemia and glycosuria in large doses.

(10) Endocrine effects: In very large doses, itcan stimulate steroid secretion by theadrenal cortex.


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Therapeutic uses

(1) Aspirin is used in restricted situation for thesymptomatic relief of fever. Because of an increased

incidence of Reyes syndrome in children who

previously were given aspirin for the relief of viral

fevers, it is now recommended that a child with anyfever be given paracetamol instead, if medication is

required.

(2) It is useful as analgesics for certain categories of

pain, such as headache, arthritis, dysmenorrhea.


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Therapeutic uses

(3) It remains the standard, first-line drug in thetherapy of rheumatoid arthritis, and can

provide relief of symptoms in acute rheumatic

fever.(4) Some clinicians recommend small daily

doses of aspirin for prophylaxis of

thromboembolism, stroke, or myocardialinfarction because of its antiplatelet activity.


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Adverse effects

(1) Salicylism: usually occurs with repeated administration

of large doses. Characteristic findings include:

----headache, mental confusion, lassitude, and drowsiness.

----tinnitus and difficulty in hearing.

----hyperthermia, sweating, thirst, hyperventilation,

vomiting, and diarrhea.

(2) Bronchospasm in aspirin-sensitive asthmatics.


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Adverse effects

(3) Gastrointestinal disturbances.

(4) Prolongation of bleed time or reduce

prothrombin level.

(5) Other: skin eruption, hepatic effects, Reyes

syndrome.


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Treatment of Aspirin poisoning

(1) Inducing emesis or administering gastric

lavage.

(2) Appropriate infusion measures to correctabnormal electrolyte balance and

dehydration.

(3) Alkalinization of the urine.

(4) Dialysis as required.


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2. p-Aminophenol Der ivatives :

Paracetamol/acetaminophen

Pharmacologic effects:

Paracetamol has analgesic and antipyretic actions butonly weak anti-inflammatory effects.

It appears to be an inhibitor of PG synthesis in the brain,thus accounting for its analgesic and antipyretic activity.

It is much less effective than aspirin as an inhibitor of

the peripherally located PG biosynthetic enzyme systemthat plays such an important role in inflammation.


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Paracetamol

Pharmacologic effects:

It exerts little or no pharmacologic effect on thecardiovascular, respiratory, or gastrointestinal systems,

on acid-base regulation, or on platelet function.


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Therapeutic uses

Paracetamol provides an effective

alternative when aspirin is contraindicated

(e.g., in patients with peptic ulcer orhemophilia) and when the anti-inflammtory

action of aspirin is not required.


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Adverse effects

At therapeutic doses, paracetamol is well

tolerated; however, adverse effects include:

-----Skin rash and drug fever.-----Rare instances of blood dyscrasias.

-----Renal tubular necrosis and renal failure.

-----Hypoglycemic coma At overdose, it can result in severe hepatotoxicity,

resulting in centrilobular hepatic necrosis.


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3. I ndoles and Related Compounds

: Indomethacin Pharmacologic effects :

(1) Inhibit COX nonselectively .

(2) Inhibit phospholipase A and C.

(3) Reduce PMN migration.

(4) Decrease T cell and B cell proliferation.

(10-40 time more potent anti-inflammatory

than aspirin)


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Indomethacin

Therapeutic uses:

Because of its toxicity and side effect, it is

not routinely used for analgesia orantipyresis.

The major uses of indomethacin are in thetreatment of rheumatoid arthritis,ankylosing spondylitis, osteoarthritis, andacute gout.


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Indomethacin

Adverse effect:

(1) Gastrointestinal complaint:

(2) CNS effects: 25%-50%

(3) Hematologic reactions:

(4) Hypersensitivity reactions: asthma

(aspirin- sensitive patients may exhibit

cross-reactions to indomethacin).


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Arylpropionic Acid Derivatives

: Naproxen and Ibuprofen They have prominent anti-inflammatory action.

Therapeutic uses: rheumatoid arthritis,

osteoarthritis, ankylosing spondylitis, acutetendinitis, dysmenorrhea, et al.

Adverse effect: gastrointestinal effects,

dermatologic problems, thrombocytopenia.

apply to long-term treatment because they are

better-tolerated.


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4. Fenamates

Ex : Meclofenamate (Meclomen),merupakan turunan asam fenama

waktu paruh pendek,efek samping yang

serupa dengan obat-obat AINS baruyang lain dan tak ada keuntungan lain

yang melebihinya.

obat ini meningkatkan efek antikoagulanoral. dikontraindikasikan pada

kehamilan.


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5. Pyrazolone Der ivatives

Contoh Obatnya : Phenylbutazone

(Butazolidin)untuk pengobatan artristis

rmatoid,dan berbagai kelainan otot rangka. obat ini mempunya efek anti-inflamasi yang

kuat. tetapi memiliki efek samping yang

serius seperti agranulositosis, anemiaaplastik,anemia hemolitik,dan nekrosis

tubulus ginjal.


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6. Oxicam Der ivatives

Contoh Obatnya : Piroxicam (Feldene),

obat AINS dengan struktur baru.

waktu paruhnya panjang

untuk pengobatan artristis rmatoid,dan

berbagai kelainan otot rangka.

efek sampingnya meliputi tinitus ,nyerikepala,dan rash.


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7. Acetic Acid Der ivatives

Contoh Obatnya : Diclofenac (Voltaren) obat ini adalah penghambat siklooksigenase yang

kuat dengan efek antiinflamasi,analgetik, dan

antipiretik.

waktu parunya pendek.

dianjurkanuntuk pengobatan artristis

rematoid,dan berbagai kelainan otot rangka. efek sampingnya distres saluran cerna,

perdarahan saluran cerna,dan tukak lambung.


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8. M iscel laneous Agents

Contoh Obatnya : Oxaprozin (Daypro),

obat ini mempunyai waktu paruh yang

panjang. obat ini memiliki beberapa keuntungan dan

resiko yang berkaitan dengan obat AINS

lain.


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Selective COX-2 inhibitor

Celecoxib, Meloxicam and Rofenxib

more selective for COX-2 than for COX-1.

Adverse effects are slighter than other

NSADs.

Long-term studies of the incidence of

clinically significant gastrointestinal ulcersand bleeding are not yet completed.


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Clinical uses of the NSAIDs

For analgesia in painful conditions (e.g. headache,

dysmenorrhoea, backache, bony metastases of

cancers, postoperative pain):

The drugs of choice for short-term analgesia are aspirin,

paracetamol and ibuprofen; more potent, longer-acting

drugs (diflunisal, naproxen, piroxicam) are useful for

chronic pain.

The requirement for narcotic analgesics can be

markedly reduced by NSAIDs in some patients with

bony metastases or postoperative pain.


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For anti-inflammatory effects in chronic or acuteinflammatory conditions (e.g. rheumatoid arthritisand related connective tissue disorders, gout and

soft tissue diseases). With many NSAIDs, the dosage required forchronic inflammatory disorders is usually greaterthan for simple analgesia and treatment may need

to be continued for long periods; Treatment couldbe initiated with an agent known to have a lowincidence of side-effects. If this provesunsatisfactory, more potent agents should be used.


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To lower temperature. Paracetamol is preferred

because it lacks gastrointestinal side-effects and,

unlike aspirin, has not been associated with Reyes

syndrome in children.

There is substantial individual variation in clinical

response to NSAIDs and considerable

unpredictable patient preference for one drugrather than another.

OPIOID ANALGESICS


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OPIOID ANALGESICS

Analgetik opioid merupakan golongan obat

yang memiliki sifat seperti opium/morfin. Sifat

dari analgesik opioid yaitu menimbulkan adiksi:

habituasi dan ketergantungan fisik. Oleh karena

itu, diperlukan usaha untuk mendapatkananalgesik ideal:

- Potensi analgesik yg sama kuat dengan morfin

- Tanpa bahaya adiksi


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Obat yang berasal dari opium-morfin

Senyawa semisintetik morfin

Senyawa sintetik yang berefek seperti

morfin


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Analgetik opiad mempunyai daya

penghalang nyeri yang sangat kuat dengan

titik kerja yang terletak di susunan syarafpusat (SSP).

Umumnya dapat mengurangi kesadaran

dan menimbulkan perasaan nyaman(euforia).

Analgetik opioid ini merupakan pereda

nyeri yang paling kuat dan sangat efektifuntuk mengatasi nyeri yang hebat.


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Tubuh sebenarnya memiliki sistem

penghambat nyeri tubuh sendiri (endogen),

terutama dalam batang otak dan sumsumtulang belakang yang mempersulit penerusan

impuls nyeri

Beberapa senyawa yang termasuk dalampenghambat nyeri endogen antara lain:

enkefalin, endorfin, dan dinorfin.


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Opioid endogen ini berhubungan dengan

beberapa fungsi penting tubuh seperti :

- fluktuasi hormonal,- produksi analgesia,

- termoregulasi,

- mediasi stress dan kegelisahan, dan

- pengembangan toleransi dan ketergantungan

opioid.

Baik opioid endogen dan analgesik opioid bekerja

pada reseptor opioid, berbeda dengan analgesik

nonopioid yang target aksinya pada enzim.

Mekanisme m m


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Mekanisme umum

opioid terikat pada reseptor

penguranganmasuknya ion Ca2+ke dalam sel, dan

mengakibatkan pula hiperpolarisasi dengan

meningkatkan masuknya ion K+ke dalam sel.

terjadinya pengurangan terlepasnya dopamin,

serotonin, dan peptida penghantar nyeri, seperti

contohnya substansi P, dan mengakibatkan

transmisi rangsang nyeri terhambat.


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Penggolongan Opioid berdasar


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gg g preseptor kerjanya

1.Agonis opioid menyerupai morfin (pd reseptor

, ). Contoh: Morfin, fentanil

2. Antagonis opioid. Contoh: Nalokson

3. Menurunkan ambang nyeri pd pasien yg

ambang nyerinya tinggi

4. Opioid dengan kerja campur. Contoh: Nalorfin,

pentazosin, buprenorfin, malbufin, butorfanol


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Penggolongan berdasarkan efek kerjanya :

1.Agonis Kuata. Fenantren

Morfin, Hidromorfin ,danoksimorfon

merupakan agonis kuat yang bermanfaat dalampengobatan nyeri hebat. Heroinadalah agonis

yang kuat dan bekerja cepat .


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b F ilh til i


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b. Fenilheptilamin

Metadonmempunyai profil sama dengan morfin

tetapi masa kerjanya sedikit lebih panjang. Dalamkeadaan nyeri akut,potensi analgesik dan

efikasinya paling tidak sebanding dengan morfin

Levometadil asetat merupakan Turunan Metadonyang mempunyai waktu paruh lebih panjang

daripada metadon

F il i idi


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c. Fenilpiperidin

Meperidindan Fentanil adalah yang paling luas

digunakan diantara opioid sintetik yang ada,mempunyai efek antimuskarinik.subgrup

fentanil yang sekarang terdiri dari sufentanil dan

alventanil.d. Morfinan

Levorfanoladalah preparat analgesik opioid

sintetik yang kerjanya mirip dengan morfinnamun manfaatnya tidak menguntungkan dari

morfin.

2 A i Ri i d


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2. Agonis Ringan sampai sedang

a. Fenantren

Kodein,Oksikodoa,dihidrokodein, dan

hidrokodon,

semuanya mem-punyai efikasi yang kurang

dibanding

Penggunaan dengan kombinasi dalam

formulasi-formulasi yang mengandung

aspirin atau asetaminofen dan obat-obat

lain.

b. Fenilheptilamin


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Propoksifen aktivitas analgesiknya

rendah,misalnya 120 mg propoksifen = 60 mg

kodein

c. Fenilpiperidin

Difenoksilatdan metabolitnya,difenoksin

digunakan sebagai obat diare dan tidak untuk

analgesik,digunakan sebagai kombinasi dengan

atropin.

Loperamid adalah turunan fenilpiperidin yang

digunakan untuk mengontrol diare.Potensi

disalahgunakan rendah karena kemampuannya

rendah untuk masuk ke dalam otak.

3. Mixed Opioid Agonist

Antagonists


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or Partial Agonists

a. Fenantren

b. Morfinan

c. Benzomorfan

4. Antagonis Opioid


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g p

Naloksondan Naltrekson

Penggunan utama nalokson adalah untukpengobatan keracunan akut opioid,

masa kerja nalokson relatif singkat, Sedangkan

naltrekson masa kerjanya panjang, untuk program pengobatan penderita pecandu

individu yang mengalami depresi akut akibat

kelebihan dosis suatu opioid ,antagonis akanefektif menormalkan pernapasan,tingkat

kesadaran, ukuran pupil aktivitas usus,dan lain-

lain.

5 Drugs Used Predominantly as


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5. Drugs Used Predominantly as

Antitussives

Analgesic opioid adalah obat yang paling efektif

dari semua analgesic yang ada untuk menekan

batuk.

Efek ini dicapai pada dosis dibawah dari dosis

yang diperlukan untuk menghasilkan efek

analgesik.

Contoh obatnya adalah Dekstrometrofan,Kodein,Levopropoksifen.


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Referensi


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Katzung, G.Bertram.,2007,Basic & Clinical Pharmacology10th

Ed.,The McGraw-Hill Companies. Inc, New York.

Craig, R.Craig and Robert E.Stitzel,2007,Modern Pharmacology With

Clinical Application-6th Ed,, Lippncott Williams & Wilkin, Virginia.

Neal,J.Michael, 2002,Medical Pharmacology at a glance-4th Ed.,

Blackwell science Ltd,London

Goodman and Gilman,2006,The Pharmacologic Basis of Therapeutics

11th Ed.,McGraw-Hill Companies. Inc, New York.

Lllmann, Heinz [et al.] ,2000,Color Atlas of Pharmacology 2nd

Ed.,Thieme,New York

Farmakologi dan terapeutik FK UI

Anti Nyeri

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