Pharmacokinetics Part 1 (RCSI 2024) PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Pharmacokinetics: Basic Principles and Drug Absorption FFP1-63 Prof Will Ford 337 [email protected] ...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Pharmacokinetics: Basic Principles and Drug Absorption FFP1-63 Prof Will Ford 337 [email protected]  2 Learning outcomes 1. Differentiate between pharmacokinetics and pharmacodynamics 2. List the four key processes involved in pharmacokinetics: Absorption, distribution metabolism and elimination (ADME) 3. Compare the common routes of administration 4. Describe how absorption can influence plasma drug levels and define the term 'Bioavailability' 5. 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 PK-PD underpins relationship between Dose and Effect * Clinically one looks at how the conditions change with time after therapeutic intervention  5 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) Metabolism + Excretion = Elimination – the removal of drug from the body – this may involve metabolism or excretion or both – Clearance (Cl) – Plasma Half -Life (t1/2) ADME overview  7 Drug passage across membranes (absorption processes) Of importance to absorption, distribution and excretion: Lipid Bilayer Through pores or Passive Carrier- Pinocytosis ion channels diffusion mediated By diffusing through aqueous Diffusing directly process Transport by pores formed by aquaporins though the lipid vesicles. Rare 1. Facilitated that traverse lipid bilayer. Passive movement for drugs diffusion, e.g., Passive movement along along concentration e.g., IgG levodopa & blood- concentration gradient. gradient. Drug must brain barrier Water soluble small be somewhat lipid 2. Active transport, molecules, e.g., lithium soluble e.g., 5-fluorouracil  8 Passive diffusion  9 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  10 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  11 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  13 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  14 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  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, aspirin Only a proportion of drug reaches the circulation Alternative routes of administration (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) – 100% bioavailable Sublingual Glyceryl trinitrate (angina attacks) (also buccal) – straight into systemic circulation without entering portal system so escapes first-pass metabolism. Also avoids intestinal enzymes & low pH Per rectum Diazepam (epilepsy) – 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 Nicotine patches, oestrogen hormone replacement – usually used for local effect but absorption can lead to systemic effects. Only suitable for lipid-soluble drugs and expensive Intramuscular Adrenaline Inhalation Bronchodilators, gaseous anaesthetics  18 Advantages of various routes of administration Avoids first Controlled Rapid onset Localized pass release effect metabolism Oral - + -/++ 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 Typical plasma level curve after a administration of an IV bolus dose 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, Dale, Ritter, Moore Section 1, General Principles, Chapter 7: Absorption and distribution of drugs Pharmacokinetics Texts – 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