Chapter 2 Absorption PDF

CHAPTER II Pharmacokinetics- Absorption PHARMACOKINETICS The fate of drugs in the body “What the body does to the drug” - Absorption - Distribution - Metabolism (biotransformation) - Elimination  AP in solid dosage form Ex. tablet Desintegration AP in partic...

CHAPTER II Pharmacokinetics- Absorption PHARMACOKINETICS The fate of drugs in the body “What the body does to the drug” - Absorption - Distribution - Metabolism (biotransformation) - Elimination  AP in solid dosage form Ex. tablet Desintegration AP in particules AP in tissus Dissolution Distribution Absorption AP in solution AP in blood Receptor Metabolism Elimination AP eliminated Response Phase Biopharmaceutique Pharmackinetic Pharmacodynamic  Drug Fate Absorption : – After absorption, A.P. is present in extracellular liquid especially i.e. plasma Dosage form influences rate and duration of action Dosage of drugs’ Plasmatic concentration possible How to skip this step???  Route of administration Dose administered Diffusion rate CONCENTRA TION SITES Pharma cologica l effet  Distribution : – Via the plasma, a drug will be distributed in differents compartments to : bind to its receptor and lead to a pharmacological answer Be metabolized and eliminated bind or to be stored in non target tissus / adipose tissus  Metabolism : Drug transformation via enzymatic reactions in one or multiple metabolites (active or non active) Metabolism sites : LIVER, intestine, kidney, lung… The first step of elimination  Elimination : – a parent drugs or its metabolites can be eliminated by : URINE BILE Saliva Transpiration  Elimination EXCRETION D M DRUG TARGET BLOOD D D DEPOT D D-protein D D OTHER TISSUES G.I. TRACT LIVER M Absorption Metabolism Distribution TARGET ABSORPTION  1- GENERALITIES Absorption is defined as the passage of a drug from its site of administration into the plasma. – It is therefore important for all routes of administration, except intravenous injection. For solid dosage forms, absorption first requires dissolution of the tablet or capsule, thus liberating the drug. The absorption, distribution, metabolism, and excretion of a drug all involve its passage across cell membranes.  Factors affecting drug absorption Physico-chemical properties of drugs – Chemical nature, particle size and formulation (solution, suspension, or solid dosage form), molecular weight, solubility,… Physicological factors (foods and drugs interactions) – Gastrointestinal motility (diarrhea…) affected by : Chronic diseases/migraine, diabetic neuropathy drugs Drug treatment (anticholinergic drugs ; metoclopramide) – pH at the absortpion site ; surface of absorbtion ; – blood flow to the site of absorption ; Drug-food or drug-drug interaction ROUTE OF ADMINISTRATION  2- TRANSFER OF DRUGS ACROSS MEMBRANES Absorption, distribution, metabolism, and excretion of a drug all involve its passage across cell membranes. Characteristics of a drug that predict its movement and availability at sites of action are – its molecular size and shape, – degree of ionization, – relative lipid solubility of its ionized – nonionized forms, – binding to serum and tissue proteins.  FATE OF A DRUG IN THE ORGANISM Organism is assimilated to different acqueous compartments separtaed by membranes The drug should be in a acqueous phase to circulate So drug should be hydrophilic Different membranes should be crossed to reach the target site So drug should be lipophilic Membrane cells are : Permeables to Water : passage by diffusion or by difference of osmotic pressure NON permeables to proteins : only free form of drugs are diffusible LIQUID COMPARTMENTS PLASMA INTERSTITIAL LIQUID INTRACELLULAR LIQUID La BCS « Biopharmaceutics Classification System » classe les médicaments Classe 1 : médicaments apolaires ionisables – Rapidement dissous, ils traversent aisément les membranes intestinales et sont absorbés facilement. Il s’agit de certains acides et bases faibles. Classe 2 : médicaments apolaires non ionisables – Peu solubles, leur faible fraction solubilisée traverse aisément les membranes intestinales. Classe 3 : médicaments polaires ionisables – Très solubles, ils traversent cependant mal les barrières intestinales. Classe 4 : médicaments polaires non ionisables – A la fois peu solubles et traversant mal les membranes intestinales, leur biodisponibilité est amédiocre. Néanmoins, on aura parfois recours à la voie orale pour une action locale 18 19  There are four main ways by which small molecules cross cell membranes : – by diffusing directly through the lipid – by diffusing through aqueous pores formed by special proteins ('aquaporins') that traverse the lipid – by combination with a transmembrane carrier protein that binds a molecule on one side of the membrane then changes conformation and releases it on the other – by pinocytosis (invagination of part of the cell membrane and the trapping within the cell of a small vesicle containing extracellular constituents) Diffusion through lipid and carrier-mediated transport are particularly important in relation to pharmacokinetic mechanisms  MECHANISMS OF TRANSMEMBRANE PASSAGE  Passive Diffusion Diffusion along a concentration gradient by virtue of its solubility in the lipid bilayer. Directly proportional to: – the concentration gradient across the membrane, – the lipid-water partition coefficient of the drug, – the membrane surface area exposed to the drug. The greater the partition coefficient, the higher is the concentration of drug in the membrane, and the faster is its diffusion.  Fick Law M/t = Pk x A (C1 – C2) M/t = flux of drugs that diffuse (unité de masse/temps) Pk = permeability coefficient (time/ cm2) A = diffusion surface (cm2) C1 et C2 = concentrations of drugs at the 2 sides of the membrane (unité de masse / par unité de volume)  Non-polar molecules dissolve freely in membrane lipids and consequently diffuse readily across cell membranes 2 physicochemical factors contribute to permeability coefficient P: – solubility in the membrane expressed as a partition coefficient for the substance distributed between the membrane phase and the aqueous environment – Diffusivity Is a measure of the mobility of molecules within the lipid and is expressed as a diffusion coefficient. Close correlation between liposolubility and permeability of the cell membrane. This mechanism is : non saturable non spécific : NO COMPETITION between molecules Diffusion medium are : Lipidic phase for lipophilic substances : non ionized Acqueous phase for hydrophilic substances: ionized Factors that limit this passage hydrosolubility : necessary liposolubility: Kp ↑with partition coefficient Ex vaseline oil Molecular weight Factors that influence this passage: Binding to PP: M+P ↔MP pH of the medium: ionization depends on pKA of the molecule and pH of the medium. The RATIO ionized/non ionized forms differs with the pH of the medium and is defined by Henderson-Hasselbach equations – Weak Base : pH =pKa + log [B]/[BH+] – Weak Acid : pH = pKa + log [A-]/[AH]  Diffusion passive l’etat d’ionisation du médicament conditionne la diffusion dans le cas : PLASMA/ESTOMAC (pH 7,4 ; pH 2,0) PLASMA/URINE, PLASMA /INTESTIN (pH 7,4 /pH 8,0) En pratique : les acides faibles mais pas les bases faibles sont absorbés dans l’estomac: quelques exceptions: NH4+ , barbituriques, ASPIRINE l’acidification des urines entraîne une accélération de l’excrétion des bases faibles l’alcalinisation des urines entraîne une accélération de l’élimination urinaire des acides faibles. (transparent)  Influence of pH on the distribution of a weak acid between plasma and gastric juice separated by a lipid barrier  Carrier-Mediated Membrane Transport For sugars,amino acids, neurotransmitters and metal ions. A carrier molecule is a transmembrane protein that binds one or more molecules or ions, changes conformation, and releases them on the other side of the membrane. Such systems may operate purely passively, without any energy source; in this case, they merely facilitate the process of transmembrane equilibration of the transported species in the direction of its electrochemical gradient, and the mechanism is called facilitated diffusion (insulin and GLUT4) Alternatively, they may be coupled to the electrochemical gradient of Na+ (Na+,K+-ATPase) ; in this case, transport can occur against an electrochemical gradient and is called active transport.  Secondary active transport uses the electrochemical energy stored in a gradient to move another molecule against a concentration gradient – the Na+-dependent glucose transporters SGLT1 and SGLT2 move glucose across membranes of gastrointestinal (GI) epithelium and renal tubules by coupling glucose transport to downhill Na+ flux.  Carrier-mediated transport, because it involves a binding step, shows the characteristic of saturation. – With simple diffusion, the rate of transport increases directly in proportion to the concentration gradient – With carrier-mediated transport the carrier sites become saturated at high ligand concentrations and the rate of transport does not increase beyond this point. Competitive inhibition of transport can occur in the presence of a second ligand that binds the carrier.  Characteristics of facilitated diffusion: With the concentration gradient No need of energy the transportor is: saturable selective Blocked by competitive inhibitors Ex : passage of glucose from plasma to red blood cells Characteritics of active transport: Passage of non lipophilic large molecules Against concentration gradient Need energy Membrane Transportor : Saturable Selective Inhibited by competitive and non competitive inhibitors role : Influx of nutriments , drugs, ions Efflux of dechets cellulaires , toxins, xenobiotics  P-glycoprotein An important efflux transporter present at many sites encoded by the multidrug resistance-1 (MDR1) gene. Present in renal tubular brush border membranes, in bile canaliculi, in astrocyte foot processes in brain microvessels, and in the gastrointestinal tract. P-glycoprotein localized in the enterocyte limits the oral absorption of transported drugs because it exports compounds back into the GI tract subsequent to their absorption by passive diffusion. The P-glycoprotein also can confer resistance to some cancer chemotherapeutic agents. The importance of P-glycoprotein in the elimination of drugs is underscored by the presence of genetic polymorphisms in MDR1 that can affect therapeutic drug levels.  4- Membrane Transporters Two major superfamilies : – ABC (ATP binding cassette) – SLC (solute carrier) transporters  ABC superfamily Active transporters – ATP hydrolysis to pump their substrates across membranes There are 49 known genes for ABC proteins that can be grouped into 7 subclasses (ABCA to ABCG). Ex: P-glycoprotein (P-gp, encoded by ABCB1, also termed MDR1) and the cystic fibrosis transmembrane regulator (CFTR, encoded by ABCC7).  ABC transporters are expressed in the polarized tissues of kidney and liver: – MDR1 (ABCB1), MRP2 (ABCC2) , and MRP4 (ABCC4) on the brush-border membrane of renal epithelia – MDR1, MRP2, and BCRP (ABCG2) on the bile canalicular membrane of hepatocytes.  Some ABC transporters are expressed specifically on the blood side of the endothelial or epithelial cells that form barriers to the free entrance of toxic compounds into naive tissues: – the BBB (MDR1 and MRP4 on the luminal side of brain capillary endothelial cells), – the blood-cerebrospinal fluid (CSF) barrier (MRP1 and MRP4 on the basolateral blood side of choroid plexus epithelia), – the blood-testis barrier (MRP1 on the basolateral membrane of mouse Sertoli cells and MDR1 in several types of human testicular cells), – and the blood-placenta barrier (MDR1, MRP2, and BCRP on the luminal maternal side and MRP1 on the antiluminal fetal side of placental trophoblasts).  SLC superfamily Includes genes that encode facilitated transporters and ion-coupled secondary active transporters that reside in various cell membranes. There are 43 SLC families with approximately 300 transporters Many serve as drug targets or in drug absorption and disposition. Ex: serotonin and dopamine transporters (SERT, encoded by SLC6A4; DAT, encoded by SLC6A3). Drug-transporting proteins operate in : Therapeutic drugs responses – PK (in ADME phases) – PD (ex: SERT) – Drug resistance (ex: P-glycoprotein) Adverse drug responses  4.1. TRANSPORTERS INVOLVED IN PHARMACOKINETICS Hepatic Transporters Renal Transporters  Hepatic Transporters Hepatic uptake by SLC-type transporters in the basolateral (sinusoidal) membrane of hepatocytes by either facilitated or secondary active mechanisms – For organic anions (e.g., drugs, leukotrienes, and bilirubin) by OATPs (SLCO) and OATs (SLC22) – For cations by OCTs (SLC22) – For bile salts by NTCP (SLC10A1) Hepatic efflux by ABC transporters such as MRP2, MDR1, BCRP, BSEP, and MDR2 in the bile canalicular membrane of hepatocytes by active transport. Responsible of Drug-Drug interactions – ex: cyclosporin +statins  Vectorial transport of drugs from the circulating blood to the bile using an uptake transporter (OATP family) and an efflux transporter (MRP2) is important for determining drug exposure in the circulating blood and liver. Ex: The efficient first-pass hepatic uptake of statins by OATP1B1 after their oral administration helps to exert the pharmacological effect and also minimizes the escape of drug molecules into the circulating blood, thereby minimizing the exposure in a target of adverse response, smooth muscle.  Renal transporters Organic Cation Transport – Diverse organic cations (choline and dopamine, cimetidine, procainamide, metformine, nicotine) , hydrophobic or hydrophilic, are secreted in the proximal tubule – For the transepithelial secretion, the compound should traverse two membranes sequentially the basolateral membrane facing the blood side – OCT1 (SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3) the apical membrane facing the tubular lumen – novel organic cation transporters (OCTNs) : OCNT1 (SLC22A4) and OCTN2 (SLC22A5) Hexagons depict transporters in the SLC22 family, SLC22A1 (OCT1), SLC22A2 (OCT2), and SLC22A3 (OCT3). Circles show transporters in the same family, SLC22A4 (OCTN1) and SLC22A5 (OCTN2). MDR1 (ABCB1) is depicted as a dark blue oval. Carn, carnitine; OC+, organic cation.  Organic Anion Transport (OAT) – OAT move both hydrophobic and hydrophilic anions (statines, captopril, penicillines, toxines) – from interstitial fluid to tubule cell: OAT1 (SLC22A6) and OAT3 (SLC22A8) on the basolateral membrane – against an electrochemical gradient in exchange with intracellular a-ketoglutarate, which moves down its concentration gradient from cytosol to blood. – Transporters for efflux transport of organic anions from the CNS identified in the BBB and the blood-CSF barrier include OATP1A4 and OATP1A5 and organic anion transporter (OAT3) families Rectangles depict transporters in the SLC22 family, OAT1 (SLC22A6) and OAT3 (SLC22A8), and hexagons depict transporters in the ABC superfamily, MRP2 (ABCC2) and MRP4 (ABCC4). NPT1 (SLC17A1) is depicted as a circle. OA-, organic anion; a-KG, a-ketoglutarate.  4.2. TRANSPORTERS INVOLVED IN PHARMADYNAMICS Transporters involved in the neuronal reuptake of the neurotransmitters and the regulation of their levels in the synaptic cleft belong to two major superfamilies, SLC1 and SLC6. Transporters in both families play roles in reuptake of g-aminobutyric acid (GABA), glutamate, and the monoamine neurotransmitters norepinephrine, serotonin, and dopamine. These transporters may serve as pharmacologic targets for neuropsychiatric drugs.  SLC6 family members localized in the brain and involved in the reuptake of neurotransmitters into presynaptic neurons include : – norepinephrine transporters (NET, SLC6A2),and dopamine transporter (DAT, SLC6A3), Target of tricyclic antidepressants, amphétamine NAT inhibited by desipramine – serotonin transporter (SERT, SLC6A4), Target of SSRI: fluoxetine,paroxetine – several GABA reuptake transporters (GAT1, GAT2, and GAT3) Inhibited by tiagabine  4.3. TRANSPORTERS IN ADVERSE RESPONSES Increase in the plasma concentrations of drug due to a decrease in the uptake and/or secretion in clearance organs such as the liver and kidney.  Ex: After oral administration of an HMG-CoA reductase inhibitor (e.g., pravastatin), the efficient first-pass hepatic uptake of the drug by the organic anion-transporting polypeptide OATP1B1 maximizes the effects of such drugs on hepatic HMG-CoA reductase. Uptake by OATP1B1 also minimizes the escape of these drugs into the systemic circulation, where they can cause adverse responses such as skeletal muscle myopathy. Transporters in the liver and kidney, which control the total clearance of drugs, thus have an influence on the plasma concentration profiles and subsequent exposure to the toxicological target.  cyclosporin /cerivastatin cyclosporin/ pravastatin ↑ statins cyclosporin/rosuvastatin Cyclosporin: inhibitor of OAT1B1 and CYPs OAT1B1 responsible of hepatic reuptake of statins CYPs metabolizes ONLY Cerivastatin interaction due to inhibition of OAT1B1  Increase in the concentration of drug in toxicological target organs due either to the enhanced uptake or to reduced efflux of the drug.  Ex: to restrict the penetration of compounds into the brain, endothelial cells in the BBB are closely linked by tight junctions, and some efflux transporters are expressed on the blood-facing (luminal) side. The importance of the ABC transporter multidrug- resistance protein (ABCB1, MDR1; P-glycoprotein, P- gp) in the BBB has been demonstrated in mdr1a knockout mice. – The brain concentrations of many P-glycoprotein substrates, such as digoxin, used in the treatment of heart failure and cyclosporin A, an immunosuppressant, are increased dramatically in mdr1a(-/-) mice, whereas their plasma concentrations are not changed significantly.  Ex : loperamide + quinidine. Loperamide is a peripheral opioid used in the treatment of diarrhea and is a substrate of P- glycoprotein. Coadministration of loperamide and the potent P- glycoprotein inhibitor quinidine results in significant respiratory depression, an adverse response to the loperamide. Because plasma concentrations of loperamide are not changed in the presence of quinidine, it has been suggested that quinidine inhibits P-glycoprotein in the BBB, resulting in an increased exposure of the CNS to loperamide and bringing about the respiratory depression.  Drug-induced toxicity sometimes is caused by the concentrative tissue distribution mediated by influx transporters. Ex: Biguanides (e.g., metformin, an oral hypoglycemic agents) can produce lactic acidosis, a lethal side effect. – Biguanides are substrates of the organic cation transporter OCT1, which is highly expressed in the liver. After oral administration of metformin in oct1(-/-) mice: – the distribution of the drug to the liver is markedly reduced compared to wild-type mice. – Plasma lactic acid concentrations induced by metformin are reduced compared with wild-type mice, although the plasma concentrations of metformin are similar in the wild-type and knockout mice. These results indicate that the OCT1-mediated hepatic uptake of biguanides plays an important role in lactic acidosis  OAT1 provides another example of transporter-related toxicity. OAT1 is expressed mainly in the kidney and is responsible for the renal tubular secretion of anionic compounds. Substrates of OAT1, such as cephaloridine, a β-lactam antibiotic, sometimes cause nephrotoxicity. OAT1-expressing cells are more susceptible to cephaloridine toxicity than control cells.  Increase in the plasma concentration of an endogenous compound (e.g., a bile acid) due to a drug's inhibiting the influx of the endogenous compound in its eliminating or target organ. The diagram also may represent an increase in the concentration of the endogenous compound in the target organ owing to drug- inhibited efflux of the endogenous compound.  EX: Bile acids are taken up mainly by Na+- taurocholate cotransporting polypeptide (NTCP) and excreted into the bile by the bile salt export pump (BSEP, ABCB11). Bilirubin is taken up by OATP1B1 and conjugated with glucuronic acid, and bilirubin glucuronide is excreted by the multidrug-resistance-associated protein (MRP2, ABCC2). Inhibition of these transporters by drugs may cause cholestasis or hyperbilirubinemia. – Troglitazone was withdrawn from the market because it caused hepatotoxicity. Troglitazone sulfate induces cholestasis by inhibition of BSEP function. BSEP-mediated transport is also inhibited cyclosporin A and the antibiotics rifamycin and rifampicin  Membrane transportors and drug resistance MT and DRUG RESISTANCE anticonvulsants antivirals, Increase of MRP4 increase resistance anticancer Increase of Pgp expression in tumoral cells increase efflux of anticancer drugs MT and BBB MT limits drug influx into the CNS because of Pgp in the BBB  3- RESORPTION QUANTIFICATION Pharmacokinetic parameters that permit to quantify resorption amount of drugs : - Bioavailibility : passage through membranes first pass - Absorption rate  A- Bioavailability (F) Indicate the fraction of an orally administered dose that reaches the systemic circulation as intact drug, taking into account both absorption and local metabolic degradation. The areas under the plasma concentration time curves (AUC) are used to estimate F as AUCoral/AUCintravenous.  Absolute Bioavailibility Absolute Bioavailibility(F in %): Extra-vascular route compared to i.v route Reference route: I.A. route F= 100 % Bioavailibility of i.v. route ~ 100 % Bioavailibility of extravascular route : from 0 to 100%  Bioavailability (F) Strong Bioavailibility Week Bioavailibility  Relative Bioavailibility The reference route is not the i.v. route. Objectives: to compare 2 dosage forms administered by the same route (ex capsules vs tablets) to determine dosages equivalence for a same drug (ex for generic drugs) : BIOEQUIVALENCE  Bioequivalence Drug products are considered to be pharmaceutical equivalents if they contain the same active ingredients and are identical in strength or concentration, dosage form, and route of administration. Two pharmaceutically equivalent drug products are considered to be bioequivalent when the rates and extents of bioavailability of the active ingredient in the two products are not significantly different.  Factors decreasing bioavailibility after oral administration: FIRST PASS Intestinal Hepatic First pass First pass  First-pass metabolism Most drugs absorbed from the GI tract enter the portal circulation and encounter the liver before they are distributed into the general circulation. These drugs undergo first-pass metabolism in the liver, where they may be extensively metabolized before entering the systemic circulation. Note: First-pass metabolism by the intestine or liver limits the efficacy of many drugs when taken orally. – Ex: more than 90% percent of nitroglycerin is cleared during a single passage through the liver, which is the primary reason why this agent is not administered orally. Drugs that exhibit high first-pass metabolism should be given in sufficient quantities to ensure that enough of the active drug reaches the target organ.  Factors influencing FIRST PASS – Pulmonary level: Smokers have increased enzymatic activity – Intestinal level: Different factors decrease absorption rate: – Food – Decrease of gastro-intestinal motility → increase contact with enzymes of the intestinal flora – Large spectrum ATB – Hepatic level Physiological factors : age Pathological factors : hepatitis, cirrhosis Drug interactions : drug-drug ; drug-food HEPATIC First-pass metabolism  HEPATIC FIRST PASS Source of LOSS of the parent drug This CAN decrease the therapeutic effect BUT NOT ALWAYS. WHEN favorable? Important for lipophilic drugs Saturable Important interindividual variations  Bêta- Intestinal Hepatic First absorption Pass Bioavailibility Blocker Propranolol >90% +++ Weak (lipophilic) Atenolol 50% %0 Mild  B- Absorption rate Appreciated by the time (Tmax) necessary to reach the maximal concentration (Cmax) Importance of the absorption phase Bioavailibility + absorption rate influence the therapeutic and undesirable effects of drugs -ONSET OF APPARITION -EFFECT INTENSITY  3- ROUTES OF ADMINISTRATION The drug may enter the body in a variety of ways ENTERAL ROUTE Epidural Oral (po) Intracerebroventricular Intratracheal Sublingual (sl) Intraosseus PARENTERAL ROUTE Rectal (pr) Topical Intravascular Transdermal Intravenous (iv) Inhalation Intra-arterial (ia) Intranasal Intramuscular (im) Intraocular Subcutaneous (sc) Intra-aural Intrathecal 2 types of routes : Indirect routes (mediate) : the A.P. should pass through a physiological berrier to reach the systemic circulation Limiting factors? Direct routes (immediate): the A.P. is adminitered directly in blood, lymph or interstitial liquids. Limiting factors? The therapeutic effect of a drug is affected by the drug quatntity that reach the site of action. TWO ROUTES Local route Local but also general effects General route General and local effects The choice of the route of administration depends on Action desired: Local or systemic effect, Rate of action desired, duration of treatment, number of administration per day Physico-chemical Properties of drugs Stability (in GI tract ) ex: Penicilline G, Insuline, Volatility : pulmonray route Causticity : ouabaine Patient : Age (infant or elderly) situation (standing or in bed, at home or in hospital, conscious or not, urgent or not…) Ex : Injectable or rectal but not oral forms for patients in coma Commonly used routes of drug administration. IV = intravenous IM = intramuscular SC = subcutaneous Digestive absorption can occur at all the levels of the GI tract rectum  A. Enteral Routes (by mouth) The simplest and most common means of administering drugs. – Oral route: the drug given in the mouth is swallowed allowing oral delivery – Sublingual route: the drug is placed under the tongue a drug which allows the drug to diffuse into the capillary network and, therefore, to enter the systemic circulation directly. ORAL ABSORPTION  A.1. ORAL ROUTE The mechanism of drug absorption is the same as for other epithelial barriers : – passive transfer at a rate determined by the ionization and lipid solubility of the drug molecules. – There are a few instances where intestinal absorption depends on carrier-mediated transport rather than simple lipid diffusion such as levodopa, fluorouracil, iron , Ca … For drugs given in solid form, the rate of dissolution may be the limiting factor in their absorption, especially if they have low water solubility.  Since most drug absorption from the GI tract occurs by passive diffusion, absorption is favored when the drug is in the nonionized and more lipophilic form. – Based on the pH-partition concept, drugs that are weak acids would be better absorbed from the stomach (pH 1 to 2) than from the upper intestine (pH 3 to 6), and vice versa for weak bases. – Strong bases of pKa 10 or higher are poorly absorbed in the intestine, as are strong acids of pKa less than 3, because they are fully ionized.  Summary weak ionizable drugs : absorption by lipidic phase High ionizable drugs : non absorbed, local effect in GIT (gastric or intestinal elimination) Hydrophilic : acqueous pores  Influence of pH on the distribution of a weak acid between plasma and gastric juice separated by a lipid barrier  Remarks Since the villi of the upper intestine provide an extremely large surface area in contrast to the stomach , the rate of intestinal absorption > absorption in stomach even if the drug is predominantly ionized in the intestine and largely nonionized in the stomach. Regardless of the characteristics of the drug, any factor that accelerates gastric emptying will the rate of drug absorption and vice versa. Enteric coating dosage forms if drugs are destroyed by gastric secretions or cause gastric irritation. Surface 1 m2 Acidic pH Low blood flow Small contact time No acqueous pores Thick epithelium LIMITED ABSORPTION  Surface 200-300 m2 with villi Basic pH (6-8) High Blood flow (1l/min) Thin epithelium MAJOR SITE OF ABSORPTION The drug should pass the pylore to reach the intestine : principal source of variability of the absorption rate FACTORS AFFECTING PYLORE OPENING: Food Pathologies (migraine) Drugs : Increased by cafeine and metoclopramide Decreased by anticholinergic drugs Patient state : lying down position retard emptying Righ get longer retard emptying rather than left  FACTORS AFFECTING GI ABSORPTION Physiological Empty stomach, food nature (fat, hot beverages, milk) Pathological: Diarrhea, biliary retention Factors related to drugs: Dosage form Pharmacological properties Alcalinizing Atropin antispasmodics 108  Advantages and disadvantages of oral route Advantages : – easily self-administered – limit the number of systemic infections that could complicate treatment. – toxicities or overdose may be overcome with antidotes such as activated charcoal. – Long acting forms possible Disadvantages : – the drug is exposed to harsh gastrointestinal (GI) environments that may limit its absorption. – These drugs undergo first-pass metabolism in the liver, where they may be extensively metabolized before entering the systemic circulation – Taste ; delay of onset of action – Administration difficulties if vomiting, coma or children  A.2. SUBLINGUAL ROUTE Venous drainage from the mouth is to the superior vena cava (ex: isoprenaline, nifedine, nitroglycerin…) Thus, drugs absorbed from the mouth pass directly into the systemic circulation without entering the portal system – Escape first-pass metabolism by enzymes in the gut wall and liver Ex: Nitroglycerin (Trinitrine) (nonionic, very high lipid solubility, very potent) – Thus, drug is absorbed very rapidly – Relatively few molecules need to be absorbed to produce the therapeutic effect.  SUBLINGUAL ROUTE (SL) Advantages: – Rapid absorption – Convenience of administration – Low incidence of infection – Avoidance of the harsh GI environment – Avoidance of first-pass metabolism. Diadvantages: – Bad taste – Causticity  B. Parenteral Routes The parenteral route introduces drugs directly across the body's barrier defenses into the systemic circulation or other vascular tissue. Faster absorption Used when drug is inactive orally or oral route not possible , or fast effect needed The major routes of parenteral administration are intravenous, subcutaneous, and intramuscular.  Absorption from subcutaneous and intramuscular sites occurs by simple diffusion along the gradient from drug depot to plasma. The rate is limited by the area of the absorbing capillary membranes and by the solubility of the substance in the interstitial fluid. Drugs administered into the systemic circulation by any route, excluding the intraarterial route, are subject to possible first-pass elimination in the lung prior to distribution to the rest of the body.  INTRAVENOUS (IV) No absorption steps Bolus injection versus IV infusion N.B: Drugs in an oily vehicle, those that precipitate blood constituents or hemolyze erythrocytes, and drug combinations that cause precipitates to form must not be given by this route.  Advantages: – Complete and rapid bioavailability – No gastro-intestinal or liver first-pass metabolism – Rapid effect and maximal degree of control over the circulating levels of the drug. Disadvantages: – Overdoses cannot be recalled by strategies such as emesis or by binding to activated charcoal. – Pain and Risk of infection at the site of injection – Risk of hemolysis – Adverse reactions if too-rapid delivery of high concentrations of drug – Need of specialized staff  INTRAMUSCULAR (IM) Aqueous solutions (fast absorption) or specialized depot preparations (slow absorption) Absorption depends on the rate of blood flow to the injection site. This may be modulated to some extent by local heating, massage, or exercise. Substances too irritating to be injected subcutaneously sometimes may be given intramuscularly. – Important exchange Surface and very vascularized →imp absorption – Passive diffusion – Advantages : Rapid effect Not very painful Skip HFP – Disadvantages: Possible necrosis Intravascular Injection by error Intranerve Injection ( paralysis) Infection  SUBCUTANEOUS (SC) Subcutaneous injection minimizes the risks associated with intravascular injection. Advantage : No HFP Disadvantages: slow absorption if high volume, possibility of deposits Examples of drugs utilizing SC route: solids, such as a single rod containing the contraceptive etonogestrel that is implanted for long- term activity programmable mechanical pumps that can be implanted to deliver insulin in diabetic patients.  Injection of a drug into a SC site can be used only for drugs that are not irritating to tissue; otherwise, severe pain, necrosis may occur. How to modify absoprtion by SC route? – ↓ viscosity – Modificate vascularaization Vasodilatator Vasoconstrictor Modificate dosage form to prolong effect Modificate the vehicule Acqueous or oily suspensions  The incorporation of a vasoconstrictor agent in a solution of a drug to be injected subcutaneously retards absorption. – Ex: the injectable local anesthetic lidocaine incorporates epinephrine into the dosage form.  INTRAARTERIAL (IA) IA route localize drug effect in a particular tissue or organ, such as in the treatment of liver tumors and head/neck cancers. Diagnostic agents sometimes are administered by this route. Intraarterial injection requires great care and should be reserved for experts.  INTRATHECAL The blood-brain barrier (BBB) and the blood- cerebrospinal fluid (CSF) barrier often preclude or slow the entrance of drugs into the CNS. Drugs are injected directly into the spinal subarachnoid space – Ex: amphotericin B used in treating meningitis – spinal anesthesia or treatment of acute CNS infections – Brain tumors also may be treated by direct intraventricular drug administration.  Intrapleural route : – Rapid absopriton if hydrophilic substances – Decreased absorption if infective or fibrinotic pleura – Local effect Intra peritoneal route – Large Surface, vascularized → important absorption – Fast absorption : rapid effect – General effect – DO not skip the HFP – Application: Children Experimental Pharmacoogy Intra articular route – Local effect – Ex: Antirhumatism therapies  C. Other routes INHALATION Route used for volatile and gaseous anaesthetics. Access to the circulation is rapid by this route because the lung's surface area is large. Used for drugs that are gases (anesthetics) or those that can be dispersed in an aerosol. Particularly effective and convenient for patients with respiratory complaints (such as asthma) because the drug is delivered directly to the site of action and systemic side effects are minimized.  TOPICAL APPLICATION Drugs are applied to the mucous membranes of the conjunctiva, nasopharynx, oropharynx, vagina, colon, urethra, and urinary bladder primarily for their local effects. Appreciable absorption may nonetheless occur and lead to systemic undesirable effects. Occasionally, systemic absorption is the goal – Ex: application of synthetic antidiuretic hormone to the nasal mucosa (Absorption take place through mucosa overlying nasal- associated lymphoid tissue)  Cutaneous administration Local or general effect Forms : ointment, cream, lotion Absorption by oassive diffusion Slow absorption: low blood flow Factors influencing perméabililty Skin: Species, âge, site of application, skin state Drugs: lipophilicity, hydrosolubility , vasodilatation Applications : local: Steroids , hormons … systemic : hormones, nicotine  Nasal drops – Administration of drugs directly into the nose. Widely vascularized ; thin membrane, ciliated épithelium; Passive Diffusion passive ; Skip HFP – Ex: nasal decongestants Eye drops – Absorption through the epithelium of the conjunctival sac to produce their effects. Ex: Dorzolamide eye drops to lower ocular pressure in patients with glaucoma – Some systemic absorption from the eye occurs and result in unwanted effects Ex: Bronchospasm in asthmatic patients using timolol eye drops  TRANSDERMAL Drugs are applicated to the skin, usually via a transdermal patch, and achieved systemic effects. – Oestrogen for hormone replacement ; Trinitrine ; Nicotine ; Fentanyl (analgesic) Advantges of this route : sustained delivery of drugs steady rate of drug delivery avoid presystemic metabolism. Disadvantages : Suitable only for lipid-soluble drugs Possible irritation of skin Relatively expensive  RECTAL ROUTE Local or systemic effects ; suppositories, enema Greater absorption than oral route Advantages: Biotransformation of drugs by the liver is minimized. 50% percent of the drug absorbed from the rectum bypasses the portal circulation. Prevention of the destruction of the drug GI tract Useful if the drug induces vomiting when given orally, if the patient is already vomiting, or if the patient is unconscious; for children ; if bad tatse of drugs Disadvantages: Rectal absorption is often erratic and incomplete Many drugs irritate the rectal mucosa. END OF CHAPTER