Biopharmaceutics Lecture 3 (Distribution) PDF

Biopharmaceutics Lecture 3 (Distribution)  ADME Absorption 01 Distribution 02 Metabolism 03 Excretion 03 2 Distribution the process by which a drug disperses from the bloodstream into various tissues and orga...

Biopharmaceutics Lecture 3 (Distribution)  ADME Absorption 01 Distribution 02 Metabolism 03 Excretion 03 2 Distribution the process by which a drug disperses from the bloodstream into various tissues and organs of the body. Distribution: Reversible movement of drug from the central compartment (blood) to peripheral compartments (tissues). Following absorption (Skin, lung or GIT) or systemic administration (IV) into the bloodstream, a drug distributes into interstitial and intracellular fluids. ❑ Steps in drug Distribution Permeation of free drug through capillary wall and entry ECF (extracellular fluid) Permeation of drugs from ECF to ICF through membrane of tissue cell ❑ Rate limiting steps 1. Rate of perfusion to ECF 2. Membrane permeability of the drug.  Distribution is a passive process in which the driving force is the concentration gradient between the blood and extravascular tissues The process occur by diffusion of free drug until equilibrium is established As the pharmacological action of a drug depends upon its concentration at the site of action; Distribution plays a significant role in the onset, intensity and duration of action Distribution of a drug is not uniform throughout the body???? because different tissues receive the drug from plasma at different rates and to different extents.  Volume of distribution (Vd) Vd : means the volume of fluid in which the administered drug is distributed into the body after equlibrium Used to quantify the distribution of a drug between plasma and rest of the body after oral or parenteral dosing Relating the total amount of the drug in the body to the plasma concentration  Volume of distribution (Vd) It is apparent volume because all parts of the body equilibrated with the drug not have equal concentration Water soluble drugs will reside in the blood, and fat soluble drugs will reside in cell membranes and adipose tissue.  Vd also relates to whether a drug is Free/ proteinbound Drugs which bind selectively to plasma proteins have Vd < their real Vd e.g. Warfarin Drugs which bind selectively to extravascular tissues have Vd > their real Vd e.g: Chloroquine Drugs that are charged tend to bind to serum proteins. Protein bound drugs form macromolecular complexes that cannot cross biological membranes and remain confined to the blood stream. ❑ Factors affecting distribution of drug 1. Physico-chemical prosperities of drug 2.Binding to plasma and Tissue proteins 3. Blood flow 4. Special Compartments and barriers 5. Miscellaneous  1. Physico-chemical prosperities of drug A. Molecular size Mol wt less than 50-600 Dalton easily pass capillary membrane to extra cellular fluid (ECF). B. Degree of ionization (pKa) The pH of Blood plasma, ECF and BBB is 7.4 constant except in acidosis or alkalosis the ionized drug in plasma pH (polar/hydrophilic drug) cannot penetrate lipoidal cell membrane C. O/W partition coefficient (Ko/w) Nonpolar drug and lipophilic drugs are more likely to pass the cell membrane  1. Physico-chemical prosperities of drug Passage of drugs from ECF to cells is function of a. Molecular size b. Ionization constant c. Lipophilicity of drugs from ECF to cross cell membrane need particle size less than 50 Daltons (small)/ lipophilic Polar/ionized > 50 daltons ……Active transport 2. Binding to plasma and tissue protein ❑ Significance to plasma-protein binding 1. Affects distribution 2. Pharmacologically in active 3. Non diffusible 4. Not available for metabolism or excretion ( As they cant pass through capillaries and cell membranes because of their large size. 5. The plasma protein binding of drugs is usually reversible ( weak chemical bonds). Binding to plasma protein Different drugs binding to different proteins Binding sites for acidic agents……Albumins Ex- Bile acids, vitamin C, penicillin, Tetracyclines and warfarin Binding sites for basic agents……Globulins Ex- Streptomycin, chloramphenicol and Digitoxin The albumin can bind several compounds having varied structures, some substances even to a single site. Groups of drugs that bind to the same site compete with each other for binding. Some drugs may bind to blood components other than plasma proteins Ex: (Phenytoin and pentobarbitone bind to haemoglobin) Properties of plasma protein-drug binding Saturable: ❖ One plasma protein can bind a limited number of drug molecule Non-selective: ❖More than one kind of drug which has different chemical structures or pharmacological effects can be bound to the space on plasma protein Reversible: ❖The bonds between the drug and plasma protein are weak bonds like hydrogen or ionic bonds. ▪ Binding to tissue protein Many drugs accumulate in tissues at higher concentrations than those in the extracellular fluids and blood called Localization liver>kidney>lungs>muscle>skin>eye>bone>Hair, nail Tissue binding of drugs (cellular constituents): Proteins and phospholipids are generally reversible or some case irreversible ( Covalent chemical bonding) ▪ Importance of tissue distribution Firstly, it increases the apparent volume of distribution ( in contrast to plasma protein binding which decreases it) Secondly, it results in localization of a drug at specific site in the body produce local activity and toxicity ▪ Tissue reservoir Many lipid soluble drugs are stored in the fat tissues In obese persons, the fat content of the body may be as high as 50%, and even in lean individuals it constitutes 10% of body weight; hence fat may serve as reservoir for lipid soluble drugs  ▪ Bone reservoir Some drugs and heavy metals may accumulate in bone Ex: Tetracycline antibiotics and heavy metals ( Ca, Fluroide, lead or radium) may accumulate in bone and become a reservoir by adsorption onto the bone crystal surface may cause toxicity Adsorption process for some drugs shows therapeutic advantages for the treatment of osteoporosis 3. Blood flow ( Perfusion rate) ✓The rate of blood flow to tissue capillaries varies widely as a result of unequal distribution of cardiac output to various organs ✓ There is a positive correlation between the blood flow in the tissue and the distribution of the drugs. ✓The drug distribution to a particular organ or tissue depends on the size of the tissue (tissue volume) and tissue perfusion rate (volume of blood that flows per unit time per unit volume). ✓ Kidney, liver, l ung, brain and heart have a high perfusion rate in which the drugs distribute higher and rapidly equilibrated with drugs ✓Skin and muscle have a moderate perfusion rate, so they equilibrate slowly with the drug present in blood ✓ Adipose tissues, bones and teeth being poorly perfused, take longer time to get distributed with the same drug ✓ The total concentration of a drug increases faster in well-perfused organs 4. Specialized compartment and Barriers A. Blood brain barrier (BBB) ✓BBB capillaries highly specialized and have tight junction much less permeable to hydrophilic/ ionized drugs ✓The lipid solubility of the non-ionized and unbound species of a drug is an important determinant of its uptake by the brain. ✓ The More lipophilic the drug is, the more likely to cross BBB ❑ Different approaches to Blood brain barrier (BBB) A) Permeation enhancers: DMSO B) Pro-drug approach: Dopamine-levodopa C) Carrier system: Dihydropyridine (lipid soluble) moiety which is high lipophilic and cross BBB The Complex formed after entering in brain; (DHP) metabolized by CNS enzyme in brain and drugs gets entrapped in side the brain N.B Sugars and amino acids are transported using active transport  B. Placental barrier The characteristics of placental barrier is generally the same BBB However, restricted amounts of lipid insoluble drugs, especially when present in high concentration or for long period in the maternal blood gain access to the fetus by non carrier-mediated processes. Thus, the placental barrier is not as effective as BBB and impermeability of the placental barrier to polar compounds is relative rather than absolute Mol wt < 1000 Dalton and moderate to high lipid soluble drugs pass by simple diffusion (e.g. Steroids, Narcotics, Barbiturates and some Antibiotics) So care must be taken while administration of all types of drugs during pregnancy because of the uncertainty of their harmful effects on developing fetus 5. Miscellaneous - Age Difference in distribution pattern is mainly due to: (A) Total body water……greater in infants (B) Fat content ……..higher in infants and elderly (C) Skeletal muscle ……..lower in infants and elderly (D) BBB is poorly developed in infants and cerebral blood flow is high, hence greater penetration of drug in brain (E)Plasma protein content…………low albumin in both infants and elderly  5. Miscellaneous - Pregnancy During pregnancy, due to growth of uterus, placenta and fetus…. Increases the volume available for drug distribution Fetus has separate compartment for drug distribution, plasma and ECF volume also increase but albumin content is low 5. Miscellaneous - Obesity In obese persons, high adipose ( fatty acid) tissue so high distribution of lipophilic drugs 5. Miscellaneous - Disease state ✓Distribution characteristics of several drugs are altered in disease states 1. In hypoalbuminaemia, plasma protein binding of drugs may be reduced and high concentration of free drugs may be attained. 2. In congestive heart failure or shock, the perfusion rate to the entire body decreases, which affect distribution of drugs. 3. In meningitis, The BBB become more permeable and the polar antibiotics like penicillin-G, which don’t normally cross it, gain access to the brain