Drug Transport and Absorption PDF

Jones Ofori-Amoah ( BSc MPhil PhD, MPH CTM DHSM DipHRM) Department of Pharmacology and Toxicology, School of Pharmacy, UHAS. “Never allow yourself to think that any task is...

Jones Ofori-Amoah ( BSc MPhil PhD, MPH CTM DHSM DipHRM) Department of Pharmacology and Toxicology, School of Pharmacy, UHAS. “Never allow yourself to think that any task is beyond you, any position too high. Think big and your deeds will grow; think small and you’ll fall behind. Believe that you can and you will, for it’s all in the state of the mind” ❑ Sigmund Freud Drug Transport across Membranes 1  Drug Transport across membranes Learning Objectives Discuss the mechanisms by which drugs traverse biological membranes and factors affecting them Explain the influence of drug transport across membranes on its pharmacokinetics and pharmacodynamics. Exemplify how these processes can be affected by disease, diet and other factors Appreciate how alterations in these processes can affect the outcome of drug treatment. 2  Drug Transport Mechanisms for drug transport across membranes ❑Passive (simple) diffusion 1. Rate of transfer of substances are directly proportional to the concentration gradient on both sides of the membrane 2. Rapid for lipophilic, non-ionic, small molecules 3. No energy or carrier required ❑Aqueous transport 1. Small hydrophilic drugs ( 1000. E.g. Vaccines 4  SCHEMATIC REPRESENTATION OF DRUGS CROSSING CELL MEMBRANE OF EPITHELIAL CELL OF GASTROINTESTINAL TRACT. Aqueous diffusion of a water-soluble Passive diffusion of a lipid-soluble drug through an aqueous channel or pore. drug dissolved in a membrane. ATP Carrier-mediated active transport of drug 5 Drug Drug Absorption 6  Drug Absorption Is defined as the passage of a drug from the site of administration across a biological membrane/barrier (down a concn gradient) into plasma or systemic circulation. The effect of a drug (i.e. therapeutic or toxic) is more closely proportional to its plasma concn than its dose. Thus the onset and intensity of drug action are influenced by its rate and efficiency of absorption. which depends on a drug’s route of administration 7  Drug Absorption : Routes of Administration The main routes of administration for drugs can be categorized: Enteral route (i.e. through the GIT) → oral ingestion, sub-lingual, buccal and rectal Parenteral route (any route that by-passes the GIT; it’s usually by injections) → Intravenous, intra-arterial, subcutaneous, intramuscular, intraperitoneal and intrathecal Topical route (i.e. application to epithelial surfaces or mucous membranes → skin, cornea (eye), vagina and nasal mucosa, etc.) – usually for local effects Inhalational route Drugs administered this way to achieve much higher concns in the lungs than elsewhere in the body; e.g. Inhalers, Inhalational anaesthetics, etc. 8  Drug Absorption: Routes of Administration ENTERAL ROUTES – (any route that involves the GIT; i.e. through the mouth or anal canal) ⚫ Oral ⚫ A. Site of absorption ▪ 1. Oral mucosa →→ buccal route ▪ Direct access to systemic veins - will avoid hepatic first pass effect (direct absorption into systemic venous circulation) ▪ (Drugs that are extensively metabolized) ▪ Ex: nitroglycerin ▪ 2. Stomach ▪ Drugs that are weak acids tend to be absorbed here ▪ Ex: aspirin, ethanol ▪ 3. Small intestine ▪ Drugs that are weak bases tend to be absorbed here 9 Drug Absorption :Routes of Administration B. Advantages of oral route ▪ Most convenient ▪ Least unpleasant method for most drugs ▪ No equipment required ▪ Safest (drug absorbed more slowly) C. Disadvantages of oral route 1. Certain drugs destroyed by pH and/or enzymes ▪ Ex: Insulin ⚫ Some drugs metabolized in gut wall by Cyp3A4 ⚫ Bacterial metabolism in gut can affect bioavailability ▪ Ex: As a result, digoxin is only 70% bio-available 2. Slow onset of action 3. Cannot give to unconscious patient 10 Drug Absorption: Routes of Administration Disadvantages of oral route cont’d 4. Irritating substances cause nausea and vomiting, resulting in drug loss 5. Drug may have significant 1st pass effect from stomach or intestine because of direct access to portal veins » Liver can excrete drug into the bile 6. Irregular absorption may occur due to: a) Variation in process of solution b) pH variation » If drug is too hydrophilic (e.g. atenolol), the drug cannot cross the lipid cell membrane; if too lipophilic (e.g. acyclovir), the drug is not soluble enough to cross the water layer adjacent to the cell c) Binding to food (e.g. tetracycline chelated to Ca2+ and other heavy metals) d) Variation in motility and emptying time of GIT 11 Sublingual Route Drug is placed directly underneath the tongue – it is highly vascularized venous drainage is direct → the superior vena cava → hence general circulation. Drugs bypass the first-pass hepatic effect. Highly recommended for very potent and highly lipid- soluble drugs used in emergency situations (e.g. nitroglycerin for the treatment of angina pectoris) 12 Rectal Route (pr) Used when oral administration is not feasible (especially children, convulsing or unconscious patients) Only 50% of venous drainage from the rectum enters the portal circulation, and therefore not entirely subject to first-pass effect Explanation 50% drained by inferior and middle haemorrhoidal veins directly into inferior Vena Cava, by-passing the hepatic portal vein. 13  Rectal Route Cont’d However, as the suppository moves upward in the rectum, access to superior haemorrhoidal vein is more likely and this leads to the liver. Disadvantages Irregular & incomplete absorption irritation of the mucous membrane of rectum → ejection of drug absorption ✓ Absorption may be unreliable. 14 Drug Absorption: Routes of Administration PARENTERAL ROUTES – (any route that by-passes the GIT). Types: 1. injection routes 2. non-injection routes Injection Routes - Intra-venous - Intramuscular - Subcutaneous - Intra-arterial - Intrathecal - Intradermal - Intraperitoneal - Epidural Non-injection routes Transdermal Transmucosal 15  Absorption Intravenous (IV) – agent injected directly into blood stream A. Advantages of intravenous route – Rapid onset of action, controlled – Most irritating substances may be given (i.e. have to be soluble drugs). – Large volumes may be given – Useful in emergency situations (i.e. when patient is unconscious) – 100% bioavailability B. Disadvantages of intravenous route – Dangers associated with too-rapid delivery of large volumes (e.g. embolisms, elevated blood pressure) or with toxic doses of a drug – Technical difficulties of administering the drug (i.e. getting the correct rate for dosing) 16  Intramuscular (IM) – often done by injecting drugs into the ff muscles: deltoid vastus lateralis gluteus maximus drug passes through capillary walls to enter the blood stream Rate of absorption is usually abt 30 min. Rate tend to differ from muscle to muscle – Rate of absorption: deltoid > gluteus maximus (especially in women where gluteus maximus muscle is endowed with much fatty tissue) Obese individuals exhibit ↓absorption due to the deposition of adipose tissue 17  Absorption Advantages of IM route » 1. Generally more rapid absorption than SC » 2. Larger volumes and relatively irritating substances may be given » 3. Absorption may be hastened or slowed by various manipulation » Rate of absorption depends on drug formulation: ✓ oil based preparation has slow rate of absorption ✓ aqueous preparation has rapid rate of absorption Disadvantages of IM route » 1. Vasoconstriction (e.g. given epinephrine) cannot be used to slow absorption as in SC » 2. More painful than SC 18  Absorption Subcutaneous (SC) – drug is injected beneath the skin and permeates capillary walls to enter the blood stream Route is for drugs that are meant for slower and more continuous absorption ✓ Blood flow to these areas are low and absorption is therefore slower ↑ area blood flow → ↑ absorption of SC drugs (i.e. apply warmth or massage) SC drugs usually have ↑ lipid solubility Rate of release depends on the lipid:water coefficient. ❑ These drugs are often in the form of pellets, discs, etc. 19  Absorption A. Advantages of SC route – Slow absorption (i.e. sustained drug effect) – Rate of absorption may be altered by a. Drug solution b. Local vasoconstriction c. Tourniquet or other manipulations altering blood flow B. Disadvantages of SC route – Irritating drugs may result in severe pain and necrosis of the surrounding tissues 20  Absorption Intradermal (ID): administration into the dermal layer of the skin, just beneath the epidermis Advantage: usually small amount of liquid is used, for example 0.1ml. Disadvantages: absorption is slow. Breaks skin barrier 21  Absorption Intra-arterial route (i.a.) – Injecting drug directly into an artery. aims at localizing the effect of the drugs in specified organs or tissues ✓ Requires great care Rarely used (dangers associated with it) Uses Administering diagnostic agents cancer chemotherapeutic agents. 22  Absorption Intraperitoneal (i.p.) – drugs injected directly into the peritoneum Advantages Exposes drug to a large surface area of absorption common route in rodent laboratory studies. Disadvantage Much of drug lost through hepatic first-pass effect (absorption through portal vein) Caution: Not used in humans (possibility of introducing infection → serious adhesions of the abdominal viscera) 23  Absorption Intrathecal (i.t.) – Drug administered into subarachnoid space (into the spinal cord). BBB prevents many drug molecules gaining access to the brain or spinal chord i.t. by-passes the BBB, allowing for local and rapid effect of drugs on meninges and in the CNS. Uses life-threatening conditions (e.g. meningitis) for drugs excluded by the blood-brain barrier (e.g. methotrexate in childhood leukaemias to eliminate malignant cells from the CNS) administering anaesthetic agents ❑ Risks: neurotoxicity, death or permanent neurological disability 24  Other specialized infusions 1. Intra-atria/ventricular: injected into the atrial or ventricular regions of the heart. 2. Intrapleural: injected into pleural cavity. 3. Intra-osseous: injected into rich vascular network of long bone. 4. Epidural: injected into epidural space, outside the dura mater of spinal cord (target: lower part of the body). 5. Intra-articular: injected into joint. 25  Absorption: Other routes of administration Transdermal – drug seeps out of patch, through skin and into capillary bed » Drug from the outer layer of skin → keratin layer and cells of epidermis → dermis → blood stream Drugs designed for decreased systematic effect » Slow absorption » prolong the duration of drug absorption Convenient for self administration – increases compliance Transmucosal – absorption directly from the mucosal cavities such as otic, rectal, conj, vaginal, nasal mucosae. 26  Absorption: Other routes of administration Topical route – application to epithelial surfaces or mucous membranes Drugs administered per this route are usually designed for restriction to local effects maximize the drug concn at the site of action and minimize it elsewhere particularly for drugs which have toxic effects if administered systemically Includes drugs applied on skin, conjunctiva, ears, vagina and other body surfaces Ex: dermatologic, ophthalmic, vaginal, otic Disadvantages Possible systemic side effects – e.g. atenolol eye drops → Atenolol is absorbed via the lacrimal duct into systemic circulation 27 Absorption: Other routes of administration Inhalational route – drugs absorbed via the larynx or nasopharynx into circulation For gaseous/volatile drugs; local and systemic Local effect - in the case of respiratory disease offers delivery closest to the target tissue systemic effect - rapid absorption (large alveolar surface) Includes drugs administered as nasal spray – mostly for local effects → Gonadotropin-releasing hormone and calcitonin. – Used for drugs: quickly destroyed in the G.I.T inactive when given orally. – E.g. ephedrine nasal drops, desmopressin for patients with diabetes insipidus 28  Inhalational route of administration Advantages Rapid absorption due to large # of blood capillaries lining alveoli pulmonary alveolar epithelium provides a large absorbing surface area avoids first-pass metabolism. Very useful for administering respiratory drugs e.g. anti-asthmatic drugs 29  Drug Absorption Drug absorption after drug administration has two (2) components: The Rate of Absorption Bioavailability of the drug Clinical importance: Changes may necessitate adjustment of dose or interval between subsequent dose administrations. 30  Drug absorption RATE OF ABSORPTION The rate of absorption is partially controlled by the physicochemical characteristics of the drug. This could be modified by drug formulation to enhance or slow the rate of absorption. BIOAVAILABILITY Is the term used to describe the fraction of an administered drug that gets into systemic or blood circulation in its unchanged/unionised form. ✓Says nothing about effectiveness. ✓It depends on a number of physicochemical & clinical factors. 31  Drug absorption ❑Oral bioavailability may be altered by: Low solubility of the drug Destruction by acid in the stomach (e.g. Penicillins). Presence of food in the G.I.T. When a drug is given orally, food may impair or enhance its absorption. Co-administration with other drugs. e.g. Heavy metals in antacids can reduce the absorption of quinolones (e.g. Ciprofloxacin) and tetracyclines by binding them in the gut. 32  Factors Influencing Drug Absorption (i) formulation of drug (ii) physicochemical characteristics (iii) dose (iv) blood supply at the absorbing site (v) absorbing surface area 33  Factors Influencing Drug Absorption Formulation of Drugs Tablets Suspensions Capsules Solutions Pills Syrups Creams Ointments Balms Applications Suppositories Pessaries The formulation of a drug affects its absorption ✓ Liquid drugs tend to be more rapidly absorbed than those in solid forms ✓ Solid forms need to be liberated before going into solution for effective absorption. 34 BIOEQUIVALENCE ▪ Different drug formulations with same bioavailability may not have the same bioequivalence. Drugs may have the same bioavailability, but they may not be bioequivalent (don’t have the same rate and extent of pharmacological effect). ▪ Bioequivalence is used mostly in describing the relative similarity/parity of multiple formulations of a drug in terms of bioavailability. 35  Factors Influencing Drug Absorption Physicochemical Properties (i) lipid solubility (ii) pH of the site of administration (iii) molecular weight Lipid solubility: The rate and extent of the drug absorption depends on the lipid:water coefficient. The ↓partition coefficient, the ↓lipid solubility, hence ↓absorption – Because the drug remains in the aqueous phase instead of permeating through the lipid bilayer of cell membranes. 36  Factors Influencing Drug Absorption cont’d Molecular Size The lower the mol. size the more rapid and complete the absorption. pH at the site of Administration The pH of the environment influences the ionization of drug Ionized forms are water soluble and do not permeate the lipid layer of the membrane Non-ionized forms, however, easily pass through the membrane and are absorbed. 37  Factors Influencing Drug Absorption cont’d Therapeutic implications Depending on pH of environs; ↑↓absorption rate Differences in pH exist between body compartments and within different areas in same body segment (e.g. GIT...saliva 5.6-7.9, stomach 1-3, duodenum 6-6.5) – Examples 1. Tetracycline absorption: ↑ upper segments of GIT; ↓ the lower parts of GIT 2. Urine (4.6-8.0) excretion: alkalinizing urine to facilitate the excretion of acidic drugs (poisons), or acidifying urine to enhance the elimination of basic substances. We can manipulate drug excretion by the kidney by changing the pH of the urine – induces ionized state to “trap” drug in urine. 38  Factors Influencing Drug Absorption Dose ([drug] at site) ↑ [drug] → ↑ concentration gradient → ↑ absorption rate Absorbing Surface Area ↑ absorbing-surface area → ↑ absorption rate E.g. of large surface areas: pulmonary alveolar epithelium, intestinal mucosa, peritoneum, skin ❑ The flux or rate of diffusion are influenced by factors as predicted by Fick´s law: permeability coefficient Rate = (c1 − c2) x x area thickness Permeability coefficient (PC) = Temp. x Lipid Solubility √ Mol. size 39  Factors Influencing Drug Absorption Blood Supply to Absorbing Site ↑ blood flow to absorbing site → ↑absorption Activities such as massage or local application of heat → ↑ absorption. Administration of vasoconstrictors (local anesthetics + vasoconstrictors) → ↓ absorption and consequently prolonging therapeutic effect The routes of drug administration determines (a) surface area of absorption (b) extent of absorption of the drug into circulation 40 Drug Distribution 41  DRUG DISTRIBUTION Once the drug enters the blood stream, it moves from circulation into interstitial and cellular fluids; i.e. movement into tissues By this mechanism a drug reaches either its site of action, storage, biotransformation and elimination Drug distribution: the transfer of drug from systemic circulation to tissues or site of action A drug initially distributes in the water phase of blood plasma and then passes into body fluids, tissues and cells ❖ Distribution of drugs may involve 3 steps 42  DRUG DISTRIBUTION Steps involved in Distribution: 1. Drugs from systemic circulation → vascular bed of tissues 2. tissue vascular bed → intestitium 3. intestitial space → intracellular compartment. ✓ Plasma protein-bound drugs are retained in the vascular compartment ✓ Only free form of drugs diffuse into the extravascular compartment. 43 Factors that influence Drug Distribution The extent of drug distribution depends on: Drug Binding to plasma proteins Partition co-efficient into tissues or Membrane permeability (i.e. lipid solubility). Regional blood flow Size of the organs/tissues The pKa of the drug 44 Factors that influence Drug Distribution 1. Protein binding Quite a number of drugs bind to circulating plasma proteins – Weak acid drugs bind to plasma albumin (e.g. phenytoin, salicylates, disopyramide) – Weak basic drugs bind to serum globulins α1 acid glycoprotein (e.g. quinidine, lidocaine, propranolol) Binding in the blood or tissue compartment will tend to increase the drug’s concn in that compartment. – Limits the drug concn in tissues, because bound drug cannot enter tissues; as a result, leads to high concn of drug in the blood plasma 45 Factors that influence Drug Distribution Protein binding ▪ The amount of drug that binds the plasma proteins depends on: ✓ The drug concentration. ✓ Affinity of the drug for the binding sites. ✓ The protein concn in the body or # of binding sites available ❑ Usually it is the unbound or the free drug that distributes into the tissues of the body ✓ responsible for the clinical effect or toxicity of drugs. Only the unbound drug can: bind to receptors to elicit pharmacological response cross tissue membranes, and gain access to cellular enzymes be metabolized and excreted from the body 46  Factors that influence Drug Distribution Protein binding Bound drug is NOT therapeutically active There is an equilibrium between the free drug and the bound drug Clinical Significance: ↑ Protein-bound drugs serve as circulating drug reservoir in plasma As free drug is eliminated from the body, more bound drug dissociate to replace what was lost ↑ Protein binding may prolong drug availability and action 47 Factors that influence Drug Distribution Protein binding Is non-selective (i.e. not substrate-specific) The # of binding sites on plasma protein is limited – Necessary to give “Loading dose” to saturate drug-binding sites before drug will be therapeutically effective – Hypoalbuminemia → fewer binding site → ↑ [free drug] → exaggerate drug reaction → possible toxicity Drugs will compete with other drugs, hormones, or other endogenous substances for protein binding sites These interactions may necessitate a dosage adjustment or discontinuation of the other drug. 48  Factors that influence Drug Distribution Clinical implications: 1. Warfarin can be displaced by indomethacin, aspirin, and other NSAIDs which can ↑ bleeding. 2. Sulfonylureas (e.g. tolbutamide) can be displaced by warfarin, phenytoin, salicylates, etc. and cause ↑ hypoglycaemic effects →→ (more free drug in body) 3. Sulfonamides displace bilirubin from plasma proteins → ↑[free bilirubin] in circulation [Free bilirubin] may gain access into the infant brain (BBB is not fully developed) → Bilirubin deposition and subsequent destruction of the basal ganglia and subthalamic nuclei → KERNICTERUS (i.e. Bilirubin Encephalopathy) Caution: Administration of sulfonamides to infants or to pregnant women near term should NOT be encouraged 49  Factors that influence Drug Distribution 2. Membrane permeability For a drug to enter an organ (or tissue), it must permeate all membranes that separate the organ from the site of drug administration. A. Blood brain barrier (BBB) – lipid membrane located between plasma and the extracellular space in the brain – The entry of drugs is restricted into the CNS and CSF (cerebrospinal fluid) – Lipid solubility and cerebral blood flow limit permeation of the CNS – Highly lipophilic drugs can pass the BBB (e.g. benzodiazepines) – It is difficult to rx the brain or CNS; however, the difficulty of passage into the brain can also serve as a protective barrier when treating other parts of the body 50  Factors that influence Drug Distribution B. Blood-placenta barrier – the foetus is exposed to most drugs the mother ingests at anytime during the pregnancy. ✓ Lipid soluble drugs may cross the placenta and cause developmental toxicity Nicotine withdrawal symptoms in neonates. Down syndrome babies for alcoholic mothers. C. Mammary transfer of drugs – breast milk is acidic so basic drugs concentrate in this fluid ✓ Non-electrolyte drugs (do not depend on pH gradient – e.g. alcohol) readily reaches the same concn as in the plasma, independent of the pH of breast milk NB: pregnant and lactating mothers should be advised against alcohol and smoking 51 Factors that influence Drug Distribution 3. Organ/Tissue Perfusion - Amount of drug reaching each tissue or organ = amount of blood flow to the tissue or organ - Volume flow of blood to any organ is determined by the fraction of cardiac output received - Highly perfused organs such as kidneys, brain, lungs receive >20% of the cardiac output, hence much drug is distributed into these organs. - If the drug is lipid soluble, [drug in tissues] [drug in circulation] is rapidly established → rapid onset of action Less perfused tissues or areas within an organ receive ↓ blood → ↓ drug is delivered → relatively long time for [drug in tissues] to be established → slow onset of drug action 52 Factors that influence Drug Distribution Clinical implications ✓ as a result of a disease state → ↓ blood flow and subsequently drug delivery to such organs Example: Renal insufficiency → ↓ blood flow to the kidneys → ↓ drugs delivered for elimination → ↓drug elimination → extended therapeutic effects or even drug toxicity 53  Factors that influence Drug Distribution 4. Tissue binding capacity (Storage Depots) Some tissues have the ability to take up and hold on to drugs Drugs may collect in certain body tissues A. Fat – lipophilic drugs accumulate here and are released slowly (due to low blood flow) – Ex: thiopental (or other anaesthetics) – causes ↑ sedation in obese patients B. Bone – Ca++ binding drugs accumulate here – Ex: tetracycline can deposit in bone and teeth → will cause mottling or discoloration of teeth C. Liver – many drugs accumulate in the liver due to an affinity for hepatic cells – Ex: quinacrine (antimalarial agent) – has higher concn (abt 22,000 times) in the liver than in plasma due to long term administration 54  Factors that influence Drug Distribution D. Skin – some drugs accumulate here – Ex: griseofulvin (antifungal of skin, hair and nails) binds to keratin protecting the skin from new infection – Chloroquine - highly tissue bound and stays in the body for a longer time. ❑ Drug Redistribution – after a drug has accumulated in tissues (e.g. thiopental in fatty tissues), the drug is gradually returned to the plasma. 55  Factors that influence Drug Distribution Clinical implications Drug accumulation in adipose tissue → ↓ therapeutic activity due to the removal of drug from the circulation o → prolonged activity for drug that need only low levels to produce therapeutic effect. Drug reservoirs can also serve as potential source for drug toxicity. o Should body fat be drastically reduced, especially during starvation, stored compounds such as DDT may be mobilized and toxic symptoms may ensue. Tetracycline, heavy metals and other divalent-ion chelating agents may accumulate in the bone o → browning of teeth of infants (e.g. tetracycline) o → bone becoming the source of slow release of toxic materials into the blood, prolonging toxicity of these substances (e.g. Pb or Ra) 56  VOLUME OF DISTRIBUTION (Vd) Vd ▬ Defined as the volume of fluid into which drug distributes based on the amount in the body and the concentration in the plasma (measured in L/kg) Dose( Amount in body Q) – Vd = Conc in plasma Cp Thus, Volume of distribution (Vd) relates the amount of drug in the body to the concentration of drug in blood or plasma. If the drug is wholly confined to the plasma, the volume of distribution (vd) would be equal to the plasma volume. If the drug is widely distributed through out the body water, vd would be higher. 57  VOLUME OF DISTRIBUTION (Vd) The am’t of drug in a living tissue cannot be known precisely, but Vd gives an indirect measure of drug distribution. Apparent volume of distribution – is the volume of fluid required to contain the total amount of drug in the body at the same concn as that in the plasma. If the drug is tissue bound, the plasma concn will be low but the apparent volume of distribution will be high. If the drug is highly bound to plasma proteins, the concn in the blood/plasma will be high, and the drug will have a low volume of distribution. 58 Volume of Distribution – Body fluid Body water (body fluid) is partitioned into 4 main compartments in the body: 1. THE PLASMA WATER 2. INTERSTITIAL FLUID 3. INTRACELLULAR FLUID 4. TRANSCELLULAR FLUID – Transcellular fluid include: C.S.F., intra-ocular fluid, peritoneal fluid, pleural fluid, synovial fluid, digestive secretions, etc. o ~Body fat (the fifth) – ECF = Blood plasma + Interstitial fluid+ Lymph. – ICF = sum of fluid contents of all cells in the body. ✓ To enter transcellular compartments, drug molecules must cross cellular barriers 59 RELATIVE SIZE OF VARIOUS DISTRIBUTION VOLUMES WITHIN A 70 kg INDIVIDUAL Total body water 42 litres Intracellular volume Extracellular volume 28 litres 14 litres Interstitial volume Plasma volume 60 10 litres 4 litres Volume of Distribution – Body fluid Clinical prediction: If Vd = 2L, you can assume drug is distributed in plasma only If Vd = 18L, you can assume drug is distributed in plasma and tissues If Vd > 46L, the drug is likely stored in a depot because the body only contains 40-46L of fluid ❖NB: Obese patients need to have their volumes calculated using their ideal body weight 61  Drug Distribution ❖ Lipid soluble drugs can reach all the compartments of the body and may accumulate in body fat. Generally: ✓ Small volume of distribution occurs when: o The Lipid solubility properties of the drug is low o High degree of plasma protein binding o Low level of tissue binding ✓ High Vd however occurs when: o Lipid solubility properties of the drug is high o Low degree of plasma protein binding o High degree of tissue binding 62  Drug Distribution ▪ Drugs confined to plasma compartment Heparin, insulin → molecule large, cannot cross the capillary wall. ▪ Drugs distributed in the ECF compartment Aminoglycosides, Penicillins, suxamethonium, Tubocurarine, etc. ▪ Drugs distributed throughout body water Phenobarbitone, Phenytoin, Alcohol, Amitryptilline, Haloperidol, morphine etc. 63