FFP1-63 PK1 STS 2023.pptx

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Pharmacokinetics: Basic Principles and Drug Absorption FFP1-63 Prof Steve Safrany 341 [email protected] 2 Learning outcomes • Differentiate between pharmacokinetics and pharmacodynamics • List the four key processe...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Pharmacokinetics: Basic Principles and Drug Absorption FFP1-63 Prof Steve Safrany 341 [email protected] 2 Learning outcomes • Differentiate between pharmacokinetics and pharmacodynamics • List the four key processes involved in pharmacokinetics: Absorption, distribution metabolism and elimination (ADME) • Compare the common routes of administration • Describe how absorption can influence plasma drug levels - define the term 'Bioavailability' • Describe first pass metabolism and its importance 3 Factors determining the response of a patient to a drug • Pharmacodynamics • Actions of the drug on the body • physiological & biochemical effects of drug • interactions with macromolecular ‘targets’ • Specific to drug or drug class • Pharmacokinetics • Effects of the body on the drug • Drug movement • movement of drugs into, around and out of the body • Non-specific, general processes 4 Four basic processes of pharmacokinetics - ADME • Absorption – the transfer of drug from the site of administration to the general circulation – Bioavailability (F) • Distribution – the transfer of drug from the general circulation into different organs of the body – Apparent volume of distribution (Vd) • Elimination – Metabolism, Excretion – the removal of drug from the body – this may involve metabolism or excretion or both – Clearance (Cl) – Plasma Half -Life (t1/2) ADME • Absorption, moving from the site of administration into the body • Distribution moving between locations within the body • Elimination: • excretion (irreversible loss of unchanged drug) • metabolism (conversion to another chemical entity / biotransformation) • All of the processes are defined relative to the site of measurement, usually plasma • 6 Drug passage across membranes (absorption processes) Of importance to absorption, distribution and excretion: Lipid Bilayer Through pores or ion channels By diffusing through aqueous pores formed by aquaporins that traverse lipid. Passive movement along concentration gradient. Water soluble small molecules, e.g., lithium Passive diffusion Diffusing directly though the lipid Passive movement along concentration gradient. Drug must be somewhat lipid soluble Carriermediated process 1. Facilitated diffusion, e.g., levodopa & bloodbrain barrier 2. Active transport, e.g., 5-fluorouracil Pinocytosis Rare for drugs, e.g., IgG 7 Passive diffusion 8 Drug passage across membranes (absorption processes) Carrier-mediated processes: • Solute carrier transporters (SLCs) • Facilitate transport DOWN a concentration gradient Organic anion transporters (OATs) Organic cation transporters (OCTs) • ATP binding cassette transporters (ABCs) • Require ATP to pump material e.g., P-glycoproteins • Common cause of multidrug resistance 9 Drug absorption Routes of administration can broadly be divided into: 1. Topical: local effect, substance is applied directly where its action is desired 2. Enteral: desired effect is systemic (non-local), substance is given via the digestive tract 3. Parenteral: desired effect is systemic; substance is given by routes other than the digestive tract The U.S. Food & Drug Administration (FDA) recognises >100 distinct routes of administration 10 Examples of common routes of administration • Topical – Application to epithelial surfaces (e.g., skin, cornea, vagina, nasal mucosa, lung) • Enteral – Oral - (per os / PO), by mouth – Sublingual - placed under the tongue – Rectal - (per rectum), suppositories or enemas • Parenteral – Inhalation – Injection: • IM injections given in a large muscle mass (deltoids or gluteals) – best for larger volumes and when faster absorption desired, e.g. antibiotic • Subcutaneously (SC/SQ) - below the dermis and epidermis – when a slower, more prolonged effect is desired, e.g. insulin, many immunizations, heparin (an anticoagulant) • Intravenous (IV) - directly into a vein • Intradermal (ID) - into dermis, just below the epidermis – longest absorption time of all the parenteral routes, used for allergy tests and local anaesthesia 12 Oral administration: Most common & convenient but drugs also face most barriers to entry into the systemic circulation Factors influencing drug absorption from the gut: • Drug structure: – Highly polar/ionized compounds poorly absorbed – Weak acids and weak bases undergo pH partitioning – Peptides broken down by digestive enzymes (insulin) • Formulation: – Capsule/tablet must disintegrate – Modified release formulations • Gastric emptying can affect rate but not quantity – Food, generally slows absorption rate due to delayed gastric emptying and stimulation of gastric acid secretion – Fasting, malnutrition 13 Oral administration: Most common & convenient but drugs also face most barriers to entry into the systemic circulation • Aspirin uncharged in stomach – good absorption • Pethidine charged in stomach – variable absorption 14 Elimination: pH affects efficiency of excretion • Weak base can be “ion-trapped” in urine • Placenta? • Mother’s plasma – pH 7.4 • Foetal plasma – pH 7.3 15 First pass metabolism (or presystemic metabolism) • Drug is absorbed from GI tract, passes via portal vein into liver where many are metabolised − propranolol, lignocaine, glyceryl trinitrate • Only a proportion of drug reaches the circulation • Alternative RoAs (e.g., intravenous, intramuscular, sublingual) avoid first-pass effect 16 First pass metabolism (or presystemic metabolism) • First-pass metabolism: • Intestinal lumen (digestive enzymes) • Intestinal wall (MAO) • Liver (multiple enzymes) – CYP450 • Lung (MAO, peptidases) (note: an example of first pass metabolism but not relevant to oral absorption) 17 Drugs not given orally Route Example • Intravenous Lignocaine / lidocaine (analgesic) • Sublingual Glyceryl trinitrate (angina attacks) (also buccal) • Per rectum Diazepam (epilepsy) – 100% bioavailable – straight into systemic circulation without entering portal system so escapes first-pass metabolism. Also avoids intestinal enzymes & low pH – either to produce local effect or to produce systemic effects. Absorption unreliable but useful in patients vomiting, fitting or postoperatively. Avoids intestinal enzymes & low pH • Transdermal replacement Nicotine patches, oestrogen hormone – usually used for local effect but absorption can lead to systemic effects. Only suitable for lipid-soluble drugs and expensive • Intramuscular • Inhalation Adrenaline Bronchodilators, gaseous anaesthetics 18 Advantages of various routes of administration Controlled release Rapid onset Localized effect Oral Avoids first pass metabolism - + -/++ rarely Intravenous +++ - +++ - Sublingual ++ - +++ - Intramuscular +++ +++ + -/+ Transdermal ++ +++ - -/+ Per rectum ++ ++ + -/+ Inhalation +++ - +++ +++ 19 Route of administration is determined by: • The physical characteristics of the drug • The speed which the drug is absorbed and / or released • The need to bypass hepatic metabolism and achieve high concentrations at particular sites 20 Learning outcomes • Differentiate between pharmacokinetics and pharmacodynamics • List the four key processes involved in pharmacokinetics: Absorption, distribution metabolism and elimination (ADME) • Compare the common routes of administration • Describe how absorption can influence plasma drug levels - define the term 'Bioavailability' • Describe first pass metabolism and its importance Drug plasma concentration versus time plots Typical plasma level curve after administration of an IV bolus dose Typical plasma level curve after a single oral dose of a drug Note maximum plasma concentration Maximum plasma concentration occurs at time = 0, immediately after (Cmax) is reached at a time tmax after dosing administration Drug [plasma] - time curve after oral administration maximum safe concentration (MSC) minimum effective concentration (MEC) • Onset of action occurs when plasma level reaches MEC • Plasma levels should remain below the MSC to minimise adverse reactions • Duration of action is the time period for which the plasma level is at or above MEC Area under the curve (AUC) AUC is a measure of the total amount of drug that enters the body after administration It is the actual area calculated from a plasma concentration– time curve The units are concentration × time (e.g., mg.hr L−1). • AUC after IV and oral administration of the same dose of a drug; shaded regions show the AUC for each • Note - the AUC and maximum plasma concentration are much higher with IV dosing than with oral dosing 24 Extent of absorption Bioavailability (F) is defined as “the fraction of the administered dose that reaches the systemic circulation as intact drug” • Bioavailability determines dose required by different routes of administration • Determination of bioavailability is by comparison of plasma levels of a drug obtained after administration (e.g., oral / IM) with plasma levels following IV administration Bioavailability (F): amount of drug reaching the systemic circulation as parent drug • % Bioavailability = AUCoral / AUCIV x 100 • Fractional availability = F • Has no units • Quote as percentage 25% or as decimal 0.25 • For i.v.: 100% and non i.v.: ranges from 0 to 100% Bioavailability (F) • Why do we care about bioavailability? • The true dose is not the amount swallowed, but is the drug available to exert its effects • Propranolol 80 mg / day oral (F 25%) – Sublingual – 40 mg (F 63%) – IV – 20 mg (F 100%) 27 Learning outcomes • Differentiate between pharmacokinetics and pharmacodynamics • List the four key processes involved in pharmacokinetics: Absorption, distribution metabolism and elimination (ADME) • Compare the common routes of administration • Describe how absorption can influence plasma drug levels - define the term 'Bioavailability' • Describe first pass metabolism and its importance 28 Further reading • Pharmacology, Rang, • Pharmacokinetics Texts Dale, Ritter, Moore Section 1, General Principles, Chapter 7: Absorption and distribution of drugs – Introduction to the Pharmaceutical Science s: An Integrated Approach, 2e – Merck Manual – Clinical Pharmacology • Absorption and Bioavailability video – http://accessmedicine.mhmedical.co m.proxy.library.rcsi.ie/MultimediaPlay er.aspx?MultimediaID=6809730 • (advanced detail): – http://www.youtube.com/watch?v=ey a9jR3v7i8