L3 Drug Absorption and Distribution PDF

06/07/2023 L3 Drug Absorption and Distribution DR ZETTY NADIA MOHD ZAIN PhD (London) 1...

06/07/2023 L3 Drug Absorption and Distribution DR ZETTY NADIA MOHD ZAIN PhD (London) 1 LEARNING OUTCOMES 1) Define drug absorption and bioavailability, the distinction between absorption and bioavailability, especially with respect to oral administration. 2) Describe the various factors that can influence the oral absorption and bioavailability of drugs: dosage forms & formulation, lipid solubility, degree of ionisation, first pass metabolism, gastric emptying rate, intestinal motility, complex formation with gut contents and disease state. 3) Describe the general factors affecting the absorption of drugs given by other routes e.g. parenteral, inhalation, topical and transdermal. 4) Define drug distribution and the general factors that can affect the rapidity and extent of distribution of a drug in different tissues e.g. lipid solubility, ionization of physiological pH, extent of binding, present of transporters and effect of blood flow. 5) Describe the reasons for the wide variation in the extent of distribution of different drugs in the body: the binding of drugs to plasma proteins, the selective accumulation of drugs by specific tissues and the existence of physiological barriers to drug distribution. 6) Briefly describe the distribution of drugs into the brain and CSF as well as passage across the placenta. 2 1  06/07/2023 3 4 2  06/07/2023 Overview - ABSORPTION Some drugs work outside the body (barrier creams, some laxatives) but most must: › enter the body: Given by: › ENTERAL - oral, sublingual, buccal, rectal › PARENTERAL sc, im, iv, it › cross lipid barriers / cell walls: gut wall, capillary wall, cell wall, blood brain barrier get into the body and (after distribution) to reach the cellular target 5 What is absorption? Process of movement of unchanged drug from its site of administration into systemic circulation 6 3  06/07/2023 Drug absorption 7 8 4  06/07/2023 Passage through lipid membranes › diffusion through gaps between cells (glomerulus = 68K; capillary 30K; brain capillary - tight junction) › passage through the cell membrane a) diffuse through pore (very small; use dependent) b) carrier mediated transport (specific, saturable; Fe in gut; L-DOPA at blood-brain barrier) c) pinocytosis (insulin in CNS; botulinum toxin in gut) d) diffusion through lipid of cell membrane (depends on AREA, DIFFUSION GRADIENT, DIFFUSION COEFFICIENT, LIPID SOLUBILITY) Ion Pinocytosis Diffusion Carrier channel 9 What factors determine drug absorption? 10 5  06/07/2023 Factors affecting absorption of drugs Related to Drugs: Related to Body: a) Lipid water solubility a) Area of absorptive b) Molecular size surface b) Vascularity c) Particle size c) pH d) Degree of ionisation e) Physical forms d) Presence of other substances f) Chemical nature e) GI motility g) Dosage forms f) Functional integrity of h) Formulation absorptive surface i) Concentration g) Diseases 11 Factors affecting absorption Aqueous solubility: › Solid form drug must be dissolve in aqueous biophase before absorption › Absorption of drug in watery solution is faster than when the same is given in solid form or oily solution *biophase : the period during which an effective concentration of a drug is maintained in the vicinity of its site of action 12 6  06/07/2023 Factors affecting absorption Concentration: › Drug given as concentrated solution is absorbed faster than from dilute solution 13 Factors affecting absorption Area of absorbing surface: › Larger is the surface area, faster is the absorption 14 7  06/07/2023 Factors affecting absorption Vascularity of the absorbing surface: › Blood circulation removes the drug from the site of absorption › Concentration gradient across the absorbing surface is maintained › ñ Blood flow hastens drug absorption 15 Factors affecting absorption Routes of administration: › Each route has its own peculiarity! 16 8  06/07/2023 ORALLY ADMINISTERED DRUGS 17 ABSORPTION OF ORAL DRUG › Epithelial lining of GIT is lipoidal › Non-ionized lipid soluble drug / acidic drugs – usually lipid soluble therefore readily absorbed from stomach › Basic drug will be ionized – absorbed only when reaching duodenum › Absorption in stomach is slower than small intestine. WHY? Thick mucosa Covered with mucus Small surface area 18 9  06/07/2023 ABSORPTION OF ORAL DRUG › Presence of villi in small intestine – faster absorption than stomach › Faster gastric emptying accelerates drug absorption › Dissolution: Particle size in solid dosage form è rate of dissolution è rate of absorption 19 What about drug absorption in the presence of FOOD??? FED VS FASTED??? 20 10  06/07/2023 ABSORPTION OF ORAL DRUG › Presence of food: § Dilute drugs and retard absorption § Food delays gastric emptying § Most drugs absorbed better if taken in empty stomach 21 CAPSULE & ENTERIC COATED TABLET › Capsule / coated tablet - Remain intact after hrs of digestion to delay absorption › Mixture of slow- and fast-release particles – rapid but sustained absorption › Modified-release preparation – less frequent dosing * Also can reduce adverse effect related to high peak plasma concentration 22 11  06/07/2023 ABSORPTION OF ORAL DRUG › Other factors: § Drug degradation in GIT eg insulin by peptidases § Efflux transporter P-gp located in gut epithelium – extrusion of drug back into intestinal lumen § Luminal effect – formation of insoluble complexes in the case of concurrently ingested drugs. Eg phenytoin & sucralfate § 2-3 hrs administration intervals between 2 drugs 23 ABSORPTION OF ORAL DRUG › Other factors: § Alteration of gut flora by antibiotics – eg oral contraceptives § Gut wall effects caused by certain drugs such as: § Altering motility – eg TCA § Mucosal damage – eg vinblastine 24 12  06/07/2023 SUBLINGUAL ADMINISTERED DRUGS 25 ABSORPTION OF SUBLINGUAL DRUG › Useful when rapid response is required › Pass directly into systemic circulation (escape first pass metabolism) 26 13  06/07/2023 RECTAL ADMINISTERED DRUGS 27 ABSORPTION OF RECTAL ADMINISTERED DRUG › Useful to produce local effect or to produce systemic effects › Absorption is unreliable but useful in patient with vomiting or unable to take medication by mouth › Eg diazepam for children with status epilepticus as difficult for IV 28 14  06/07/2023 S.C. & I.M. ADMINISTERED DRUGS 29 ABSORPTION OF S.C. & I.M. DRUG › Drug is deposited directly in the vicinity of capillaries › SC site slower absorption that IM , both still faster & stable than oral absorption › To accelerate drug absorption, blood flow is increased with application of heat and muscular exercise › Vasoconstrictor such as adrenaline retard absorption 30 15  06/07/2023 Bioavailability › Describes rate and extent to which a drug is absorbed and becomes available at the site of action. › i.v injection gives 100% bioavailability (F=1). › Calculated from comparison of the area under the curve (AUC) relating plasma concentration to time for IV dosage compared with other route. › Says nothing about effectiveness. 31 Bioavailability IV vs oral › Oral administration is lower because § The drug may be incompletely absorbed § The absorbed drug may undergo first pass metabolism in the intestinal wall/liver or be excreted in bile 32 16  06/07/2023 Bioavailability Destroyed Not Destroyed Destroyed in gut absorbed by gut wall by liver to Dose systemic circulation 33 Bioavailability › Determines therapeutic efficacy because it affects onset, intensity and duration of therapeutic response of a drug. › rate and extent refer to Tmax & Cmax AUC › onset,intensity and duration refer to onset, Cmax,Tmax and AUC 34 17  06/07/2023 Cmax = max conc achived tmax = time between dosing and Cmax AUC = areas under plasma conc time curves Rate of absorption = Cmax / tmax For oral drug: Bioavailability F = AUC oral / AUC IV 35 BIOEQUIVALENCE › A value indicating the rate at which a substance enters the bloodstream and becomes available to the body. - When 2 drugs show comparable bioavailability and similar times to achieve peak plasma concentration › This is important in cases in which small differences in the amount of drug in the bloodstream can make a very large difference in the drug's effectiveness 36 18  06/07/2023 BIOEQUIVALENCE Different manufacturer or different batches from the same manufacturer may have the same amount of drug (chemically bioequivalent) BUT may not yield the same blood levels (biologically bioequivalent) 37 BIOEQUIVALENCE 2 drugs are “bioequivalent” when rate and extent of bioavailability of the active drug from them is not significantly different under suitable test conditions 38 19  06/07/2023 Two versions of a drug are generally said to be bioequivalent if the 90% confidence intervals for the ratios of the geometric means (brand vs. generic) of the AUC and Cmax fall within 80% and 125%. The Tmax (brand vs. generic) must also be comparable — and there should not be any significant differences between different patients. 39 Overview - DISTRIBUTION The body is a container in which a drug is distributed by blood (different flow to different organs) - but the body is not homogeneous. › plasma (3.5 l); extracellular fluid (14 l); intracellular fluid (50 l); + special areas (foetus, brain) › note::: › plasma protein binding › tissue sequestration brings drug to target tissue and affects concentration at site of action/elimination 40 20  06/07/2023 Distribution into body compartments ›Plasma 3.5 litres, ›Extracellular fluid 14 litres, ›Total body water 40 litres, ›Transcellular small, (must pass tight junctions) 41 Factors affecting drug distribution 1)Lipid solubility 2)Ionization at physiological pH 3)Extent of binding to plasma and tissue proteins 4)Presence of tissue-specific transporters 5)Differences in regional blood flow 42 21  06/07/2023 43 When is the cut-off point of the movement of drugs for distribution ? 44 22  06/07/2023 When is the cut-off point of the movement of drugs for distribution ? Until equilibrium is reached between unbound drug in the plasma and the tissue fluids 45 Volume of distribution › A hypothetical volume of fluid into which a drug is dispersed ~ into the water compartment in the body › Large volume of distribution ~ increase in half life and extend the duration of action of drug 46 23  06/07/2023 Volume of distribution (Vd) Q (volume that would contain the total body content of the drug, mg) Vd = _________________ Cp (plasma concentration, mg/L) **A large value of V indicates that larger quantity of drug is present in extravascular tissue 47 Redistribution ①Distribution of highly lipid soluble drugs to high blood flow organs (eg brain, heart, kidneys) ②Distribution in less vascular organs (fat, muscle) è drop of plasma concentration *if site of action is highly perfused organs , redistribution results in termination of drug action **greater the drug lipid solubility, faster redistribution 48 24  06/07/2023 Penetration into brain and CSF › Blood-brain barrier (BBB) – capillary endothelial cells in brain have tight junctions and lack large paracellular spaces › Blood-CSF barrier – located at choroid plexus › Both barriers are lipoidal & limit entry of nonlipid soluble drugs › Other than BBB/ B-CSF barrier: efflux transporter P-gp anion transporter – adsorptive transcytosis enzymatic transporter (eg MOA) ** ANTIPARKINSONIAN DRUGS – dopamine, levodopa, selegiline 49 50 25  06/07/2023 Passage across placenta › Placental membrane is lipoidal, allow free passage for lipophilic drugs › Also have placental efflux P-gp & other transporter § Limit foetal exposure to maternally administered drugs › Placenta is also site of metabolism ² Nonlipid-soluble drugs when present in high concentration for long periods in maternal circulation will gain access to the fetus ² There is also “influx transporter” which means any drugs taken by the mother can affect the fetus or the newborn eg morphine 51 Plasma Protein Binding › Acidic drugs bind to plasma albumin › Basic drugs bind to α1 acid glycoprotein › Bound drugs are pharmacologically inactive › Free unbound: § binds to active site § Elicit biological response § Available for elimination 52 26  06/07/2023 Plasma Protein Binding › Binding capacity is reversible › Affinity Albumin has strong affinity with anionic drugs (weak acids); hydrophobic drugs › Competition for binding – drug displacement (clinical consequences is seen with narrow therapeutic index) 53 Alter plasma binding of drugs 1000 molecules 99.9 % bound 90.0 1 molecules free 100 100-fold increase in free pharmacologically active concentration at site of action Effective 54 27  06/07/2023 Plasma Protein Binding › ñ drug concentrations can saturate the binding sites › Fractional binding may be lower when large amounts of drug is given 55 What are the clinical implications of plasma protein binding ? 56 28  06/07/2023 What are the clinical implications of plasma protein binding ? a) Highly plasma protein bound drugs are restricted to vascular compartment because protein bound drugs does not cross membranes b) Bound fraction is not available for action c) High degree of protein binding makes drugs to be “long acting” (bound fraction is not available for metabolism or excretion) d) Plasma concentration of drug includes BOTH bound fraction & free drug e) One drug can bind to many sites on albumin molecule 57 Tissue storage: › Drugs may also accumulate in specific organs by active transport or get bound to specific tissue › Eg: § Liver – tetracycline § Thyroid – iodine § Brain – isoniazid § Bone and teeth – tetracycline § Adipose tissue - thiopentone 58 29  06/07/2023 ADME of knowledge: A- Absorption of new knowledge D- Distribution of knowledge M- Metabolism and synthesizing knowledge E- Elimination of outdated facts & figures Thank you! 59 30