Interaksi Dadah

INTERAKSI DADAH Dr. Nur Azlina Mohd Fahami Jabatan Farmakologi Universiti Kebangsaan Malaysia

PENGENALAN Many patients receive more than one drug during a course of treatment because: Combination therapy is preferable or necessary for producing a single effect or response, such as the chemotherapy of malignant disease; or treatment of hypertension. A single condition or pathology may give rise to a variety of symptoms that are controlled by different drugs. The patient may suffer from more than one condition or pathology requiring treatment with drugs that are unrelated pharmacologically ⇒ The combination of drugs used may result in drug interactions

INTERAKSI DADAH BERLAKU: Apabila satu dadah mengubah kesan dadah yang lain Cth: dadah A menyebabkan dadah B mengalami ... • peningkatan atau pengurangan kesan • tempoh berkesan yang lebih lambat atau cepat • kesan samping yang baru atau meningkat.

Interaksi Farmakokinetik vs Farmakodinamik Farmakokinetik: Jumlah dadah dalam darah di ubah

Farmakodinamik: Jumlah dadah di dalam darah tetap sama tetapi kesannya berubah.

Changes in intestinal motility

Piscitelli, et al. N Engl J Med, Vol 344 (13): March 29, 2001

INTERAKSI FARMAKOKINETIK

ADME Absorption/ Serapan Distribution/ Sebaran Metabolism/ Metabolisme Excretion/ Ekskresi

INTERAKSI SEMASA SERAPAN. (A) Satu dadah menyebabkan serapan dadah yang kedua … •

lebih capat atau perlahan

• berkurang atau lebih menyeluruh (complete)

MEKANISMA • pH (dadah & persekitaran) • Motiliti gastrousus • Interaksi Fiziko-kimia

Perubahan pH pada kandungan G.I.T. Perut/Gaster:

pH berbeza2. Antacids pH Alcohol dan sesetengah makanan menyebabkan sekresi asid. pH

Usus kecil & Besar. pH dekat neutral. Tiada perbezaan signifikan.

ALLEGED MECHANISM Stomach contents

Stomach contents

Blood

A-H

A-H

A- + H+

A- + H+

Lipid membrane

Antacid

Blood

Lipid membrane

A = Acidic drug

Alcohol

THEORY Antacids

Alcohol

Less acidic stomach contents

More acidic stomach contents

More ionisation

Less ionisation

Slower absorption

Faster absorption

Above is for acid drug. Opposite pattern for a basic drug.

MOTILITI GIT • Serapan drpd usus lebih efisien drpd gaster. • Dadah A mengubah kadar motiliti gastrousus menyebabkan.. • Kadar serapan dadah B juga berubah. • Contoh: Morfin mengurangkan motili usus.

MOTILITI GIT • Morphine reduces GIT motility. • This in turn could decrease the rate of absorption of other drugs taken by mouth. • On the other hand, metoclopramide, a drug given to prevent nausea, has been reported to increase gastro-intestinal motility and therefore speed up the onset and sedative effects of orally administered morphine.

INTERAKSI FIZIKO-KIMIA Dua dadah bergabung di dalam kandungan G.I.T. dan keduaduanya tidak diserap Contoh: • Tetracycline

TETRACYCLINES & CATIONS e.g. Ca2+, Al3+, Mg2+ or Fe2+ Form non-absorbable chelates with tetracyclines. Antacids - Al3+, Mg2+ etc Dairy products (Milk, cheese) - Ca2+ Effect is considerable. Antacids can reduce absorption of tetracyclines by 80%. Solution: Leave a 2 hour gap between the two drugs.

INTERAKSI SEMASA DISTRIBUSI (D) Pengikatan pada plasma protein menghasilkan interaksi apabila dadah-dadah bersaing untuk ikatan pada protein plasma. Maka kesan satu dadah itu akan bertambah. Contoh: Aspirin & Warfarin Aspirin can displace a number or agent from protein including wafarin. These results in excessive amount of free wafarin available and may result in increased bleeding tendency.

INTERAKSI SEMASA METABOLISME (M) a)

Enzyme Induction (Penginduksi enzim) Mengurangkan aktiviti dadah dengan peningkatan biotransformasi/metabolisme satu dadah oleh dadah yang lain. Contoh: Nicotine and other tobacco products speed up the metabolism of theophylline, an asthma drug Thus, smokers may need larger than normal doses of this drugs for it to work

Interactions During Metabolism. b) Enzyme Inhibitor (Perencat Enzim) Peningkatan aktiviti dadah dengan perencatan biotransformasi/metabolisme satu dadah oleh dadah yang lain. Contoh: Ritonavir (antiviral) inhibits CYP450 thus increasing the effect of MDMA (ecstasy)

INTERAKSI SEMASA EKSKRESI Dadah bersaing untuk diekskretkan. Kerana ginjal merupakan organ utama ekskresi dadah maka kebanyakan interaksi berlaku disini. Ini termasuk: A.

Sekresi Aktif Tubul : Bersaing untuk sistem pengangkutan yang sama.

1. Dadah Berasid Contoh: Probenecid & Penicillins 2. Dadah Beralkali Contoh: Procainamide & Cimetidine

INTERAKSI SEMASA EKSKRESI B.

Serapan semula Tubul (pasif)

Dadah yang menghasilkan urin beralkali meningkatkan ekskresi dadah yang bersifat asid lemah Dadah yang menyebabkan urin berasid meningkatkan ekskresi dadah bersifat bes lemah.

INTERAKSI SEMASA EKSKRESI Example: Substances that acidify the urine (such as cranberry juice) or alkalinise it (bicarbonate and other over-the-counter indigestion remedies) may have an effect on amphetamine pharmacokinetics. This is because the elimination of amphetamine from the body is increased when urine is acidic and decreased when alkaline. This procedure has been used to reduce the likelihood of amphetamine detection by urine analysis.

INTERAKSI FARMAKODINAMIK Apabila dadah dengan kesan farmakologi yang serupa diberi bersama2, kesan aditif atau sinergistik boleh berlaku. Dadah2 ini mungkin bertindak pada reseptor yang sama atau berlainan. Dadah dengan kesan farmakologi yang berlawanan (opposite) boleh mengurangkan respon satu atau kedua2 dadah (respon antagonisme).

KESAN ADITIF Terma kesan aditif biasanya digunakan dalam kes di mana kesan gabungan dadah2 yang bertindak melalui mekanisma yang sama ialah sama dengan kesan yang dijangkakan melalui campuran ringkas (simple addition) 1+1=2 Contoh: Acetaminophen & Aspirin Acetaminophen and aspirin when administered together for relief of pain, the combined effect is call additive since the two drugs apparently act on the same receptors.

KESAN SINERGISTIK Kesan sinergistik di lihat apabila kesan gabungan (joint effect) kedua2 dadah lebih besar daripada campuran kesan individunya. (1 + 1 > 2). Terma ini biasanya di gunakan dalam kes di mana dua dadah bertindak pada tapak tindak yang berbeza dan salah satu dadah (synergist) meningkatkan kesan dadah kedua. Peningkatan kesan/ tindakan dadah

pemanjangan

tempoh

Contoh: Pengambilan bersama alkohol dan heroin

KESAN SINERGISTIK Mixing depressant drugs like alcohol and heroin or alcohol and tranquillisers is the most common kind of drug interaction within the non-medical use of drugs. It also one of the most dangerous because the effect of one will potentiate' the effect of the other - in other words, the user is doubling up on the drugs effects. Alcohol is probably the most dangerous mixer. Heroin overdose deaths often involve alcohol while a medical dose of barbiturates can easily become lethal if taken with alcohol.

Log Effect of Drugs

SINERGISME NO DRUG DRUG A - 10 % DRUG B - 40 %

A + B - 90 % 0 12 Hours after innoculation

KESAN ANTAGONISME Any time the conjoint effect of two drugs is less than the sum of the effects of the drugs acting separately, the phenomenon is called drug antagonism. (1+1<2) Example: Morphine & Naltrexone An antagonist like naltrexone reduces the effect of an agonist like morphine by preventing it from combining with its receptor.

Log of number of viable bacteria/ml

ANTAGONISM E NO DRUG DRUG C - 10 % A + C - 40 % DRUG A - 90 % 0 12 Hours after innoculation

INTERKSI DADAHMAKANAN/MINUMAN Hasil daripada interaksi dadah dengan bahan makanan atau minuman. Interaksi ini mengurangkan, meningkatkan/mengurangkan kadar serapan dadah; mengubah metabolisme dadah, dan meningkatkan/mengurangkan risiko toksisiti dadah. Contoh: a) Minuman berkaefin seperti coke, kopi menyebabkan gaster lebih berasid maka serapan dadah yang bersifat asid lemah akan?, manakala bes lemah akan? b) Alcohol boleh menyebabkan kerosakan pada mukosa gaster & usus dan ini boleh mengurangkan serapan dadah/ bahan organik lain.

INTERKSI DADAHMAKANAN/MINUMAN Contoh: a) Grapefruit juice & tefenadine (antihistamine) Previously healthy 29-year old male used terfenadine twice daily for one year to treat allergic rhinitis. The patient drank grapefruit juice two to three times weekly. On the day of his death, he consumed two glasses of juice, took his terfenadine dose, and proceeded to mow the lawn. He became ill, collapsed and died.

INTERAKSI DADAHPERSEKITARAN Interaksi di antara dadah dan persekitaran boleh berlaku apabila seseorang terdedah kepada polutan persekitaran seperti asap dan insecticide. Contoh: Pendedahan kepada insecticide menginduksikan beberapa enzim

boleh

Apa akan terjadi kepada pesakit yang mengambil dadah yang dimetabolismekan oleh enzim ini? Mengurangkan kesan teraputik/ pendekkan T1/2 dadah tersebut.

INTERAKSI DADAH SEBAGAI RAWATAN Morphine – naloxone/naltrexone Alcohol – Disulfiram Disulfiram reaction Berpeluh, flushing, palpitation, nausea, headache, etc Alcohol → acetaldehyde → Acetate Block by disulfiram

DRUG-DISEASE INTERACTIONS Interactions between certain drugs and specific disease states Severe liver disease can be associated with reduced metabolic clearance and higher plasma levels of drugs extensively metabolized by the liver. Heart failure reduces liver blood flow and causes a reduction in clearance for drugs such as lidocaine or propranolol that are usually extensively cleared by the liver These changes are usually only clinically important in cases of extremely impaired organ function.

DRUG-SOCIAL HABIT INTERACTIONS Interactions between certain drugs and social habits, such as smoking tobacco/marijuana and alcohol consumption Nicotine & polycyclic hydrocarbon from tobacco induce liver enzymes (theophylline, propranolol, diazepam etc) Cannabinoids in marijuana can inhibit (within hrs of use)/increase (10-14 days of regular use) metabolism of drugs (theophylline, propranolol etc)) Alcohol consumption with some drugs can cause disulfiram-like reaction (Sulfonylureas, cephalosporins), potentates hepatotoxicity of acetaminophen, Acute intake – inhibits enzyme (barbiturates, warfarin). Chronic – stimulates enzyme

TERIMA KASIH