Drug interaction PP005 Lec 3.pdf

Lecture 3 Drug interactions Pharmacokinetic Drug Interactions II Dr Naglaa El-Orabi  Drug interaction 1- Pharmacokinetic Drug Interactions ii-Drug interaction and altered drug distributi...

Lecture 3 Drug interactions Pharmacokinetic Drug Interactions II Dr Naglaa El-Orabi  Drug interaction 1- Pharmacokinetic Drug Interactions ii-Drug interaction and altered drug distribution Drug distribution is the reversible process of delivering a drug from the bloodstream to the various body compartments. Distribution of a drug can be altered by other drugs that compete for binding sites on plasma proteins. It depends mainly on the affinity of the drug to binding with plasma proteins and other tissues. The most likely bound drugs is capable to displace others. The free drug is increased by displacement by another drug with higher affinity.  Drug interaction 1- Pharmacokinetic Drug Interactions ii-Drug interaction and altered drug distribution Changes in uptake of a drug to a certain body site can also occurs as a result of modulation of drug transporter proteins. Changes in drug distribution can occur if one agent alters the size of the physical compartment in which another drug distribute.  Drug interaction 1- Pharmacokinetic Drug Interactions ii-Drug interaction and altered drug distribution a) Alteration in drug protein binding (Drug displacement): Most drugs reversibly bind to plasma proteins, and competition for binding sites is common. The bound and unbound molecules are established in equilibrium. One drug can displace another drug from protein binding site. This displacement depends on the affinity of the drug to plasma protein. The most likely bound drugs is able to displace others. The free drug is increased by displacement by another drug with higher affinity. Only the unbound molecules remain free and pharmacologically active, while bound molecules are pharmacologically inactive and protected from metabolism and excretion(temporary reservoir)  Druginteraction Drug interaction 1- Pharmacokinetic Drug Interactions ii-Drug interaction and altered drug distribution Drugs with high affinity to bind with plasma proteins (especially albumin) like Aspirin, Sulfonamides, Phenylbutazone, can displace other drugs like Phenytoin is a highly bound to plasma protein (90%), Tolbutamide (96%), and Warfarin (99%) leaving high concenteration of them in unbound active form. When the drug is displaced by the other drug, the unbound form of the active drug becomes more leading to toxic level in the blood and presenting as drug toxicity.  Drug interaction 1- Pharmacokinetic Drug Interactions ii-Drug interaction and altered drug distribution Increased risk of supratherapeutic concentrations of Warfarin is highly expected with coadministration with Valproic acid because of displacement of warfarin from protein binding sites in addition to inhibition of hepatic metabolising enzymes activities especially CYP2C9. Hence CYP2C9-mediated warfarin metabolism is inhibited.  Drug interaction 1- Pharmacokinetic Drug Interactions ii-Drug interaction and altered drug distribution Another example, Quinidine displaces Digoxin from skeletal muscles sites increasing serum concentration of digoxin –increases risk of toxicity. Additional significant changes can be expected when displacement from plasma proteins occurs concurrently with a change in the intrinsic clearance of unbound drug. The impact of drug displacement of highly protein bound drugs can be muted through a compensatory increase in metabolism and clearance of the newly released, unbound active drug.  Drug interaction 1- Pharmacokinetic Drug Interactions ii-Drug interaction and altered drug distribution For example, Chloral hydrate is metabolised to trichloroethanol, and trichloroacetic acid that displaces Warfarin from plasma proteins and stimulate its hepatic metabolism hence increase the clearance of unbound Warfarin and decrease it is duration of action.  Drug interaction 1- Pharmacokinetic Drug Interactions ii-Drug interaction and altered drug distribution b) Alteration in Drug transporter activity: Drug transporter proteins represent another mechanism for drug-drug interactions that can affect drug absorption, distribution, or elimination. These proteins can be classified into two groups: the ATP-binding cassette family (e.g. P-glycoprotein) and the solute carrier superfamily; (e.g. organic anion transporter protein; OATP). Drug transporter proteins affect the pharmacokinetics of drugs within the body through uptake and efflux actions.  Drug interaction 1- Pharmacokinetic Drug Interactions ii-Drug interaction and altered drug distribution Inhibition or induction of transporter proteins (e.g. P-gp) can alter distribution as well as absorption of a drug. The resulting action of P-gp inhibition depends on the site of the interaction. For instance, inhibition of P-glycoprotein in enterocytes leads to increased oral bioavailability, whereas inhibition of P-gp in the liver or kidney can result in reduced drug elimination. In both cases, Drug bioavailability is enhanced.  Drug interaction 1- Pharmacokinetic Drug Interactions ii-Drug interaction and altered drug distribution For example, Induction of intestinal Pgp by Rifampicin results in a significant reduction in the oral bioavailability of Digoxin where Digoxin is ejected back into gut lumen leading to decrease absorption. Increased exposure of Ritonavir in the CNS through Ketoconazole induced–inhibition of P-gp leading to reduced transport out of the CNS and increase its CSF concentration.  Drug interaction 1- Pharmacokinetic Drug Interactions ii-Drug interaction and altered drug distribution Hepatic uptake can be affected through OATP1B1 because it affects that amount of drug entering hepatocytes, the site of major metabolism pathways. The best-characterized drug-drug interactions related to OATP1B1 involve Statins. Inhibition of OATP1B1, for instance, can lead to increased serum plasma concentrations of statins, increasing the risk of adverse effects like muscle pain, myopathy ,elevated liver enzymes, renal impairment, sleep disorders. Examples of OATP1B1 inhibitor: Atazanavir, Ritonavir, Lopinavir , Clarithromycin, Cyclosporin, and Gemfibrozil.  Drug interaction Mechanisms of drug interaction 1- Pharmacokinetic interactions c) Alteration in the size of the physical compartment : Changes in drug distribution can occur if one agent alters the size of the physical compartment in which another drug distributes. For example, diuretics, by reducing total body water, can increase plasma levels of Aminoglycosides and Lithium, possibly enhancing drug toxicities.