Introduction to Pharmacokinetics PDF

Introduction to Pharmacokinetics Drug Absorption, Distribution Metabolism and Excretion  Objectives for the Introduction Explain the application of Pharmacokinetics to clinical practice Describe the basic relationship between biopharmaceutics, pharmacokinetics and pharmacodynamic...

Introduction to Pharmacokinetics Drug Absorption, Distribution Metabolism and Excretion  Objectives for the Introduction Explain the application of Pharmacokinetics to clinical practice Describe the basic relationship between biopharmaceutics, pharmacokinetics and pharmacodynamics – Describe key requirements for drug to work at its desired site of action. Discuss the key four components of pharmacokinetics (ADME) – Explain how substances travel across plasma membranes – Discuss the factors affecting drug absorption – Explain the metabolism of drugs and its application to pharmacotherapy Explain enterohepatic circulation and effect on drugs – Discuss how drugs are distributed throught the body – Describe how plasma proteins affect drug distribution – Identify major processes by wich drugs are excreted – Explain the application of plasma half life to pharmacotherapy – Explain how a drug reaches and maintains therapeutic range in the plasma – Differentiate between loading and maintenance dose  Lesson Format Preliminary Introduction of principles Discussion Absorption and Distribution Discussion Metabolism and Excretion  Therapeutic Objective To provide maximum benefit with minimum harm Main factors that determine intensity of medicines response Administration – dosage size and route of administration Pharmacokinetic processes Pharmacodynamics Individual Variations NEXT STEPS  Overview Body consists of organised systems organs, tissues and cells. Various systems produce endogenous substances (enzymes, hormones, mediators etc) that play an important role in maintaining physiological/biological processes. Drugs are exogenous molecules that can influence the various biological processes in the body under the following key principles – Pharmacokinetics – Pharmacodynamics 1. Basic Relationship Pharmacokinetics and Pharmacodynamics Describe key requirements for drug to work at its desired site of action  3. Describe key requirements for drug to work at its desired site of action Note drugs encounter numerous obstacles to reaching their target site Reach Target Site/Tissue In what part of the body does an antibiotic for diarrhea work? In what part of the body does an antibiotic for meningitis work? Achieve adequate concentration at target site The recommended analgesic adult dose for paracetamol is 500mg, what is likely to be the effect of administering 1 teaspoon of the suspension 24mg/ml to an adult? Retain target concentration, at target site, for desired duration of action Frequency of administration for diclofenac sodium 50mg tablet is 2-3 times daily and diclofenac SR 100mg SR capsules is 1/day. Explain the difference  Discuss the key four components of pharmacokinetics (ADME) Definitions When drug is administered to a patient it is First absorbed from site of administration into the bloodstream (ABSORPTION) From the bloodstream it is transported throughout body to site of action in various tissues and cells where it will (DISTRIBUTION) Produce pharmacological effect Possibly undergo Metabolism/biotransformation in the relevant tissues (covert to soluble form for ease of elimination) (METABOLISM) Possible undergo excretion through the relevant tissues. (EXCRETION) Please note that the transport of drugs across cell membranes is ESSENTIAL for the above processes. 3. Describe ke3. Describe key requirements for drug to work 4. List key processes that facilitate ADME to work at its desired site of action Note the numerous obstacles that drugs face to reach their respective sites of action To reach various sites in the body, the drugs have to cross cell membranes, and are carried in the blood by molecules including proteins and they can partition into body tissues (how drugs enter and exit the body and explains how concentrations in the body change over time) I. Movement of drug molecules across cell membranes – barriers II. Binding of drugs to plasma proteins/molecules III. Partitioning into body fats and other tissues Movement of drug molecules across cell membrane barriers: Passive diffusion Facilitated diffusion Active transport diffusion through ion channels Movement of drug molecules across cell membrane barriers: Passive diffusion Passive diffussion = main method used by the majority of pharmacological agents to cross cell membranes. Passive Diffusion across lipid membranes and driven by – conc gradient. – lipophilicity of the drug molecule Effect of pH and Ionization on solubility of drugs: Most drugs exist as weak acids or weak bases and therefore exist in non-ionised/ionised forms depending on surrounding environments (pH)  Movement of drug molecules across cell membrane barriers: Facilitated Diffusion Facilitated diffusion is Carrier meditated i.e requires a physiological carrier. – Occurs along concentration gradient – It is selective, – It is saturable. May also be subject to competitive inhibition of transport carrier e.g. glucose using glut4 receptors.. – No energy is required Movement of drug molecules across cell membrane barriers: Active transport Active transport e.g active secretion at renal tubule – Occurs against concentration gradient. – Requires energy – Example Drug Interaction – Probenecid and Penicillin Processes that facilitate ADME: Movement of drug molecules across cell membrane barriers: Passive, Facilitated and Transport Movement of drug molecules across cell membrane barriers: Filtration/Diffusion through open ion pores Small, water soluble drug (ionized or polar) is readily absorbed via aqueous channels or pores in cell membrane. SUMMARY: Movement through cell menbranes water soluble drug (ionized or polar) is readily absorbed via aqueous channels or pores in cell membrane. Lipid soluble drug (non-ionized or non polar) is readily absorbed via lipid membrane itself. Facilitated diffusion requires similarity between physiological substrate and drug using the transporter Processes that underlie ADME + Factors: Movement across cell membrane barriers Exercise 1. For each of the following methods that drugs use to cross cell membrane, state at least 1 key drug characteristic necessary for the drug to cross the cell membrane Diffusion through aqueous Ion pores Passive diffusion Facilitated diffusion Active transport 2. For each of the above state which mechanism allows for drugs to cross cell membrane Down the concentration gradient Against the concentration gradient ABSORPTION& DISTRIBUTION OF DRUGS  What is drug absorption ? Note: Most drugs with a few exceptions e.g topical need to be absorbed to produce their pharmacological effects. Drug absorption can be simply defined as: – The movement of drug molecules from a site of administration into the blood stream – involves going across barriers. – There are many sites of drug administration but the two major sites of drug administration are: 1. ENTERAL 2. PARENTERAL Absorption is the major pharmacokinetic parameter determining onset of action of a drug – Onset of action diclofenac dispersable vs diclofenac sustained release – Benzyl penicillin vs benzathine penicillin Absorption following Oral administration  Factors influencing absorption Route of administration (e.g sublingual vs oral) Formulation: Drug Particle size and formulation (liquid, capsule, coating, modified release and why) – Syrup versus capsule versus sustained release table – Solubility: Ideal drug should be water soluble and lipid soluble for absorption through GIT Streptomycin only water soluble – issues? Liquid paraffin Gastrointestinal conditions and Food e. digestive motility Degree of ionisation – Ph of the environment: e.g aspirin in acidid vs alkaline environment Physicochemical factors – Drug Interactions – chelation Tetracycline and Ferrous. Ferous with antiacid – First Pass Metabolism Reflection: Partitioning, PH and Passive diffusion Reflection To test your understanding of the effect of environmental pH and drug absorption, try out this questions Aspirin is a weak acid – what is likely to be the predominant form of aspirin in an Acidic environment Alkaline environment Is Aspirin likely to be absorbed in the stomach or intestines? Drug Distribution  What is drug distribution? Refers to the specific location of drugs within the body. Involves how pharmacological agents are transported throughout the body. Once drugs have been absorbed into the blood stream they are carried around the body in the blood stream prior to reaching their specific site of action Drug can be distributed within a number of different compartments of the body including: ❖plasma ❖Interstitial (fluid which surrounds the cells ❖Intracellular(fluid contained in the cells) ❖Fat ❖CNS Drug Distribution: Factors affecting drug distri 1. Amount of blood flow to the organ. o The following are highly perfused Heart, liver, kidney and brain o The following have lower blood flow Skin, bone and adipose tissue 2. The physicochemical properties of a drug o Lipid solubility o Protein binding – drugs bound to plasma are not free to leave and be distributed. Unbound form will be distributed. o Size of drug molecules 3. Some tissues have ability to accumulate drugs o Adipose tissue e.g thiopental, diazepam o Bone – e.g tetracycline complexing with bone 4. Physiological barriers e.g BBB, Placenta  Absorption and effect on distribution= Movement Across Cell Barriers Some tight junctions between cells – Ex: CNS, placenta, Some freely permeable – Ex: Liver, spleen Vascular endothelium differs in permeability What is the importance of tight junctions in the cells surrounding CNS and placenta?? DISTRIBUTION OF DRUG IN THE BODY: Volume of Distribution Apparent Volume of Distribution – The Volume of distribution also known as the apparent volume of distribution is used to quantify the distribution of drug between plasma and the rest of the body following oral or parenteral administration – Apparent volume of distribution abbreviated (Vd) is the theoretical volume of fluid into which the total drug administered (Q) would have to be diluted to produce the concentration in plasma same as that in the body. – Significance of Vd: It is an important pharmacokinetic property of a drug candidate. It is a major determinant of half-life and dosing frequency of a drug. – Calculation of Volume of Distribution for later when we calculate loading dose  Drug Elimination Metabolism/biotransformtion Excretion  DRUG METABOLISM - Introduction Consequences of drug metabolism– – Active to Inactive – Active to Active – e.g BZP – Prodrug to Active-  DRUG METABOLISM - Introduction What is the purpose of Metabolism in the Human Body? Three main purposes – Breakdown of food to produce energy necessary to run cellular processes – Breakdown of food to produce elements that serve as building blocks for complex organic processes e.g lipids, nucleic acids – Aid with clearance of nitrogenous waste Borrowing from Normal Physiology – Why should body have processes to clear chemicals What is Drug Metabolism What are the main organs involved in drug metabolism  DRUG METABOLISM - Sites Sites of Drug Metabolism – Liver – main site – Gut – salbutamol, tyramine – Plasma – suxamethonium – Lungs -  Metabolism Hepatic Enzymes - Introduction Nature – Cytochrome P450 superfamily Classification – Isoenzymes with different families – Substrate specificity with some overlaps P450 and inter-individual Biological variation of importance in therapeutics – Genetic polymorphism – Enzyme are inducible and can be inhibited and importance thereof in pharmacology  Metabolism Enzyme Induction Enzyme Induction – Mechanisms Increase in activity of microsomal oxidase and conjugating enzymes e.g. repeated rifampicin, ethanol, carbamazepine – Consequences Impact on intensity of drug action? Interference with dose adjustment of another agent administered concomitantly? – Clinical Implications - Exercise Exercise key interactions – Rifampicin and Dolutegravir  Metabolism Enzyme Inhibition Enzyme Inhibition – P450 – Mechanisms- inhibitors differ in selectivity What is hepatic enzyme inhibition? What effect does the competitive inhibitor have on the substrate when given together? What are some of the clinical implications of the above interaction? – Examples – INH, Erythromycin, cimetidine, ritonavir, ketoconazole – Clinical Implications –Exercise Ritonavir and lopinavir Ritonavir and atorvastatin Erythromycin with theophylline  Factors that Influence Drug Metabolism - Internal Factors that influence Metabolism – Internal (Physiological, Pathological) Genetic - Age – – New born - e.g. grey baby syndrome due to chloramphenicol, – Geriatric - reduction in microsomal activity with age Disease states e.g cirrhosis – Decreased plasma protein synthesis causes lower plasma protein concentrations and possibly a higher fraction of unbound drug. – A reduction or impairment of drug-metabolising enzymes in the liver may cause reduced metabolism  Factors that Influence Drug Metabolism – External (Diet, environmental etc, drug itself) Enzyme inhibition on induction diet, environmental, self medication with natural products/alternative medicine – St John’s Wort - Exercise drug interactions with concomitant use – Grapefruit juice – exercise drug interaction with concomitant use Illustration: First pass metabolism  DRUG METABOLISM - 1st Pass Metabolism Concept of First Pass Metabolism – – Definition: – Consequences of First Pass Metabolism – Drugs with high first-pass can will have reduced bioavailability when swallowed e.g. glycerol dinitrate. They can therefore be given by other routes like IM, Sublingual or IV – Drugs affected by First Pass Metabolism e.g. propranolol  Excretion of Drugs Introduction Definition: process whereby the drug is removed from the body either as a metabolite or unchanged drug. What is the difference between excretion and elimination Drugs may be excreted via a number of routes including: – urine, bile, sweat, saliva, tears, milk, and stool. By far, the most important excretory organs are the kidney and liver. RENAL EXCRETION Mechanisms  Factors Affecting Renal Excretion Physicochemical Blood flow to Biological properties the kidneys factors Drug Plasma Disease states Interactions concentration Distribution and Urine pH binding of drug  Physicochemical Properties Molecular size. Size < 300 Daltons - easily excreted in urine. 300-500 - urine and bile. >500 bile: Urine pH versus Drug pKa – Important in drugs that are weak bases and weak acids why where the urine pH versus drug pKa influences extent of tubular reabsorption? Explain the underlying mechanism or how these can affect the amount of drug excreted. – Exercise: weak acids such as Aspirin are excreted faster when the urine is slightly more alkaline. Explain why. Note this relationship can be used to speed up excterion of certain drugs in overdose, poisoning emergency. E.g NaHCO3 in aspirin overdose  Disease States Renal dysfunction: Greatly impairs elimination of drugs primarily excreted by kidneys. Patients are put on dialysis to remove toxic waste products and drugs Impaired Glomerular Filtration→ Accumulation of certain drugs→ Toxicity.  Excretion and Drug Interactions:Active Tubular Secretion of Drugs competition for active secretion transport processes leads to drug interactions – e.g. probenecid inhibits active tubular secretion of penicillin used to prolong actions of first-generation penicillin – drugs may inhibit normal tubular secretion of uric acid e.g. thiazides and implications – Therapeutic disadvantages of competition: Inhibition of nitrofurantoin secretion by probenecid → decreased efficacy 47  Processes that facilitate ADME: Plasma protein binding The role of plasma proteins is essentially a transport system one Protein bound drugs are not available to cross cell membrane Likely effect of protein binding on drug availability at site of action Likely effect of protein binding on duration of action Although there are other proteins to bind drugs Albumin the most important one – Albumin levels will therefore affect protein binding. Clinical significance for highly protein bound drugs?  Excretion Drug Interactions Forced diuresis: All diuretics increases elimination of drugs whose renal clearance gets affected by urine flow rate.  Excretion Drug Interactions Drug interactions – Alteration of urine pH: Acidification- enhances excretion of basic drugs – Group 1-5 Alkalinization- enhances excretion of acidic drugs - Grup 5- 10  Exercise Explain how duration of action for some drugs can be increased in the case of renal failure  Nursing Implications: ADME Drug food interactions and related interventions Drug interactions and related interventions and/or monitoring. Note dose variation between oral and parenteral routes of administration for drugs with high first pass effect. Hepatic failure and impact on drug elimination and related monitoring Renal failure and related monitoring Note adjustment of urinary pH to manage overdose for some medicines