2. Pharmacokinetics_Absorption, Distribution.pdf

INTRODUCTION TO PHARMACOLOGY Prof. Marta Marín Vázquez, PhD. [email protected] Dept. of Pharmacy Office 324 (3rd floor, Health Sciences Building) Tutorials: Upon request by email   1. Introduction to Pharmacology  2. Pharmacokinetics 1....

INTRODUCTION TO PHARMACOLOGY Prof. Marta Marín Vázquez, PhD. [email protected] Dept. of Pharmacy Office 324 (3rd floor, Health Sciences Building) Tutorials: Upon request by email   1. Introduction to Pharmacology  2. Pharmacokinetics 1. GENERAL  3. Pharmacodynamics PHARMACOLOGY:  4. Drug interactions  5. Factors modifying dosage and drug action  6. Adverse effects Pharmacokinetics is a branch of Pharmacology that deals with ABSORPTION, DISTRIBUTION, METABOLISM and EXCRETION of drugs. ‘What a Body does to the Drug’ input process = absorption output processes responsible for drug delivery and removal from the body = distribution, metabolism, elimination ABSORPTION Movement of the drug: site of administration plasma important for the main routes of administration, except IV Mechanisms of drug absorption:  most drugs are absorbed into the systemic circulation via passive diffusion  other mechanisms: active transport, facilitated diffusion, pinocytosis/phagocytosis A pure artificial phospholipid bilayer is permeable to small hydrophobic molecules and small uncharged polar molecules  ABSORPTION B. Membrane permeation: transport A. Membrane permeation: diffusion C. Membrane permeation: receptor-mediated endocytosis, vesicular uptake, and transport Filtration (molecular size and weight)  ABSORPTION Bioavailability (F): the rate* and extent* to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. * Rate: How rapidly does the drug get from its site of administration, to the general circulation * Extent: How much of the administered dose enters the general circulation *IV dose have 100% Factors affecting F: BIOAVAILABILITY → F = 1 drug absorption **drugs with a low F may require a much larger oral dose when metabolism in the gut wall compared to the IV dose hepatic first-pass effect e.g. β-blockers: metoprolol 5 mg IV vs metoprolol 50 mg p.o.  ABSORPTION Factors Affecting the Rate and Extent of Drug Absorption Partition coefficient (Poil/water) → relative solubility in oil (lipid) vs water – Drugs with high lipid solubility can rapidly diffuse across a cell membrane e.g. anaesthetics are very lipid soluble and thus have a rapid onset of action Local blood flow at the site of administration → ↑blood flow →↑ Bioavailability (F) e.g. intestine has greater blood flow than stomach e.g. sublingual vessels provide significant blood flow → rapid absorption Molecular size e.g. small molecular weight drugs are absorbed faster Dosage forms → depend on particle size and disintegration ease of dissolution (solution > suspension > capsule > tablet)  ABSORPTION Factors Affecting the Rate and Extent of Drug Absorption Ph and drug ionization – Drugs are usually weak acids (e.g. acetylsalicylic acid) or weak bases (e.g. ketoconazole) and thus have both ionized (water soluble) and non-ionized (lipid soluble) forms → Only nonionized forms are absorbable Weakly acidic drugs ionized at Weakly basic drugs are ionized alkaline pH → absorbed only at more at acidic pH → absorbed acidic pH (gastric environment) only at alkaline pH (intestine) Total surface area available for absorption – The small intestine has intestinal microvilli → ↑ surface area for absorption → primary site of absorption for most oral drugs ABSORPTION Hepatic First-Pass Effect: drug metabolism by the liver following absorption, but before it reaches systemic circulation with ORAL administration: GI tract (absorption) → portal vein in liver (first-pass metabolism) → systemic circulation significant first-pass effect can drastically ↓ F occurs to a much lesser extent with p.r. administration, because drug absorbed in colon bypasses the portal system ABSORPTION Efflux Pump P-glycoprotein (Pgp) is a protein in the GI tract and renal epithelium that acts as a multidrug efflux pump involved in the transport of drugs out of cells Consequences: ↓ intestinal absorption and ↑ renal elimination of certain drugs Examples of Pgp substrates: digoxin, etoposide, paclitaxel, tacrolimus, etc… some drugs (e.g. macrolide antibiotics) inhibit Pgp ↑ absorption of Pgp substrates ↓ their renal elimination some tumors overexpress Pgp leading to multi-drug resistance to chemotherapy agents ABSORPTION ROUTES OF ADMINISTRATION CLASSIFICATION SYSTEMIC LOCAL Epidermal Intranasal Inhalation Conjunctival Parenteral Mucosal-throat Transdermal Enteral Inhalation Vaginal (digestive tract) Intravenous Mouth Oral (swallow) Injections Intramuscular Otic Sublingual Subcutaneous Buccal Intra-arterial Rectal Intra-articular Intrathecal Intradermal Intramammary ABSORPTION ROUTES OF ADMINISTRATION ORAL ROUTE Barrier : digestive tract – Better when: Lipidic or non-ionized The stomach empty Acid drugs (stomach) particle size (small ones) PARENTERAL ROUTE IV: avoids the absorption process SC an IM: Place the drug close to capillary vessels. Faster than oral SC is slower than IM administration. ABSORPTION ROUTES OF ADMINISTRATION TOPICAL ROUTE The systemic absorption depends on drug lipophilicity. Occlusive conditions improve drug absorption Damaged skin allows the easy entrance of compounds. When topical effects are desired, systemic absorption can be a disadvantage. TOPICAL ROUTES  Dermatologic  Ophthalmic  Otic  Nasal  Dental and throat  Vaginal DISTRIBUTION: Process by which drugs move between different body compartments and to the site of action DRUG IS ABSORBED ENTERS THE CIRCULATION CARRIED THROUGHOUT THE BODY DESTINATION: varies from drug to drug stored in bone or fat bound to the proteins in the blood plasma circulate freely as the unbound drug TARGET (effect)  DISTRIBUTION The major body fluid is water ** roughly 70% of normal person’s body weight is water. There are two main body compartments: The ICF (INTRACELLULAR Fluid Compartment): volume of fluid inside the cells The ECF (EXTRACELLULAR Fluid Compartment): volume of fluid which lies outside cells There are major differences between the chemical composition of the intra and extracellular fluids. e.g. sodium (Na+) is the principal extracellular cation and the K+ the principal intracellular cation ** The vast majority of the drugs distributes into several compartments, often avidly binding cellular compartments, i.e. lipids (adipocytes), proteins or nucleic acids. DISTRIBUTION Factors Affecting Drug Distribution Physicochemical properties of the drug e.g. – hydrophilic vs lipophilic compound (partition coefficient, Poil/water) – small vs large Mw compound Perfusion rate (blood flow/min/g tissue) Protein binding Anatomical restrictions  CNS - protected by the BBB  Transport across placenta  Salivary Drug Excretion  Excretion of the drug in milk DISTRIBUTION Principles of Protein Binding: drug molecules in the blood exist in two forms: 1. BOUND to plasma proteins acidic drugs → bind to albumin basic drugs → bind to a α1-acid glycoprotein 2. FREE or UNBOUND In plasma, the fractions of free and bound drugs exist in equilibrium. only free drug can leave the circulation to distribute into As free drug leaves the circulation, more tissues and exert an effect drug unbinds to equilibrate with the free drug is subject to metabolism and elimination portion that is left Saturation of binding sites → ↑ [free drug] → toxicity  DISTRIBUTION Volume of Distribution (Vd): the apparent volume (not real) of fluid into which a drug dissolves Used to quantify the distribution of a drug between plasma and the rest of the body after oral or parenteral dosing Merely a tool to understand the EXTENT of drug distribution - not a real physiological volume The value takes into account [drug distribution into tissues + protein binding] It is expressed as L/kg of BW Why does it matter? We need to know the Vd in order to calculate amount of drug in body (dose) the desired loading dose so that we can have 𝑽𝑽𝑽𝑽 = plasma drug concentration the desired drug concentration in the. plasma. ** Thus, for 2 drugs of equal potency, the drug that is more highly distributed among body tissues will generally require a higher initial dose to establish a therapeutic [plasma] than the drug that is less highly distributed.  Volume of Distribution can tell us about the pattern of distribution, e.g.… Vol. of body fluids can change: A. Vd = plasma volume B. Vd = total body fluids Plasma Water-3.5 L, C. Vd > total body fluids, - ↑ in diseases like ~4.5 % body wt (w/w) (3.5 L in 70 kg adult = (42 L, 70 kg = 0.6 L/kg), → the drug is getting Congestive Cardiac 0.05 L/kg) → the drug → the drug is E stored somewhere in Failure or severe C remains in the plasma extensively distributed the body (selective anemia W only and is not all over the body, distribution). Total extracellular water - 15 L, 20 % distributed elsewhere including the IC - ↓ in severe T body wt (w/w) in the body, compartment ([plasma] will be very dehydration or due to B W i.e. it does not leave the ([plasma] will be low low) diuretic therapy (drugs vascular compartment because of dilution) that ↑ urine output) ([plasma] will be high) [e.g. Digitalis, Total Intracellular water –20 L, 30 % [e.g. Metronidazole, Chloroquine] Thus, Vd and [plasma] body wt (w/w) [e.g. Heparin] Isoniazid] will change when such conditions develop or are corrected Total body Water 40 L, ~55 % body wt (w/w) DISTRIBUTION DISTRIBUTION Depots: a body compartment (e.g. a type of tissue) where drug molecules tend to be stored and released slowly over a long period of time – fat is a depot for very lipid soluble drugs (e.g. diazepam) some oil-based medications are injected IM for slow release (e.g. depot medroxyprogesterone acetate/every 3 months; depot risperidone/every 2 weeks) Barriers (relative): body structures that limit or prevent diffusion of drug molecules: 1. Blood- Brain Barrier Lipid-soluble and small size drugs cross easily 2. Blood-CSF Barrier Water- soluble and large size cross with difficulty A few drugs cross but transported back by Pgp in 3. CSF-Brain Barrier apical membranes of endothelial cells 4. Placental Barrier Need to consider dosing route if drugs are meant to cross these barriers