Introduction to Clinical Pharmacology and PK PDF

INTRODUCTION TO CLINICAL PHARMACOLOGY What is required at the end of our course? 1. Understand the basis of clinical pharmacology Objectives of the Course of Pharmacology 2. Understand where and how drugs act (mechanism of action) 3. Remember important issues about specific drugs Our test book G...

INTRODUCTION TO CLINICAL PHARMACOLOGY What is required at the end of our course? 1. Understand the basis of clinical pharmacology Objectives of the Course of Pharmacology 2. Understand where and how drugs act (mechanism of action) 3. Remember important issues about specific drugs Our test book Goodman and Gilman's the Pharmacological Basis of Therapeutics, 14th Edition Laurence Brunton, Bjorn Knollmann McGraw-Hill Education Our formulary A the end of each lesson dealing with a therapeutic class, a list of drugs (taken from the WHO List of Essential Medicine) whose knowledge is required for this course will be defined 2  What is pharmacology?  What is prescribing?  What is a drug, a dose and a dosage regimen?  How to choose the drug and the dosage regimen?  What are challenges for prescribers?  Important topics covered by clinical pharmacology  What are the roles of clinical pharmacologists? 3 What is pharmacology? Pharmacology is the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. The knowledge gained through basic pharmacological experimentation in cell systems, isolated tissues and animals provides a basis for the investigation of the handling and effects of the same substances in man (clinical pharmacology). 4 History of pharmacology From early times humans have looked for and experimented with substances that affect human physiology, either for recreational purposes or as therapeutic remedies. The substances in question have, for thousands of years, been naturally occurring plant derivatives. However, the scientific revolution of the nineteenth and twentieth centuries enabled many of these compounds to be characterised and new ones to be synthesized. This period marked the birth of clinical pharmacology, the scientific study of how drugs act in humans, which expanded rapidly with the increased understanding of the molecular basis of drug action. The identification of the role of hormones, neurotransmitters and growth factors, and the molecular targets they act on, has enabled the discipline to flourish, mainly with the development of small molecules that mimicked or disrupted their actions. History of pharmacology At the beginning of the twenty-first century the sequencing of the human genome has been accompanied by the development of novel therapeutic approaches involving more complex biological molecules that target gene expression, immune function, secondary messengers and other signaling pathways. Examples of such molecules include monoclonal antibodies, antisense oligonucleotides, gene modification therapy and enzymes. Therapeutics, in its wider sense, may include other non-drug therapies such as the administration of modified cells (e.g. chimeric antigen receptor T-cell therapy), intravenous fluids, blood products (e.g. red blood cells, platelets). 6 6 What is clinical pharmacology? Clinical pharmacology is the study of drug action in man providing the scientific basis for rational, safe and effective use of drugs to treat human diseases. Clinical pharmacology is a science that encompasses the investigation of:  how drugs work in man at a cellular and tissue level and  how these effects can be translated into developing medicines with beneficial effects in human disease (therapeutics). 7 What is clinical pharmacology? Discovering new Improving the effectiveness Clinical pharmacology is crucial for medicines Knowledge of the effects of drugs in human body is necessary for a correct use Reducing unwanted side effects of drugs in therapy Discovering why individuals respond differently 8 What is clinical pharmacology? It comprises many sub-disciplines that are relevant to that mission: the initial discovery and development of drugs their assessment as therapeutic agents their prescribing and administration monitoring of their beneficial and adverse effects their wider impact on society 9 What is prescribing? For many healthcare workers the ultimate importance of clinical pharmacology is that it is the science that forms the basis of rational prescribing decisions. A prescription has been defined more precisely as 'a written order, which includes detailed instructions of what medicine should be given to whom, in what formulation and dose, by what route, when, how frequently, and for how long' (Aronson 2006). Taking responsibility for writing a prescription is a significant intellectual challenge because the optimal choice of a medicine, dose, route, frequency and duration will depend on numerous factors. 10 What is prescribing? A prescription 'initiates an experiment in which the prescriber discusses the treatment with the patient and investigates and monitors the effects of the prescribed drug, with the aim of devising a dosage regimen that maximises the beneficial effects and minimises the risk of harms'. In other words, even if the very best judgment is exercised, the outcome of any prescription is uncertain and so prescribers must be prepared to counsel patients about the possible beneficial and adverse effects that might occur and understand how to monitor for these. 11 What is prescribing? Sub-competencies involved in the prescribing process 1. Make a diagnosis Weighing the risks and benefits of drug therapy 2. Establish therapeutic goal 3. Choose the therapeutic approach (in discussion with the patient) 4. Choose the drug 5. Choose the dose route and frequency 6. Choose the duration of therapy regimen Prescribing the drug 7. Write the prescription 8. Inform the patient Monitoring the impact of therapy 9. Monitor drug effects 10. Review/alter prescription in the light of further investigation 12 Good prescribing Crucial concepts Drugs must be used ONLY when it is necessary 13 Good prescribing Crucial concepts Before using a drug, both harms and benefits should be evaluated 14 Good prescribing Key Facts Risks 15 15 Good prescribing Questions to be posed before prescribing: Is the drug necessary? 3 1 What is the best way to use the drug? Different choices Are benefits superior than harms? 2 16 Good prescribing RATIONAL DRUG PRESCRIBING RATIONAL USE OF DRUGS is defined as the prescription of medications appropriate to patient’s clinical needs, in doses that meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and the community [WHO] 1. Appropriate indication 2. Appropriate drug in terms of safety, tolerability, efficacy, and suitability to the patient 3. Correct dispensing with appropriate information given to the patient 4. Appropriate dose, duration and route of administration to specific patient features 5. No existing contraindications for the patients and adverse drug reactions are minimal 6. Appropriate monitoring of the outcome of the medication to the patient, its effectiveness and untoward effects 17 What is a drug?  An active pharmaceutical ingredients (API) is the active component in a pharmaceutical drug that produces the required effect on the body to treat a condition.  A drug or medicine or medication is a substance, or mixture of substances, used in restoring or preserving health. A medicine may therefore contain one or more APIs, often mixed with several other inactive substances (excipients) that enable it to be presented in a formulation suitable for human consumption. For example, consider the drug aspirin (acetylsalicylic acid). It is possible to identify a specific chemical structure for aspirin but, when taken as a medicine, aspirin is presented in a tablet bound together with excipients. 18 What is a drug? One drug, many names  Chemical Name It identifies the chemical elements and compounds that are found in the drug. Most important to chemists, pharmacists and researchers who work with the drug at a chemical level. Example: (±)-2-(p-isobutylphenyl) propionic acid  Generic or Non-proprietary Name Also called international nonproprietary name (INN). It is the universally accepted name of a drug. It appears on all drug labels, resource guides and publications. Example: Ibuprofen  Brand or Trade or Proprietary Name The copyrighted and trademarked name given by the drug company. Example: Advil®, Motrin® 19 What is a drug? Common stems and their definition INNs often follow similar patterns for drugs of the same class or mechanism https://www.who.int/medicines/services/inn/ stembook/en/ What is a dose and a dosage regimen?  Dose is the predetermined amount of the drug administered at one time. It is expressed as flat dose (e.g. 250 mg, 10 mL, 2 drops) or units of drug mass How much? DOSE relative to the mass of the organism (e.g., mg/kg, mg/m2).  Dosage form is the physical form of a dose of drug. It contains active pharmaceutical ingredient (API) combined with excipients.  Dosage regimen (or schedule) is the modality of drug administration that is chosen to reach the therapeutic objective. It is the frequency at which the What form? FORMULATION How often? FREQUENCY drug doses are given, i.e. the schedule of doses of a drug per unit of time. It means dose and dosing interval. It includes the time between doses (e.g., every 6 hours), and the amount of a medicine (e.g., number of capsules) to be given at each specific time. How long? DURATION 21 How to choose the drug and the dosage regimen? The choice of dosage regimen depends on Economics Side Effects Therapeutic Objectives CURE MITIGATION PREVENTION 22 How to choose the drug and the dosage regimen? Different methods EMPIRICAL METHODS RATIONAL APPROACHES Based on trial and error approach Based on pharmacological knowledge Adequate concentration of drug at the site of action to have therapeutic effects 23 What are challenges for prescribers?  Increased number of drugs  High number of patients per doctor  Expanded medical information and clinical guidelines  More vulnerable patients  Higher patient expectations  Increased drug costs  NHS sustainability  Medico-legal pressures  Pharmaceutical marketing strategies 24 Prescribing documentation and information sources General information Current national guidelines The Cochrane collaboration - https://www.cochrane.org/ PubMed - https://pubmed.ncbi.nlm.nih.gov WHO List of Essential Medicines https://list.essentialmeds.org/ WHO Defined Daily Dose https://www.whocc.no/atc_ddd_index/ European Union https://www.ema.europa.eu/en/medicines Article 57 database https://www.ema.europa.eu/en/human-regulatory/postauthorisation/data-medicines-iso-idmp-standards/publicdata-article-57-database National registers of authorised medicines https://www.ema.europa.eu/en/medicines/nationalregisters-authorised-medicines United States of America Italy AIFA - https://farmaci.agenziafarmaco.gov.it/ bancadatifarmaci/home United Kingdom https://www.nice.org.uk/guidance Electronic medicines compendium https://www.medicines.org.uk/ FDA Drug Approvals and Databases https://www.fda.gov/drugs/development-approval-processdrugs/drug-approvals-and-databases Drugs@FDA https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm NIH Drug Information Portal https://druginfo.nlm.nih.gov/drugportal/ Medscape - https://reference.medscape.com/ What aspects of clinical pharmacology are relevant to healthcare? Clinical pharmacology also encompasses wider issues such as: The breadth of topics embraced by clinical pharmacology  how drugs are developed and regulated,  how we assess cost-effectiveness,  how we manage their use in healthcare,  how their impact in populations is measured,  how to prevent their misuse. Those topics in dark green are more directly concerned with the decisions made by individual prescribers. Those topics in lighter green concern the development and regulation of medicines, managing their use in healthcare or taking into account their wider impact in society. 26 Important topics covered by clinical pharmacology The two arms of pharmacology Pharmacokinetics (PK) Pharmacodynamics (PD) what the body does to the drug what the drug does to the body the study of the processes of drugs in the body the study of the effects of drugs on body processes 27 Important topics covered by clinical pharmacology Pharmacokinetics A knowledge of pharmacokinetics is the basis of every drug dosage regimen recommended by a pharmaceutical manufacturer. It enables prescribers to choose doses and dose intervals that make it likely that the target tissues will be exposed to appropriate drug concentrations for a sufficient length of time. A fundamental aspect of pharmacokinetics is the relationship between the concentration of a drug and the time that has elapsed since administration. Plasma drug concentration Pharmacokinetics is the science that describes the processes that control how drug molecules reach their site of action via the plasma (absorption, distribution) and how they are removed from the body (metabolism, excretion). Topic addressed in other lessons 28 Important topics covered by clinical pharmacology Pharmacodynamics Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body, the mechanisms of drug action and the relationship between drug concentration and drug effect. A fundamental aspect of pharmacodynamics is the dose-response curve that relates the dose of a drug to the pharmacological effect it produces. Topic addressed by prof. Pozzi 29 Important topics covered by clinical pharmacology Pharmacokinetics Dosage regimen • • • • Pharmacodynamics Drug in blood What form? How much? How often? How long? Pharmacological effects Drug at target site 30 Important topics covered by clinical pharmacology Interindividual variations Some factors affecting both pharmacodynamics and pharmacokinetics should be considered: Pharmacogenetics Pharmacogenetics is the study of how inherited genetic differences affect the pharmacological effects that drugs have in the body (pharmacodynamics) and the way that they are handled (pharmacokinetics). These differences arise because of variations in receptors, enzymes, messengers and other targets. Topic addressed in other lessons 31 Important topics covered by clinical pharmacology Adverse drug reactions Adverse drug reactions (ADRs) are unwanted or harmful reactions that are experienced following the administration of a drug and that are suspected to be related to the drug. An ADR will usually require the drug to be discontinued or the dose to be reduced. Topic addressed in other lessons 32 Important topics covered by clinical pharmacology Clinical toxicology Clinical toxicology is the science that describes the adverse effects that occur when the body tissues are exposed to excessive concentrations of drugs.  This may happen when the pharmacokinetic handling of standard therapeutic doses is altered meaning that they accumulate to toxic concentrations.  Drug toxicity also occurs when medicines are deliberately taken in overdose or otherwise misused. Drug misuse describes the misuse of prescription medicines or use of illegal drugs for recreational purposes. These phenomena are widespread in most societies and represent a major threat to the public health. o Prescription drugs that are commonly involved include opioid analgesics and benzodiazepines. o Illegal substances that are frequently the cause of toxicity include cannabis, cocaine, ecstasy (3,4-methylenedioxymethamphetamine (MDMA)), gamma hydroxybutyrate (GHB), heroin, and hallucinogens (e.g. lysergic acid diethylamide (LSD)). 33 Important topics covered by clinical pharmacology Drug interactions Drug interactions occur when the administration of one drug increases or decreases the beneficial or adverse responses to another drug. Although the number of potential interacting drug combinations is very large, only a small number of interactions are important in clinical practice. The mechanisms of drug interactions can be divided into:  Pharmacodynamic interactions. These occur when two drugs produce additive, synergistic or antagonistic effects at the same drug target.  Pharmacokinetic interactions. These occur when the administration of one drug affects how another is handled in the body. Topic addressed in other lessons 34 Important topics covered by clinical pharmacology Medication error A medication error is any preventable event that may lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional or patient. Errors may occur in prescribing, dispensing, preparing solutions, administration or monitoring. Common prescribing errors in hospitals include omission of medicines that should have been prescribed, dosing errors, unintentional prescribing and poor use of documentation. Approaches to the prevention of errors involves better training of prescribers, improving the supervision and support that they are given (e.g. access to clinical pharmacists), reducing workloads, improved decision support and implementation of electronic prescribing systems. 35 Important topics covered by clinical pharmacology Prescription A prescription is a means by which a prescriber communicates the intended plan of treatment to the pharmacist who dispenses a medicine and to a nurse or patient who administers it. It should be precise, accurate, clear and legible. The information supplied by the prescriber must include: • the date, • the identity of the patient, • the name of the medicine, • • • • • the formulation, the frequency of administration, the route and method of administration, the amount to be supplied (primary care only), instructions for labelling (primary care only), and • the prescriber’s identity (signature). 36 Important topics covered by clinical pharmacology Monitoring drug therapy Monitoring drug therapy is important because it allows prescribers to measure the impact of their prescription, both beneficial and harmful, and to inform decisions about dose titration (up or down), discontinuation or substitution of treatment. Monitoring can be achieved subjectively by asking the patient about symptoms (e.g. pain, depression) or more objectively by measuring a clinical effect (e.g. blood pressure, blood glucose concentration). 37 Important topics covered by clinical pharmacology Adherence Adherence (compliance) describes the extent to which a patient's taking of their medicine matches the intentions set out in the prescription they have been given. Adherence to treatment regimens is an important issue affecting the success of drug therapy. Around half of patients being treated for long-term conditions do not adhere to the intended regimen. This is more likely if the condition is asymptomatic (e.g. hypertension), the regimen is complex (e.g. twice daily or more frequent administration) or the patient is not fully engaged in or motivated to take the treatment. Poor adherence is a major issue for healthcare because it means that patients don't achieve the benefits of drug therapy, clinicians make inappropriate decisions because of making false assumptions about exposure to medicines and a substantial resource is wasted. These challenges now force clinicians to look increasingly to a more inclusive relationship with patients involving shared decision-making where patients express their own views about what constitutes an acceptable benefit/harm balance. It is hoped that a more open and shared decision-making process might resolve any misunderstandings at the outset and foster improved adherence, as well as improving satisfaction with healthcare services and confidence in prescribers. 38 What are the roles of clinical pharmacologists? Clinical pharmacology is a recognised medical specialty in many countries around the world. Clinical pharmacologists are all qualified doctors who have undertaken a postgraduate specialty training pathway that focuses on research methodology, clinical trials, prescribing, medicines management and policy, and health technology assessment. They often work in collaboration with pharmacists on medicines management and prescribing quality issues. Although clinical pharmacologists are relatively small in number, they are often very influential in medicines policy through their work on local, regional and national medicines advisory bodies. They have a role in four main areas: Healthcare University academic National advisory Pharmaceutical industry 39 INTRODUCTION TO PHARMACOKINETICS  Aims and processes of pharmacokinetics  Measurement of drug concentration  Pharmacokinetic plots  Drug transport across cell membranes  Pharmacokinetic parameters: Cmax, tmax, AUC, t1/2 41 Aims of pharmacokinetics There is generally a correlation between drug concentration at the target site and its effects. The aim is to have a drug concentration at the target site that is sufficient to achieve the therapeutic effect. 42 Aims of pharmacokinetics The most precise PK analysis would ideally measure drug concentrations at the target site that mediate the effect. However,  measurement of drug concentration at the Accordingly, a common compromise is to measure drug concentrations in more accessible compartments (e.g., venous blood) target site is often difficult; that usefully approximate drug concentrations  the target site might be unknown or broadly distributed. across broad areas within the organism. 43 Aims of pharmacokinetics Drug levels can be measured from blood (or plasma) over time. From concentration in plasma, drug concentration in tissues can be predicted. However, the tissue concentration may be greater or less than plasma drug concentration. 44 What is pharmacokinetics? Pharmacokinetics can be defined as the study of  the rate and extent to which drugs are absorbed into the body and distributes to the tissues  the rate and pathways by which drugs are eliminated from the body by metabolism and excretion  the kinetics of plasma drug concentration following drug administration 45 Processes of pharmacokinetics Absorption Distribution How the drug gets from How the drug moves its site of administration from the blood to into the blood? organs and tissues? Metabolism Excretion How the drug is How the drug is transformed by the body removed from into different molecules the body? (metabolites)? ADME 46 Models of pharmacokinetics One-compartment model Two-compartment model absorption absorption Compartment 1 elimination Compartment 1 Multi-compartment models elimination Blood Organism distribution Compartment 2 elimination Tissue Before administration After administration These models can be used to predict the time course of drug concentrations in the body 47 Models of pharmacokinetics Examples Aminoglycosides Aminoglycosides are polar molecules, so their distribution is limited primarily to extracellular water. They are generally well described by the one-compartment model. Digoxin After an intravenous dose is administered, plasma concentration of digoxin rises and then rapidly declines as drug distributes out of plasma and into muscle tissue. After equilibration between drug in tissue and plasma, plasma concentrations decline less rapidly. It is well described by the two-compartment model. Benzodiazepines Benzodiazepines are lipophilic drugs that extensively distributed in tissue. They may be better described by a more complex model. 48 How to describe the PK profile of a drug 1. Blood sampling Blood samples are taken before and after dosing with the drug. Typically: • post-dose every 30 minutes, every hour and then at greater time points Plasma or serum extraction will follow. 2. Measuring drug concentration Different techniques can be used in relation to the tested drug. 3. Plotting PK profile PLASMA CONCENTRATION • pre-dose TIME  Plotting plasma concentration-time curve  Calculating PK parameters 49 Measuring drug concentration Technique to measure drug concentration in biological fluids - 1  Chromatography UV • Liquid chromatography (HPLC) Fluorescence Mass spectrometry Thermal conductivity • Gas chromatography (GC) Photoionization Mass spectrometry 50 Measuring drug concentration Technique to measure drug concentration in biological fluids - 2  Immunoassay (especially for therapeutic antibodies and antibodies drug conjugates) • Radioimmunoassay • Enzymatic immunoassay • Fluorescent immunoassay 51 Measuring drug concentration Chromatography PROs: Immunoassay PROs: • high sensitivity and specificity • superior sensitivity • robust and reliable • high throughput • straightforward method development • no sample preparation • no labeling need • simple instrumentation • applicable to every analyte CONs: CONs: • long sample preparation • labeling needed • long acquiring time • long and complex method set up • complex and costly instrumentation • need to generate the desired antibody 52 Measuring drug concentration Techniques to measure drug concentration are characterized by different sensitivity and specificity Method Detection technique Sensitivity* Labelling HPLC-UV UV-Vis adsorbance > 25-50 ng/ml No HPLC-FLUO Fluorescence > 5 ng/ml No HPLC-MS Mass spectrometry > 0.1 ng/ml No GC-MS Mass spectrometry < 50 pg/ml No Radioimmunoassay Counting radioactivity < 10 pg/ml Radioactive atom Enzyme immunoassay UV-Vis absorbance of the colored enzymatic product < 50 pg/ml Enzyme Fluoroimmunoassay Fluorescence < 1 ng/ml Fluorochrome * in samples extracted from complex biological matrix; indicative value; highly analyte dependent 53 Pharmacokinetic plots One-compartment model Plasma drug concentration (ng/ml) Plasma drug concentration (ng/ml) Intravenous (i.v.) bolus  Drug distribution occurs instantaneously  Plasma concentration declines in a straight line on a semilogarithmic axis 54 Question given intravenously at the same dose? A. Drug B is eliminated faster than Drug A. B. Drug B remains longer in the blood circulation than Drug A. C. Drug B does not distribute to tissues. D. Drug B is absorbed easier than Drug A. Plasma drug concentration (µg/ml) How do you describe the kinetics of Drug B compared to Drug A, Drug A Drug B 55 Intravenous (i.v.) bolus Two-compartment model Plasma drug concentration (µg/ml) Pharmacokinetic plots Distribution phase Elimination phase  Immediately after the dose is given, plasma concentration declines rapidly = distribution phase. During the distribution phase, drug is distributing between blood and tissues and is partly removed from the body via hepatic metabolism and renal elimination.  Later, plasma concentration declines more slowly = elimination phase. During the elimination phase, drug is primarily being removed from the body. 56 Pharmacokinetic plots These PK processes overlap in time At the point where plasma drug concentrations are measured, all 4 PK processes (ADME) are occurring in the body. As soon as some drug molecules have been taken up, they will start to distribute and undergo elimination, even while most others are still waiting for uptake. 57 Oral administration Plasma drug concentration Pharmacokinetic plots In the beginning, absorption is occurring at the greatest rate and at the end excretion prevails. At the point where the plasma concentration is at its peak the rate of drug entering the plasma is the same as the rate of drug being removed from the plasma. 58 Drug transport across membranes Anatomical barriers concern all stages of drug transport Examples 59 Drug transport across membranes Mechanisms of SOLUTE transport across membranes Passive transport The drug molecule penetrates along a concentration gradient. Diffusion The drug molecule penetrates by virtue of its solubility in the lipid bilayer. Facilitated diffusion Carrier-mediated transport process in which there is no input of energy. Active transport Movement of solutes against an electrochemical gradient mediated by drug efflux pumps. Active transport characterized by:  a direct requirement for energy  saturability  selectivity  competitive inhibition by cotransported compounds 60 Drug transport across membranes Transport of MACROMOLECULES across membranes Macromolecules are too large to move with membrane proteins and must be transported across membranes in vesicles. Endocytosis is a type of active transport that moves particles into a cell. The plasma membrane of the cell invaginates, forming a pocket around the target particle. The pocket pinches off, resulting in the particle being contained in a newly-created intracellular vesicle formed from the plasma membrane. Phagocytosis A process by which large particles, such as cells or relatively large particles, are taken in by a cell. Pinocytosis A process that takes in molecules, including water, which the cell needs from the extracellular fluid. Pinocytosis results in a much smaller vesicle than does phagocytosis, and the vesicle does not need to merge with a lysosome. Receptor-mediated Endocytosis A targeted variation of endocytosis that employs receptor proteins in the plasma membrane that have a specific binding affinity for certain substances. 61 Drug transport across membranes The way the drug is absorbed through phospholipid bilayer depends on its properties:  Charged drugs use ion channels;  Some specific compounds take advantage of carrier-mediated transport; Examples: • L-DOPA, α-methyldopa, baclofen  use large neutral amino acid transporter • amino-β-lactams, ACE inhibitors  use oligopeptide transporter (PEP-1) • salicylic acid, pravastatin  use monocarboxylic acid transporter  Large drugs may be endocytosed;  Most drugs are small molecule compounds that not fit the substrate specificities of any transporter. They can pass through cell membranes by passive diffusion. 62 Drug transport across membranes Active transport Drug efflux pumps There are different class of efflux transporters. In the ATP-binding cassette superfamily (ABC), the best investigated transporter is ABCB1, also known as P-glycoprotein (Pgp) and Multi Drug Resistance protein 1 (MDR1). 63 Drug transport across membranes Passive diffusion Passive diffusion involves the movement of drug molecules from region of relatively high to low concentration (concentration gradient) without expenditure of energy. Movement continues until equilibrium has been reached between both sides of the membrane. Features of passive diffusion  It does not require substancespecific carriers;  It does not become saturated with high drug concentration;  It is difficult to control. 64 Drug transport across membranes The main factors determining the rate of drug transport through passive diffusion are:  Physicochemical properties of the drug (particle size, solubility, partition coefficient, pH, pKa);  The nature of the membrane (e.g. permeability, surface area);  The concentration gradient of drugs across the membrane. Fick’s law The rate of penetration is directly proportional to • the magnitude of the concentration gradient across the membrane, • the lipid-water partition coefficient of the drug, • the membrane surface area exposed to the drug. 65 Drug transport across membranes Parititon coefficient Membrane structure The ability of drug molecules to cross a lipid bilayer by passive diffusion correlates with their ability to partition into and out of the hydrophobic membrane interior. A partition coefficient is the ratio of concentrations of a compound in the two phases of a mixture of two immiscible solvents at equilibrium (normally water and a hydrophobic solvent e.g. octanol). They are measures of how much hydrophilic or hydrophobic a chemical substance is.  Very polar molecules will fail to enter the membrane  A hydrophobic character is most conducive to transport 66 Drug transport across membranes The membrane permeability of a drug can be modified by adding/removing polar functional groups Example Methamphetamine (psychostimulant abused drug) is an analogue of epinephrine (adrenaline) that have shed some hydroxyl groups. At pharmacokinetic level, it penetrates cell membranes more readily than the parent compound, which promotes its uptake from the intestine and its distribution to the brain. However, the structural changes also cause a shift in the molecular mode of action (pharmacodynamics). While epinephrine acts directly on adrenergic receptors at the cell surface, metamphetamine act primarily on intracellular targets. 67 Drug transport across membranes The membrane permeability of a drug can be affected by pH Most drugs are weak acids or bases that are present in solution as both the pH values in the human bodies nonionized and ionized species.  The nonionized molecules are more lipid-soluble and can diffuse readily across the cell membrane.  The ionized molecules are unable to penetrate the lipid membrane because of their low lipid solubility. 68 Drug transport across membranes pKa is defined as the pH where a drug exists as 50% ionized and 50% unionized. If pKa = pH, then 50% of drug is ionized and 50% is unionized For a weakly acidic drug For a weakly basic drug pKa = the negative logarithm of Ka An acid in an acid solution (pH < pKa) will not ionize. A base in a basic solution (pH > pKa) will not ionize. An acid in a basic solution (pH > pKa) will ionize. A base in an acid solution (pH < pKa) will ionize. ION TRAPPING at equilibrium, an acidic drug will accumulate on the more basic side of the membrane and a basic drug will accumulate on the more acidic side 69 Question How do you think aspirin (acetylsalicylic acid) distributes in the empty stomach after oral intake? A. It accumulates in the gastric lumen. B. It accumulates inside gastric epithelial cells. 70 Question How do you think aspirin-induced gastritis and ulcer formation can be prevented by reducing the accumulation of the drug in the gastric mucosal cells? 71 Question Assume that the pH of the stomach is 2.5. The pKa of thiopental (a sedative-hypnotic) is 7.4 and it is acidic. If a patient is given thiopental orally instead of IV, will it put the patient to sleep? A. Yes. B. Yes, but only slightly. C. No 72 Pharmacokinetic parameters Descriptive parameters that can be measured directly from the plasma concentration-time curve Plasma concentration Plasma drug concentration • Maximum concentration - Cmax • Time to peak concentration - tmax • Area under the curve - AUC • Half-life - t1/2 Conceptual parameters Time Example of a plasma concentration-time curve after oral administration that can be calculated starting from the plasma concentration-time curve • Volume of distribution - Vd • Clearance - CL • Bioavailability - F 73 Maximum concentration (Cmax) Maximum (peak) concentration of drug in the blood after a dose is administered. Time to peak concentration (tmax) The time it takes to reach the Cmax of a drug Plasma drug concentration Maximum concentration and Time to peak concentration in the blood after a dose is administered.  After an intravenous dosing at constant rate, Cmax and tmax are related to the time of infusion.  After oral dosing, Cmax and tmax are dependent on the extent and the rate of drug absorption and the disposition profile of the drug. 74 Maximum concentration and Time to peak concentration Clinical implications Plasma drug concentration For SOME drugs, the therapeutic effect or the adverse effects are related to Cmax. Drug plasma concentrations should be within the therapeutic range to reach clinical goals. MTC = maximal tolerated concentration MEC = minimal effective concentration 75 Area under the curve Total area under the plasma drug concentration-time curve Clinical implications The AUC reflects the actual body exposure to drug after the administration of a dose, i.e. the fraction of the dose Plasma drug concentration Area under the curve (AUC) administered that reaches the systemic circulation. The dimensions of AUC are always given by CONCENTRATION x time and is expressed in mg*h/L. 76 Area under the curve It can be calculated as:  AUC(0–t) – with specification of the time period over which it is determined;  AUC(0–∞) – integral of the time-concentration curve from time zero (time of the administration of the drug) to infinite time. 77 Different excipients (inactive ingredients) may increase or decrease the absorption rate of the active ingredient. Drug A, B, C have a different absorption rate (0.3, 0.5 and 0.7/hr) while the elimination rate is kept constant. How do you think AUC will vary? A. AUCDrug A > AUCDrug B > AUCDrug C Plasma drug concentration (mg/l) Question C B A B. AUCDrug A = AUCDrug B = AUCDrug C C. AUCDrug A < AUCDrug B < AUCDrug C 78 Half-life Half-life (t1/2) The time it takes for the plasma concentration to be reduced by 50% By definition, the plasma concentration of a drug is halved after one elimination half-life. Therefore, in each succeeding half-life, less drug is eliminated. After one half-life the amount of drug remaining in the body is 50%, after two half-lives 25%, etc. After 4 half-lives the amount of drug (6.25%) is considered to be negligible regarding its therapeutic effects. 79 Half-life In first order reactions, the slope continually decreases as time progresses until it reaches zero. The amount of time between one half life and the next are the same. The half-life is considered to be independent of the amount of drug in the body. The half-life depends solely on the reaction rate constant, k. 80 Half-life Clinical implications: Half-life determines the length of the drug effect.  Drugs that have a shorter half-life tend to act very quickly, but their effects wear off rapidly.  Drugs with a longer half-life may take longer to start working, but their effects persist for longer. Examples  Methylphenidate (indicated for the therapy of Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy) has a short half-life (2-5 hours) it may require more frequent dosing to achieve a therapeutic effect.  Bevacizumab (monoclonal antibody used against some solid cancers) has a long half-life (about 20 days) 1 dose every 2-3 weeks is sufficient to achieve the therapeutic effect. 81 Question Bob is a 65-year-old man on amiodarone therapy for chronic atrial fibrillation. He arrives in your clinic complaining of symptoms of hyperthyroidism, one of the many forms of amiodarone toxicity. A blood sample confirms a drug level of 4 µg/ml, well above his normal range of 1-1.5 µg/ml. The half life of amiodarone is 25 days. If you discontinue the treatment with amiodarone, how long will you have to wait for Bob's amiodarone level to fall to a normal level of 1 µg/ml? A. 2 days B. 25 days C. 50 days D. 100 days