Pharmacokinetics I PDF

Pharmacokinetics I Prof. ChM. Dr. Zamri Chik, PhD. Department of Pharmacology, Faculty of Medicine [email protected]  Administration Liberation Permeation Pharmacokinetics from Greek words: "pharmacon" - drug "kinetiko...

Pharmacokinetics I Prof. ChM. Dr. Zamri Chik, PhD. Department of Pharmacology, Faculty of Medicine [email protected]  Administration Liberation Permeation Pharmacokinetics from Greek words: "pharmacon" - drug "kinetikos" - putting in motion “What the body does to the drug” ADME / LADME EXCRETION © Zamri Chik  Lecture contents Routes of Drug Administration Drug Permeation ↳ how drugs pass through biological barriers Drug Absorption © Zamri Chik  Routes of Drug Administration Routes the bloodstream ②applieddiret or pentersert effects throughout Local Systemic the body specifia target ↳ Topical Enteral Parenteral − Skin − Oral − Rectal − Injection − Rectal sundertheat − Inhalation − Inhalation − Sublingual, − Eyes − Transdermal − Buccal > - cheek − Nasal, etc. ↳applying on the surface a − Gastric feeding © Zamri Chik  Local Topical Skin Oral cavity GI tract Rectum Eyes, ENT Bronchial E.g. Local E.g. E.g. Tablet for E.g. Evacuant E.g. Eye E.g. anesthetic Clotrimazole gut enema drops, Bronchodilator cream troche sterilization ointment, (salbutamol) before sprays for surgery, etc. infection, etc. (neomycin) © Zamri Chik  Systemic Enteral Oral Sublingual Buccal Rectum Gastric feeding Tablets, capsules, E.g. Glyceryl E.g. E.g. E.g. Solid E.g. NG or PEG syrup, etc. trinitrate (GTN) Testosterone (suppository) or tubes (for patient for angina buccal liquid (enema cannot swallow such as laxatives) due to stroke etc. Diazepam rectal for seizure © Zamri Chik  Oral Delivery Not suitable (NS) for Convenience and well accepted emergency/slow absorption Avbl for slow release (extend duration) (NS)-highly irritant drugs irritation to tissues (inflammation pain , ulcer ↳ can cause , (NS)-Unabsorbed drugs (e.g. Mostly safe aminoglycosides)/degradation by Repeated and prolonged use stomach acid/enzyme Can be self administered Unpredictable absorption (NS)-Infant/baby, unconscious people, vomiting, etc. (NS)-Drugs with high first pass metabolism (e.g. lignocaine) ↳ metabolised by the liver before they reach the systemic circulation. © Zamri Chik  Sublingual/Buccal avoids the digestive system and liver g allowing the drug to reach the bloodstream Bypass gastric and Holding the dose in the mouth is hepatic metabolism ↳ does not go into stomach. inconvenience - discomfort > causes in the mouth for keeping a long Rapid absorption time. Small doses only can be Drug stability-pH in accommodated easily mouth neutral Flow of saliva may wash away the Action can be drug into stomach terminated by spitting Not suitable for children out Can be self administered © Zamri Chik  Rectal Small surface area, inconsisten or &unpredictable Bypass gastric & hepatic erratic absorption absorption metabolism (certain part only) Unsuitable for irritant drugs Rapid absorption Less patients’s Stable environment for the compliance absorption of drugs Rectum has no enzymes and thus no metabolism occurs For vomiting or seizure patients, infants, etc. E.g. Diazepam rectal for seizures ↳ if mouth can't be entered , better through the rectur. © Zamri Chik  Parenteral Involves skin puncture such as IV, IM, SC, implant, etc. or applied on the skin but the drug will go to systemic Used for drugs which inactivated in the gut and liver or poorly absorbed through mucosal membrane –E.g. gentamicin has poor oral absorption and most anticancer drugs are irritant and toxic © Zamri Chik  Intravenous (IV) Drug normally given in solution forms Bolus or infusion –E.g. General anaesthetic agents such as thiopentone Almost instantaneous response Only water soluble drugs can be given Water insoluble can be given if they are dissolved in surfactants etc. or integrated into nano carriers ↳ surface active agents (between liquid and solid © Zamri Chik  Pros & Cons- IV Pros Cons Bypass gastric & hepatic metabolism Painful procedure- needle phobia Rapid – a quick response is possible Self administered impossible-Requires trained personnel Constant plasma level of drug can be Increase chances of overdose maintained by iv infusion threatening allergic - life reaction Total dose Risk of anaphylaxis (greater for this route than others) and embolism For vomitting or unconscious patient Increase chances of blood-borne infections or local reactions Large volume of fluid can be administered continuously Suitable for irritant drug such as anticancer © Zamri Chik  Intramuscular (IM) Drug in solution/emulsion/ suspension. Fast absorption but slower than IV Given in small amounts. E.g. Anticancer drugs Pros Cons Stomacstream Bypass gastric & hepatic Painful procedure ↳ by the liver metabolism Faster absorption than oral (3- Can cause injection fibrosis development of 5 min.) ↳ scar tissue Self administered is not possible © Zamri Chik  Subcutaneous (SC) Drug in solution or suspension Only small volume can be given Fast absorption −Peptide drugs such as insulin Advantages Disadvantages Bypass gastric & hepatic metabolism Absorption into systemic dependent on subcutaneous blood flow. Faster absorption than oral but slower Absorption affected by vasoconstriction than IM (Connective tissue and less of capillaries such as cooling or vasculature) vasoconstrictors, etc. Self administered possible Not suitable during emergency Im > Sc > Oral IV > © Zamri Chik  Transdermal/Topical Transdermal/topical –Skin application such as patches, gel, etc. for systemic effect. E.g. GTN patch, or local (EMLA cream) Pros  Self administration possible  Avoid first pass effect  Convenience/ better patient compliance  Sustain release Cons  Can cause skin irritation or local reaction  Skin barrier properties, limit/slow absorption  Patch may fall unnoticed, etc. © Zamri Chik  Inhalation route Mostly in the form of aerosols or gases for systemic or local effect - E.g. anaesthetic gases such as sevoflurane (systemic)and salbutamol (local) Advantages – Rapid absorption and fast effect Disadvantage – Local irritations may causes bronchial secretion – Bioavailability depends on inhalation technique and size of drug particle © Zamri Chik  Another routes Routes Examples Intra-arterial Trombolytic drugs & in cancer chemotherapy (e.g. alteplase) Intra-thecal In CNS infection, chemotherapy and spinal anaesthesia (e.g. ampothericin B, methotrexate, lidocaine etc.) Intra-peritoneal Continous Ambulatory Peritoneal Dialysis (CAPD) and animal experiments Intra-articular Injected directly into the joint space. E.g. hydrocortisone injection for rheumatoid arthritis © Zamri Chik  Drug Permeation A movement of drug molecules across a biological membrane/barrier within body Ability to cross cell membranes is important for the ADME Routes by which solutes can traverse cell membranes distribution Y ADME-excretion absorptions 4 metabolism Lipid bilayers cell membranes © Zamri Chik  Other membrane types / barrier - Only allow high lipophilic drug Blood-brain barrier -No pores -Prevent polar materials (often toxic) from entering the brain -Smaller lipid materials or lipid soluble materials (e.g. halothane) can easily enter the brain. © Zamri Chik  Other membrane types/barrier Blood capillaries and renal Bowman capsule glomerular membranes - Membranes are quite porous Blood capillaries - Non-polar and polar molecules can pass through -size restriction applies Renal tubules -Membranes are relatively non- porous, only lipid compounds or non-ionized species (dependent of pH and pKa) are reabsorbed. © Zamri Chik Permeation mechanisms © Zamri Chik  Lipid diffusion/passive diffusion Major means of drug permeation Depends on -Lipid solubility lipophilicity (non-polar) -Degree of ionization (non ionized drug crosses membrane easily) -Concentration gradients Lipid : aqueous partition coefficient (LogP) of drugs determines drug permeation Log P value between 2 and 3 is ideal for oral drugs to compromise between permeation and clearance © Zamri Chik  Carrier mediated transport certain type of carrier Regulate entry and exit of some important molecules (e.g. sugars, amino acids, etc.) Mostly for endogenous substrates, but some also transports xenobiotics (e.g. anticancer 5-fluorouracil) Mostly passive but some active SLC (Solute carrier transporters); passive ATP-binding cassette (ABC) tranporters; active © Zamri Chik  Solute Carrier Transporters (SLC) Can be passive and active but mediated by a carrier. – Mostly uniporter For large hydrophilic molecules Factors influencing the rate of passage:: – Concentration gradient of drug – Quantity of macromolecule (carrier) – Rate of reversible interaction between drug and carrier Saturation can occur E.g. glucose transporter (GLUT1), sodium/glucose co Macromolecules transporter (SGLT1), etc. © Zamri Chik  Active transport SLC coupled to energy source (ATP) –ABC (ATP binding cassette) E.g. Ion transporters; Na+/K+ - ATPase Mostly occurs against concentration gradients (choline, uracil, etc. Secondary active transport (Use electrochemical gradient as a source of coming sodium in, carry frolecule energy (e.g. OAT and OCT) - potassium coming out — Symporter - E.g. Na+/neurotransmitter co transporter — Antiporter - E.g. Na/Ca exchangers Compound with similar structure can use the same transporter, competition occurs. E.g. penicillin and probenecid, penicillin action © Zamri Chik  Aqueous Diffusion and pinocytosis Aqueous diffusion – Aqueous pores formed by special proteins (‘aquaporins’) allows free passage of small, water soluble molecules – Depends on concentration gradient – No energy and no carrier. (E.g. urea, Li+) Pinocytosis – For large molecules such as proteins or lipophilic carriers, liposomes etc. – Biological membranes engulf macromolecules and bring them into cells in the form of vesicles – Only certain type of molecules such as Vitamin A, D, E, K  Quiz 1 Drug Administration & Permeation  Drug Absorption-Oral Process by which the drug proceeds from the site of administration into the systemic circulation The most important process in pharmacokinetic study (ADME) © Zamri Chik Drug Absorption-Oral liquid. capsules , © Zamri Chik  Absorption in small intestine Major drug absorption A great absorptive surface area of villi and microvilli in ileum E.g. Absorption of aspirin is promoted by drugs that accelerate gastric emptying such as metoclopramide. How long: Duodenum : 26 cm (9.8 in) in length Jejunum : 2.5 m (3-6 ft) Ileum : 3.5 m (6-12 ft) © Zamri Chik Factors influence Oral Abs -Stability of drugs in GI -Gastric emptying -Dosage form - Intestinal motility -Lipophilicity - First pass metabolism -Particle size - Disease state -Degree of ionisation © Zamri Chik  Drug stability in GIT Some drugs can be destroyed/inactivated in GIT, hence not suitable for oral delivery, e.g. − Penicillin G- gastric acid − Insulin- proteolytic enzyme − Nitroglycerin- first pass metabolism in GIT © Zamri Chik  Drug dosage and formulations Dosage form –Solid or liquid preparations: General absorption, solution > suspension > capsules > tablets Physicochemical properties (particle size) –Drug disintegration Disintegrate into small particles and release the drug –Drug dissolution Should be able to dissolve in – Adapted from Boomer PK course, David aqueous medium prior to systemic W.A. Bourne, 2001) absorption Dissolution test need to be done to make sure the drug formulation works © Zamri Chik  Physico-chemical properties Lypophilicity − Log P Octanol/water represents the lipid-water partitioning of drugs across the membrane − Lipid soluble compounds fastly absorb through the gut membranes but poorly excreted through the kidney − Highly polar drugs are poorly absorbed. E.g. gentamicin, etc. ↳ go through lipid bimembrane easily. © Zamri Chik  Physico-chemical properties Excipients – Added to a formulation to provide certain functional properties – Can affect drug dissolution, increase or decrease dissolution rate, therefore influence absorption – E.g. lactose, starch, magnesium stearate, calcium sulphate, etc. Generic drugs approval require bioequivalence studies mainly to assess absorption status Outbreak of Anticonvulsant Intoxication in an Australian City Tyer et al. British Medical Journal, 272, 271-273. Oct. 1970 © Zamri Chik  Specially formulated oral drugs Enteric coated − Coated with cellulose, acetate, etc. − For stomach protection − Active ingredient protection − Release the active ingredient in a specific location at higher pH Sustained release − Has different coatings that dissolve at different time − Prolong the duration of action and reduces the frequency of administration © Zamri Chik  Degree of ionisation: pH & pKa Drugs are weak acid/base, thus ionized or un-ionized Ionization of drugs reduce its ability to permeate membranes hence reduces absorption In Acidic drugs are less ionized at low pH general Basic drugs are more ionized at low pH weak Acidic drugs :HA + H2O H3O+ + A- weak Basic drugs : B + H2O BH+ + OH- Handersen Hasselbach equations For acidic drug For basic drug pKa = pH + log10 [HA] pKa = pOH + log10 [BH+] [B] [A-] Rearrange ([un-ionized]/[ionized])acidic = 10(pka-pH) ([un-ionized]/[ionized])basic = 10(pH-pka) © Zamri Chik  Degree of ionization According to the pH of gastric and small intestine Gastric pH acidic during fasting and more alkaline during meal The alkaline environment of the small intestine remain consistent © Zamri Chik  pH Partition Theory Unionized forms of the molecules are more capable of partitioning through a membrane Urinary alkalinisation has the opposite effects. E.g. Urinary acidification treatment of aspirin (weak accelerate excretion of acid) overdose by the weak bases and retards that administration of of weak acids bicarbonate © Zamri Chik  Gastric emptying (GE) The rate at which the stomach empties its contents into the duodenum The the GE rate, the drug reaches intestine: – Delay absorption for some drugs, especially basic drugs. © Zamri Chik  Factors influencing GE The following factors affect GE – Drugs that can increase or delay GE such as metoclopramide ( ), propantheline ( ) – Presence of foods can delay transit time – High caloric content foods such as fat, carbohydrate can slow GE. Generally carbohydrates transit faster than proteins and fats – Anger and agitation may increase the rate, but depression and trauma have been suggested to reduce GE rate. Absorption of drugs that poorly soluble in GI fluids may be increased in the presence of food due to release of bile salts. E.g. griseofulvin © Zamri Chik  Intestinal Motility Segmental contraction consisting of mixing contraction and propulsive contraction Small Intestine Transit Time (SITT) Two different patterns Existence of food can slow down transit time Longer SITT may increased extent of drug absorption © Zamri Chik  Drug interactions Drug-drug interactions – E.g. proton pump inhibitors raise the pH of the stomach and decrease absorption of ketoconazole – Colestyramine binds several drugs such as warfarin, therefore reduce their absorption Drug-disease interactions − Certain disease such as Crohn’s disease and ulcerative colitis (inflammatory bowel disease) may reduce the extent of drug absorption − Achlorhydria (malabsorption) Decreases nutrients, vitamin and drugs such as aspirin absorption © Zamri Chik  Absorption on other routes Inhalation – Large surface area available for drug absorption – Absorption depends on the particle size – Mainly by passive diffusion – Also depends on ventilation rate Dry powder inhaler nebuliser © Zamri Chik  Sublingual & Buccal − Absorption through mucosa into systemic circulation only by passive diffusion − Limited by molecular weight of the drug © Zamri Chik  Subcutaneous – Drug travel to the capillary wall via passive diffusion – Lipophilic drug can diffuse directly through capillary membrane – Water soluble drugs diffuse through pores on the membrane © Zamri Chik  Intramuscular – Absorption is similar to subcutaneous – Absorption from muscle to systemic circulations depends on muscle blood flow – Generally absorbed faster from deltoid than gluteal muscle © Zamri Chik  Rectal – Highly vascular region for passive diffusion – Erratic absorption – Drug absorb in upper part of rectum (Superior) vein still subject to first pass metabolism in the liver © Zamri Chik  Transdermal – Drug permeates through intercellular and intracellur routes – Stratum corneum (SC) is the rate limiting barrier in the absorption process Extent of absorption depends on Integrity of the skin (normal or disease) Skin tickness Skin biotransformation (CYP450) Drug formulations © Zamri Chik  Quiz 2 Drug Absorption  References BASIC & CLINICAL PHARMACOLOGY (Katzung, 13th edition) PHARMACOLOGY (Rang, Dale, Ritter & Flower, 9th edition) GOODMAN & GILMAN’S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS (11th edition) Lippincott’s Illustrated Reviews: PHARMACOLOGY (Richard A. Harvey, series editor, 6th edition) © Zamri Chik