1) Drug interactions can occur during absorption through changes in gastrointestinal pH, formation of complexes, and effects on motility and drug transporters.
2) Distribution interactions involve protein binding competitions and effects on transporters like P-glycoprotein.
3) Metabolism interactions include changes to first-pass metabolism through blood flow variations and enzyme induction/inhibition, as well as genetic polymorphisms affecting cytochrome P450 isoenzymes.
1) Drug interactions can occur during absorption through changes in gastrointestinal pH, formation of complexes, and effects on motility and drug transporters.
2) Distribution interactions involve protein binding competitions and effects on transporters like P-glycoprotein.
3) Metabolism interactions include changes to first-pass metabolism through blood flow variations and enzyme induction/inhibition, as well as genetic polymorphisms affecting cytochrome P450 isoenzymes.
1) Drug interactions can occur during absorption through changes in gastrointestinal pH, formation of complexes, and effects on motility and drug transporters.
2) Distribution interactions involve protein binding competitions and effects on transporters like P-glycoprotein.
3) Metabolism interactions include changes to first-pass metabolism through blood flow variations and enzyme induction/inhibition, as well as genetic polymorphisms affecting cytochrome P450 isoenzymes.
1) Drug interactions can occur during absorption through changes in gastrointestinal pH, formation of complexes, and effects on motility and drug transporters.
2) Distribution interactions involve protein binding competitions and effects on transporters like P-glycoprotein.
3) Metabolism interactions include changes to first-pass metabolism through blood flow variations and enzyme induction/inhibition, as well as genetic polymorphisms affecting cytochrome P450 isoenzymes.
2 ABSORPSI DITA MARINA LUPITANINGRUM, M.FARM., APT KONSEP
• Istilah: rate of absorption dan total
amount absorbed • For drugs that are given long-term, in multiple doses (e.g. warfarin) the rate of absorption is usually unimportant, provided the total amount of drug absorbed is not markedly altered. • drugs that are given as single doses, intended to be absorbed rapidly (e.g. analgesics such as paracetamol (acetaminophen)), where a rapidly achieved high concentration is needed, a reduction in the rate of absorption may result in failure to achieve an adequate effect
4 EFFECTS OF CHANGES IN GASTROINTESTINAL PH Dipengaruhi: pKa obat lipid-solubility pH of the contents of the gut Formulasi obat Absorpsi Asam Lebih besar pada keadaan?? salisilat Asam (pH ↓)
H-receptor antagonis Merubah pH lambung often uncertain, but some cases the effect can be significant
5 MANAGEMENT
6 ADSORPTION, CHELATION AND OTHER COMPLEXING MECHANISMS • tetracycline + divalent and trivalent metallic ions (calcium, aluminium, bismuth and iron) • to form complexes that are both poorly absorbed and have reduced antibacterial effects • Management • Separating the doses by 2 to 3 hours goes some way towards reducing the effects of this type of interaction.
7 CHANGES IN GASTROINTESTINAL MOTILITY • Sebagain besar obat diabsorpsi di bagian atas usus halus • Obat yg merubah pengosongan lambung akan mempengaruhi absorpsi • Ex:
8 INDUCTION OR INHIBITION OF DRUG TRANSPORTER PROTEINS • Ketersediaan hayati oral dari beberapa obat dibatasi oleh kerja protein transporter obat • Difusi obat dialam usus. • P-glycoprotein • Drug transporter proteins, which eject drugs that have diffused across the gut lining back into the gut. • Digoxin: substrate of P-glycoprotein • Drugs that induce this protein: rifampicin
9 MALABSORPTION CAUSED BY DRUGS • Neomycin causes a malabsorption syndrome, similar to that seen with non-tropical sprue. The effect is to impair the absorption of a number of drugs including (p.745)
Berikatan dengan protein plasma It is increasingly being recognised
albumin, bersifat Reversible that distribution of drugs into the brain, and some other organs such Aktif: free (unbond) as the testes, is limited by the action Tgt pada konsentrasi obat dan of drug transporter proteins such as afinitas ikatan dpt P-glycoprotein. berkompetisi dgn obat lain These proteins actively transport Drugs can also become bound to drugs out of cells when they have albumin in the interstitial fluid, and passively diffused in some, such as digoxin, can bind to the heart muscle tissue. Obat yang menghambat prot pembawa ↑ uptake obat ke otak Ex: warfarin, sulfonylureas, ↑ efektivitas dan eso phenytoin, methotrexate, And valproate 15 METABOLISME DITA MARINA LUPITANINGRUM, M.FARM., APT 2 Fase: • Fase I: oksidasi, reduksi & hidrolisis • Metabolisme = biotransformasi = • Mengubah obat lebih polar biochemical degradation = • CYP P450, mooamin oksidase detoxification • Fase II: coupling with other • Obat substances (As. Glukoronat) inaktif • Sedikit obat diekresi dlm bentuk yg tdk berubah • Sebag besar diubah mjd less lipid- soluble • Proses metabolism: serum, ginjal, kulit dan usus halus, tp paling banyak dimetabolisme oleh enzim pd membrane reticulum endoplasma dalam sel hati A. CHANGES IN FIRST-PASS METABOLISM
1. CHANGES IN BLOOD FLOW
THROUGH THE LIVER. • Inhibisi dan induksi enzim (terutama sitokrom P450 mengubah first-pass • portal circulation obat ke hati scr langsung sblm metabolism didistribusikan melalui aliran darah k seluruh tubuh • grapefruit juice + CCB • Few clinically relevant • inhibit the cytochrome P450 isoenzyme CYP3A4, mainly in the gut, and therefore reduces the metabolism of oral CCB
2. INHIBITION OR INDUCTION OF FIRST-PASS METABOLISM
18 B. ENZYME INDUCTION • Induksi metabolism ↑ ekskresi↑ • Most in phase I • Phase II, ex: Rifampisin + zidovudine • Barbiturat auto induksi • ↑ enzim mikrosomal • Dipengaruhi oleh obat dan dosis delayed in onset and slow to resolve • Solusi: raising the dose of • requires good monitoring (for drug need tappering off and may be an overdose when the drug metabolism has returned to normal) 19 C. ENZYME INHIBITION • Inhibisi ↓ metabolism ↑ akumulasi pd tubuh • rapid development of toxicity • Most in Phase I • Ex: sildenafil after ritonavir had also been taken for 7 days • ritonavir inhibits the metabolism of sildenafil by CYP3A4 • valpromide+ carbamazepine • phase I hydrolytic metabolism, is the inhibition of epoxide hydrolase by valpromide, which increases the levels of ‘carbamazepine’ • inhibition of carbamazepine glucuronidation by ‘sodium valproate’ • Efek interaksi • Brp konsentrasi?? Signifikan scr klinik??
20 21 D. GENETIC FACTORS IN DRUG METABOLISM • genetic polymorphism • Perbedaan isoenzim tertentu • CYP2D6, CYP2C9 and CYP2C19 also show polymorphism, whereas CYP3A4 does no • Alasan mengapa berbeda efek pd setiap individu • CYP2D6 ↓ (about 5 to 10% in white Caucasians, 0 to 2% in Asians and black people) memtabolisme beta bloker • slow metabolisers • CYP2C19 ↓ (6% of Caucasians, 1 to 7.5% of Blacks and 12 to 23% of Oriental and Indian Asians) memetabolisme PPI • slow metabolisers
22 E. CYTOCHROME P450 ISOENZYMES AND PREDICTING DRUG INTERACTIONS • prediksi melalui: in vitro tests with human liver enzymes • ciclosporin is metabolised by CYP3A4, and rifampicin is a known potent inducer of this isoenzyme, whereas ketoconazole inhibits its activity, so that it comes as no surprise that rifampicin reduces the levels of ciclosporin and ketoconazole increases them. • Ingat: satu obat dpt dimetabolisme oleh lebih dr satu cytochrome P450 isoenzyme 23 EKSKRESI DITA MARINA LUPITANINGRUM, M.FARM., APT EKSKRESI • Inhalasi, empedu, dan urin • Dipengaruhi: fluid pH, with active transport systems • and with blood flow to the kidney can alter the excretion of other drugs (A) CHANGES IN URINARY PH • Bentuk: non-ionised lipid soluble dpt berdifusi melalui membrane lipid pd sel tubulus • tgt pKa & pH urine. • Sedikit obat yg terpengaruh pH urin • Contoh:‘analgesic-dose aspirin’, (p.151) • In cases of overdose, deliberate manipulation of urinary pH has been used to increase the removal of drugs such as methotrexate and salicylates.
26 (B) CHANGES IN ACTIVE RENAL TUBULAR EXCRETION
Obat dgn sistem transport aktif yang sama pada tubulus
ginjal can compete with one another for excretion.
Contoh: • probenecid ↓ ekskresi penisilin dan obat lain melalui organic onion transporters (OATs). • Probenecid possibly also inhibits some of the ABC transporters in the kidneys. The ABC transporter, P-glycoprotein, is also present in the kidneys, and drugs that alter this may alter renal drug elimination
27 (C) CHANGES IN RENAL BLOOD FLOW • Aliran darah melalui ginjal sebagian dikontrol oleh produksi prostaglandin sbg vasodilator • Sintesis prostaglandin dihambat ekskresi obat ↓ • Ex: litium dan NSAID
28 (D) BILIARY EXCRETION AND THE ENTERO-HEPATIC SHUNT 1. Enterohepatic recirculation • obat diekskresikan dalam empedu, baik tidak berubah atau terkonjugasi (misalnya sebagai glukuronida) untuk membuatnya lebih larut dalam air. • Beberapa konjugat dimetabolisme menjadi senyawa induk oleh flora usus dan kemudian diserap kembali. • Proses daur ulang ini memperpanjang masa tinggal obat di dalam tubuh • jika flora usus berkurang dengan adanya antibakteri, obat tersebut tidak didaur ulang dan hilang lebih cepat. • Ex: kegagalan kontrasepsi hormonal yang dapat disebabkan oleh penggunaan penisilin atau tetrasiklin secara bersamaan,
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