Drug Distribution PDF

Drug Distribution Dr. Salma Naqvi Asst. Prof., Pharmacology GMU, Ajman  Drug Distribution Drug Distribution is the Key factor in the onset of drug action. It is the movement of drug from the central compartment (blood) to peripheral compartments (tissue...

Drug Distribution Dr. Salma Naqvi Asst. Prof., Pharmacology GMU, Ajman  Drug Distribution Drug Distribution is the Key factor in the onset of drug action. It is the movement of drug from the central compartment (blood) to peripheral compartments (tissues). Drugs are distributed to organs and tissues via the circulation, diffusing into interstitial fluid and into cells from the bloodstream. Most drugs are not uniformly distributed throughout total body water, and some drugs are restricted to the extracellular fluid or the plasma compartment. Drugs with sufficient lipid solubility can simply diffuse through membranes into cells. Other drugs are concentrated in cells by the phenomenon of ion trapping. Drugs can also be actively transported into cells.  Drug distribution and Body water cell Intra-vascular Interstitial Intra-cellular  Drug distribution and Body water Total body water plasma volume extracellular plasma 3 liters interstitial 5% volume interstitial volume 15 liters 25% intracellular volume intracellular 12 liters 42 liters 20% 70% Water composition in Healthy subjects 27 liters 45% Body water is distributed into four main compartments. Drug molecules exist in bound or free form in each compartment, but only the free drug is able to move between the compartments.  Distribution of drugs depends upon:  Lipid solubility: It is a major factor affecting the extent of drug distribution, particularly to the brain, where the blood-brain barrier (BBB) restricts the penetration of polar and ionized molecules.  Ionization (pKa ), molecular size: Molecular size is a factor affecting the distribution of extremely large molecules, such as those of the anticoagulant heparin. Heparin is largely confined to the plasma compartment, although it does undergo some biotransformation in the liver.  Organ Blood Flow: Drugs are rapidly distributed to highly perfused tissues, namely the brain, heart, liver, and kidney. This enables a rapid onset of action of drugs affecting these tissues. Drugs are distributed more slowly to less perfused tissues such as skeletal muscle and even more slowly to those with the lowest blood flow, such as skin, bone, and adipose (fat) tissue.  Binding to plasma and tissue proteins  Body mass  Diseases like CHF, uremia, cirrhosis  Drugs in vascular space Free form Bound form - Active - Mainly to albumin - Diffusible - Reservoir form of drug - Available for metabolism - Inert & excretion - Non-diffusible - Not available for metabolism & excretion  Plasma Extracellular water Plasma protein Tissue protein drug  Plasma Protein binding of drugs ▪ D+P DP (reversible binding) ▪ Bound drug is in equilibrium with free drug. ▪ Free drug is active and bound drug is inactive. ▪ More free drug when binding sites are saturated. ▪ Acidic drugs bind to albumin ▪ Basic drugs bind to glycoprotein & β -globulins ▪ Depends on the affinity for protein binding site Note: Expressed plasma concentrations of the drug refer to bound as well as free drug  Drugs bound to Plasma Protein Acidic drugs Basic drugs (bound to albumin) (bound to α-1 glycoprotein)  Phenytoin  Beta blockers  Benzodiazepines  Lidocaine  NSAIDs  Imipramine  Penicillins  Quinidine Significance of Plasma Protein Binding ▪ Highly bound to plasma proteins: ❖ persist in body (plasma) for longer time ❖ lower therapeutic activity ❖ less distributed ❖ less available for dialysis in poisoning ▪ Hypoalbuminemia High concentration of free drug  Clinically important interactions due to drug displacement Two drugs may have affinity for same plasma protein binding sites, thus displace each other- drug interactions  Salicylates displace sulphonylureas (antidiabetic)  Salicylates displace Methotrexate (anticancer)  Phenytoin displaces warfarin (anticoagulant) Note: Acidic drugs do not displace alkaline drugs & vice versa.  Volume of Distribution (Vd) The apparent volume of distribution, Vd , can be defined as the volume that would contain the total amount of drug in the body (Ab) at a concentration equal to that present in the plasma (Cp): Vd= Ab /Cp Vd= Volume of Distribution Ab= total drug administered Cp=Plasma concentration http://www.icp.org.nz/icp_t3.html  Clinical Significance of Vd More the Vd, larger is the distribution of the drug in the body. Larger the distribution, less of the drug is present in the blood Therefore, haemodialysis will not be effective in treat drug poisoning with large Vd. The plasma volume is about 0.05 L/kg body weight. A few drugs, such as heparin, are confined to plasma because the molecule is too large to cross the capillary wall easily. More often, retention of a drug in the plasma following a single dose reflects strong binding to plasma protein. It is the free drug in the interstitial fluid that exerts a pharmacological effect. Following repeated dosing, equilibration occurs and measured Vd increases.  Drugs accumulated in Tissues  Heart – Digoxin  Liver – Chloroquine  Thyroid – Iodine  Retina – Chloroquine  Bone and teeth – Tetracycline Note: When the drug is accumulated in the tissues the volume of distribution increases drastically.  Barriers to Drug Distribution Blood brain barrier Placental barrier The Blood–Brain Barrier (BBB) BBB consists of a continuous layer of endothelial cells joined by tight junctions and surrounded by pericytes. The brain is consequently inaccessible to many drugs of low lipid solubility. However, inflammation can disrupt the integrity of BBB, allowing normally impermeant substances to enter the brain and can also disrupt drug efflux mechanisms. Consequently, penicillin can be given intravenously to treat bacterial meningitis, which is accompanied by intense inflammation. Placental barrier Lipoidal membranes Allows free passage of lipophilic drugs Even water soluble drugs can enter fetal circulation when present in high concentrations or for long periods in maternal circulation (Incomplete barrier) Note: Water soluble, Ionized and Plasma protein bound drugs do not cross BBB and PB References: Rang & Dale's Pharmacology, 9 th Edition, 9, 117-132 (Available on clinical key- https://www.clinicalkey.com/#!/content/book/3-s2.0- B9780702074486000093?scrollTo=%23hl0000906) Tripathi K.D., Essentials of Medical Pharmacology, 7th Edition, 2013, 2, p 17-21.  Revision 1. Identify the most accurate statement concerning apparent volume of distribution (Vd). a. Higher the plasma protein binding of the drug, higher will be Vd b. The Vd is the dose of i.v. drug divided by the plasma concentration at the time of drug administration. c. The Vd is directly proportional to the dose of drug administered. d. The half-life of a drug determines the Vd. e. The Vd is used to calculate the bioavailability of a drug. 2. State true or false: a. Un-ionized molecules cross phospholipid membranes more readily than their ionised forms. b. Weak acidic drugs are mostly ionized in acid solutions. c. Weak acidic drugs, such as aspirin, are mostly absorbed in the stomach. d. Basic drugs may bind reversibly to α 1 -acid glycoprotein in the plasma. e. First-pass metabolism may limit the bioavailability of oral drugs. 3. A 50-year-old type-2 diabetes mellitus patient was maintained on tab. glibenclamide (a sulfonylurea) 5 mg twice daily. He developed toothache for which he took tab. aspirin 650 mg 6 hourly. After taking aspirin he experienced anxiety, sweating, palpitation, weakness, ataxia, and was behaving abnormally. These symptoms subsided when he was given a glass of glucose solution. (a) What could be the explanation for his symptoms? (b) Which alternative analgesic should have been taken?