Drug Interactions

Preliminary
Drug interaction is a change in the effect of a drug due to the use of other drugs (drug-drug interactions) or by food, traditional medicine and other chemical compounds. Significant drug interactions may occur if two or more drugs are used together.
Drug interactions and adverse drug reactions need attention. An American study showed that each year nearly 100,000 people had to be hospitalized or have to stay in hospital for longer than it should, even in cases of death due to interactions and / or side effects of drugs. Patients who were admitted to hospital often receive therapy with polypharmacy (6-10 kinds of drugs) as the subject for more than one doctor, so it is very possible drug interactions mainly affected the severity of illness or age.
Clinically important drug interactions result in increased toxicity when and / or a reduction in drug effectiveness. So keep in mind, especially when it comes to drugs with narrow safety margin (therapeutic index is low), such as cardiac glycosides, anticoagulants and cytostatic drugs. It is also worth noting the drugs commonly used together.
Incidence of hard drug interactions in clinical estimate because:
a. documentation is lacking
b. often escaped notice, due to lack of knowledge of the mechanisms and the possibility of drug interactions. This resulted in drug interactions include increased toxicity seen as idiosyncratic reaction to one drug, while the form of interaction penurunakn effectiveness ascribed the increased severity of illness of patients
c. the incidence or severity of drug interactions are influenced by individual variations, in which certain populations more susceptible such as geriatric patients or severely diseased, and could also be due to differences in metabolic capacity between individuals. In addition, factors specific diseases, especially renal failure or severe liver disease and other factors (large doses, the drug ingested together, chronic administration).

Mechanism Drug Interactions
Interactions are classified by involvement in a process of pharmacokinetics and pharmacodynamics. Pharmacokinetic interaction is characterized by changes in drug plasma levels, area under the curve (AUC), onset of action, half time, etc.. Pharmacokinetic interactions caused by changes in the rate or extent of absorption, distribution, metabolism and excretion. Pharmacodynamic interactions are usually associated with the ability of a drug to alter the effects of other drugs without altering the properties of farmakokinetiknya. Pharmacodynamic interactions include additive (A drug effect = 1, B = 1 effects of drugs, the effects of a combination of both = 2), potentiation (effect A = 0, B = 1 effect, the effect of the combination of A + B = 2), synergism (effect A = 1, the effect of B = 1, the effect of the combination of A + B = 3) and antagonism (effect A = 1, B = 1 effect, the effect of the combination of A + B = 0). Mechanisms involved in the interactions are pharmacodynamic effects of changes in tissues or receptors.

Pharmacokinetic interactions
1. Absorption
The drugs are taken orally bisaanya absorbed from the gastrointestinal tract into the circulatory system. There are many possibilities for drug interactions occur through the gastrointestinal tract. Drug absorption can occur through passive and active transport, where most of the drug is absorbed passively. This process involves the diffusion of the drug from an area with a high concentration to areas with lower levels of medication. On the displacement of the drug active transport against a concentration gradient (ie ion-ion and water-soluble molecules) and this process requires energy. Absorption of active drug transport is faster than in the passive tansport. Drugs in the form of non-terion fat soluble and easily diffuses across the cell membrane, whereas the drug in the form of fat and insoluble terion can not diffuse. Under normal physiological conditions, but the level of absorption is slightly delayed absorption is usually perfect.
When the absorption rate changes, significant drug interactions will occur more easily, especially drugs with short half-life time or when needed peak plasma levels were quick to get the effect. Interaction mechanism due to impaired absorption, among others:
a. Direct interaction
Interaction physically / chemically between drugs within the lumen of the gastrointestinal tract before absorption can interfere with the absorption process. This interaction can be avoided or greatly dikuangi when interacting drugs are given within a period of at least 2 hours.
b. pH changes in gastrointestinal tract
Gastrointestinal fluid alkalis, for example due to antacids, will increase the solubility of drugs that are poorly soluble acid in the gastrointestinal tract, such as aspirin. Thus aspirin accelerated by alkaline dissolution will accelerate absorption. However, the atmosphere alkalis in the gastrointestinal tract reduces the solubility of a drug that is alkaline (eg, tetracycline) in the gastrointestinal fluids, thereby reducing absorption. Decreased gastric acidity by antacids will reduce the destruction of drugs that are not acid resistant thus increasing bioavailabilitasnya.
Ketoconazole is taken by mouth requires a medium acid to dissolve the required amount so as not allows supplied with antacids, anticholinergic drugs, inhibition of H 2, or proton pump inhibitors (eg, omeprazole). If necessary, the drug should be abat-given at least 2 hours after administration of ketoconazole.
c. formation of insoluble complexes or chelate, and adsorsi
The interaction between the antibiotic group fluorokinolon (ciprofloxacin, enoksasin, levofloxacin, lomefloksasin, norfloxacin, ofloxacin and sparfloksasin) and divalent ions and trivalent (eg Ca 2 + ions, Mg 2 + and Al 3 + from antacids and other drugs) can cause a decrease in significant gastrointestinal absorption, bioavailability and therapeutic effect, because formation of complex compounds. This interaction also decreases the activity of fluoroquinolone antibiotics. This interaction effect can be significantly reduced by providing an antacid a few hours before or after administration of fluoroquinolones. If antacids are really needed, adjustment of therapy, such as drug-pbat replacement with H 2 receptor antagonists or proton pump inhibitors do.
Several antidiarrheal medication (containing attapulgite) adsorb other drugs, resulting in lower absorption. Although there is no scientific research, use of these drugs should interval with other drugs as long as possible.
d. drug being bound to the bile acid sequestrant (BAS: bile acid sequestrant)
Cholestyramine and kolestipol can bind to bile acids and prevents reabsorpsinya, consequently bonding can occur with other drugs, especially acidic (eg warfarin). We recommend the use of interval kolestipol with cholestyramine or other drugs as long as possible (minimum 4 hours).
e. changes in gastrointestinal function (acceleration or slow emptying of the stomach, changes vaksularitas or gastroduodenal mucosal permeability, or damage to the intestinal wall mucosa).
Examples of drug interactions on the absorption process can be seen in the following table:

Obat yang dipengaruhi Drugs affected	Obat yang mempengaruhi Drugs that affect	Efek interaksi Interaction effects
Digoksin Digoxin	Metoklopramida Metoclopramide Propantelin Propantelin	Absorpsi digoksin dikurangi Reduced digoxin absorption Absorpsi digoksin ditingkatkan (karena perubahan motilitas usus) Digoxin absorption increased (due to changes in intestinal motility)
Digoksin Digoxin Tiroksin Thyroxine Warfarin Warfarin	Kolestiramin Cholestyramine	Absorpsi dikurangi karena ikatan dengan kolestiramin Reduced absorption due to bonding with cholestyramine
Ketokonazol Ketoconazole	Antasida Antacids Penghambat H 2 Inhibitor of H 2	Absorpsi ketokonazol dikurangi karena disolusi yang berkurang Ketoconazole absorption is reduced due to the reduced dissolution
Penisilamin Penicillamine	Antasida yang mengandung Al 3+ , Mg 2+ , preparat besi, makanan Antacids containing Al 3 +, Mg 2 +, iron preparations, food	Pembentukan khelat penisilamin yang kurang larut menyebabkan berkurangnya absorpsi penislinamin Penicillamine chelate formation which leads to reduced absorption of poorly soluble penislinamin
Penisilin Penicillin	Neomisin Neomycin	Kondisi malabsorpsi yang diinduksi neomisin Neomycin induced malabsorption conditions
Antibiotik kuinolon Quinolone antibiotics	Antasida yg mengandung Al 3+ ,Mg 2+ , Fe 2+ , Zn, susu Antacids that contain Al 3 +, Mg 2 +, Fe 2 +, Zn, milk	Terbentuknya kompleks yang sukar terabsorpsi Complex formation is difficult adsorbed
Tetrasiklin Tetracycline	Antasida yang mengandung Al 3+ , Mg 2+ , Fe 2+ , Zn, susu Antacids containing Al 3 +, Mg 2 +, Fe 2 +, Zn, milk	Terbentuknya kompleks yang sukar terabsorpsi Complex formation is difficult adsorbed

Among the above mechanisms, the most significant is the formation of insoluble complexes, chelate formation or if the drug is bound resin that binds bile acids. There are also some drugs that alter the pH of the gastrointestinal tract (eg, antacids) which resulted in significant changes in drug bioavailability.

.1. Distribution

Once the drug is absorbed into the circulatory system, drugs brought into the workplace where the drug will react with a variety of body tissues and or receptors. During their stay in the bloodstream, the drug can be attached to various blood components, especially protein albumin. Fat-soluble drugs have a high affinity to adipose tissue, so drugs can be stored in the adipose tissue. The low blood flow to the tissue resulting in fatty tissue into depot for fat-soluble drugs. This prolongs the effects of the drug. The drugs are highly lipid soluble groups such as phenothiazines, benzodiazepines and barbiturates.

Number of acidic drugs have an affinity for blood proteins, especially albumin. The drugs have an alkaline affinity binding to α-acid-glycoprotein. Plasma protein binding (PPB: plasma protein binding) expressed as a percent indicating percent bound drug. Albumin-bound drug is pharmacologically inactive, whereas drugs that are not tied, commonly called fractions free, pharmacologically active. When two or more drugs are highly bound to protein is shared sasam, competition binding occurs at the same place, which resulted in a shift in one of the drug binding to the protein, and it finally happened peninggatan free drug levels in the blood. When the drug displaced of proteins by binding with other drugs, there will be increased levels of free drug is distributed through various networks. Albumin levels in patients with drug-free or active form will be higher.

Valproic acid was reported to shift phenytoin of bonds with proteins and also inhibits the metabolism of phenytoin. If patients take both drugs, unbound phenytoin levels will increase significantly, causing more side effects large. Conversely, phenytoin may decrease plasma levels of valproic acid. The second combination drug therapy should be monitored with tight and dosage adjustments made.

Medications that tend to interact on the distribution of the drugs are:

percent protein bound high (over 90%)

bound on the network

has a small volume of distribution

have a low hepatic excretion ratio

have a narrow therapeutic range

has a rapid onset of action

used intravenously.

Drugs that have a high ability to shift to other drugs from protein binding is salicylic acid, phenylbutazone, sulfonamides and nonsteroidal anti-inflammatory.

.2. Metabolism

To produce a systemic effect in the body, the drug must reach the receptor, means the drug must be able to pass through the plasma membrane. For the drug must dissolve fat. Metabolism can change the fat-soluble active compounds into water-soluble compounds that are not active, which will be excreted primarily through the kidneys. Drug metabolism can pass through two phases, namely phase I and II metabolism. In the phase I metabolism, oxidation, demethylation, hydrolysis, etc.. by liver microsomal enzymes that are in the endothelium, produce more drug metabolites water-soluble. In the phase II metabolism, drug reacts with the water-soluble molecules (eg glucuronic acid, sulfate, etc.) into metabolites that are not or less active, which is soluble in water. A compound can pass one or both of the above fasemetabolisme until a water-soluble form. Most of the drug interaction clinically significant result from the phase I metabolism of the phase II.

a. Increased metabolism

Some medications can increase the activity of hepatic enzymes involved in the metabolism of other drugs. For example, phenobarbital increase the metabolism of warfarin thus lowering antikoagulannya activity. In this case the dose of warfarin should be increased, but after discontinued use of phenobarbital dose of warfarin should be reduced to avoid potential toxicity. Can be used as an alternative sedative than barbiturates, benzodiazepines such groups. Phenobarbital also increases the metabolism of other medications such as steroid hormones.

Other barbiturates and drugs such as carbamazepine, phenytoin, and rifampin also cause enzyme induction.

Pyridoxine accelerate decarboxylation of levodopa into its active metabolite, dopamine, in the peripheral tissues. Unlike levodopa, dopamine can not cross the barrier blood brain to provide antiparkinsonian effects. Giving karbidopa (an inhibitor of decarboxylation) together with levodopa, levodopa activity can prevent interference by pyridoxine,

b. Inhibition of metabolism

A drug may also inhibit the metabolism of other drugs, with impacts extend or increase the action of drugs that are affected. For example, allopurinol reduces the production of uric acid by inhibiting the enzyme ksantin oxidase, which metabolizes some potentially toxic drugs such as merkaptopurin and azathioprine. Ksantin oxidase inhibition can significantly enhance the effects of these medications. So if used with allopurinol, merkaptopurin or azathioprine dose should be reduced to 1/3 or ¼ dose usually.

Cimetidine inhibits oxidative metabolic pathways and may increase the action of drugs that are metabolized by this pathway (eg, carbamazepine, phenytoin, theophylline, warfarin and mostly benzodiazepines). Cimetidine did not affect benzodiazein action lorazepam, oksazepam and temazepam, which undergoes glucuronide conjugation. Ranitidine has an effect on oxidative enzymes lower than cimetidine, famotidine and nizatidin while not affect the oxidative metabolic pathway.

Erythromycin reportedly inhibits hepatic metabolism of some drugs such as carbamazepine and theophylline thereby increasing their effect. Fluoroquinolones such as ciprofloxacin drug class also increases the activity of theophylline, presumably through the same mechanism.

3. Excretion

Unless an inhalation anesthetic drugs, most drugs are excreted via bile or urine. Blood enters the kidney along the renal artery, first delivered to the glomeruli tubules, where small molecules that fit through the glomerular membrane (water, salt and some specific drugs) filtered into the tubules. Large molecules such as plasma proteins and blood cells were detained. Blood flow then passes through another part of the renal tubule where active transport to move the drug and its metabolites from blood to tubular filtrate. Tubular cells then perform active and passive transport (by diffusion) for reabsorbing the drug. The interaction can take place due to changes in renal tubules active excretion, changes in pH and changes in renal blood flow.

a. Changes in renal tubules active excretion

b. changes in urine pH

c. Changes in renal blood flow