Basic Pharmacology: Principles of Pharmacodynamics & Pharmacokinetics (PDF)

Basic Pharmacology: Principles of Pharmacodynamics & Pharmacokinetics Dr Ong Chiat Ling Jasmine PharmD, BCPS, BCCCP Department of Pharmacy Singapore General Hospital  Conflicts of Interest I have no conflicts of interest to declare. 2  Le...

Basic Pharmacology: Principles of Pharmacodynamics & Pharmacokinetics Dr Ong Chiat Ling Jasmine PharmD, BCPS, BCCCP Department of Pharmacy Singapore General Hospital  Conflicts of Interest I have no conflicts of interest to declare. 2  Learning Objectives 1. Define the terms pharmacodynamics, pharmacokinetics and pharmacogenomics 2. Describe the general actions of drug on receptors 3. Describe the principles of pharmacokinetics 4. Explain pharmacogenomics as a factor for variation in drug response 3  Introduction Pharmacology is the study of how a drug affects a biological system and how the body responds to the drug – In clinical pharmacology, we are interested in the relationship between drugs and human body and diseases Pharmaco- dynamics Pharmaco Pharmaco- -kinetics genomics 4  Definitions Pharmacodynamics describes what the drug does to the body Pharmacokinetics describes what the body does to the drug Pharmacogenomics describes the role of genome in drug response 5  Patient Case A 62 year old male patient presents to the emergency department complaining of dyspnea and a crushing chest pain while at work. He has a history of hypertension (high blood pressure), dyslipidemia and Type 2 diabetes but has defaulted medical treatment for 2 years. An ECG performed revealed an ST-segment elevation. Laboratory markers performed showed elevated cardiac enzymes. A diagnosis of a myocardial infarction was made. He was immediately sent to the cath lab whereby a blockade in his coronary arteries was found. A stent was deployed to open up his coronary arteries. The attending cardiologist then ordered to start the patient on clopidogrel, an antiplatelet to prevent stent thrombosis. 6  Patient Case A 62 year old male patient presents to the emergency department complaining of dyspnea and a crushing chest pain while at work. He has a history of hypertension (high blood pressure), dyslipidemia and Type 2 diabetes but has defaulted medical treatment for 2 years. An ECG performed revealed an ST-segment elevation. Laboratory markers performed showed elevated cardiac enzymes. A diagnosis of a myocardial infarction was made. He was immediately sent to the cath lab whereby a blockade in his coronary arteries was found. A stent was Is the drug effect deployed to How doesopen up his coronary arteries. The attending cardiologist predictable for this then orderedwork? clopidogrel How should I dose to start the patient on clopidogrel, an antiplatelet to it and how long patient? prevent stent thrombosis. does it stay in the body? 7  Pharmacodynamics 8  Pharmacodynamics Principles Most drugs must bind to a receptor to bring about an effect Drug + Receptor —> Drug-Receptor Complex —> Effect Receptor concept: – Receptors are responsible for selectivity of drug action – Receptors determine quantitative relationships between dose or concentration of drug and effects – Receptors mediate the actions of pharmacologic agonists and antagonists. 9  Pharmacodynamics Principles Agonists Antagonists / Inhibitors (competitive) Allosteric activator 10 Antagonist / Inhibitor (non-competitive)  Classification of Drugs Classifying Drugs By: Examples Indication (What is the drug used for) Anti-diabetic Antihypertensive Antibiotics Similar Chemical Structure Beta-lactams Dihydropyridines Sulphonamides Mechanism of Action Beta-receptor agonists Proton-pump inhibitors Selective Serotonin Reuptake Inhibitors 11  Pharmacodynamics Principles Downstream signaling 12  Clinical Use of Pharmacodynamics Understand what a drug does to our body – Elucidate mechanisms of action Explain interaction between a drug and other endogenous substances Explain the efficacy and side effect profile of drugs – Receptor binding results in not just efficacy but also toxicity 13  Patient Case A 62 year old male patient presents to the emergency department complaining of dyspnea and a crushing chest pain while at work. He has a history of hypertension (high blood pressure), dyslipidemia and Type 2 diabetes but has defaulted medical treatment for 2 years. An ECG performed revealed an ST-segment elevation. Laboratory markers performed showed elevated cardiac enzymes. A diagnosis of a myocardial infarction was made. He was immediately sent to the cath lab whereby a blockade in his coronary arteries was found. A stent was deployed Howto open up his coronary arteries. The attending cardiologist does then orderedwork? clopidogrel to start the patient on clopidogrel, an antiplatelet to prevent stent thrombosis. 14  Clinical Use of Pharmacodynamics – Clopidogrel 15  Clinical Use of Pharmacodynamics – Clopidogrel Action on platelets give rise to Clopidogrel mechanism of action Important side effect – Bleeding – Also secondary to inhibitory effect on platelet function 16  Pharmacokinetics 17  Pharmacokinetic Principles The principles of pharmacokinetics (PK) are summarized: Absorption Distribution Metabolism Excretion 18  Pharmacokinetic Principles - Absorption Bioavailability describes the fraction of unchanged drug that reaches the systemic circulation after administration – Differs with route of administration – For intravenous administration, bioavailability is 100% – Oral administration is often preferred but bioavailability may not reach 100% due to incomplete absorption across gut wall and/or first pass elimination by the liver 19  Pharmacokinetic Principles - Absorption After oral admin, drug passes through gut with most drugs being absorbed in the ileum Main modes of absorption: – Passive diffusion (“go with the flow”) – Facilitated passive diffusion (“go with the flow on a raft”) – Active transport (“go against the flow”) 20  Pharmacokinetic Principles - Absorption Some drugs experience significant first pass effect Intestines Drug Drug Drug Liver Drug Drug Bloodstream 21  Pharmacokinetic Principles - Absorption Factors affecting oral drug absorption: Drug factors Patient Factors Lipid solubility Area of absorptive surfaces Molecular size Gut pH Degree of ionization Gut motility pKa Presence of food or other Stability in gastric acid drugs 22  Pharmacokinetic Principles – Distribution After absorption into the bloodstream, drugs are distributed into various tissues in the body (e.g. muscles, heart, brain) The volume of distribution describes the amount of drug in the body, in relation to the concentration in plasma or blood: Vd = Amount of drug in body / Concentration in plasma 23  Pharmacokinetic Principles – Distribution Vd can vastly exceed physical volume of body Drugs with small Vd e.g. aminoglycosides have values close blood volume (~5L) Drugs with large Vd e.g. digoxin have values that exceed body weight Drugs can also bind to proteins (e.g. albumin) 24  Pharmacokinetic Principles – Distribution Factors affecting drug distribution: Drug factors Patient Factors Lipid solubility Fat and water content (age, Molecular size gender, obesity) Degree of ionization Protein levels (e.g. albumin) Partition coefficient Disease states (e.g. Protein binding (e.g. albumin) meningitis, sepsis) Concomitant drugs 25  Pharmacokinetic Principles – Metabolism Biotransformation of drugs into more hydrophilic forms for elimination by kidneys Most metabolism occur in liver Two main enzymatic phases: – Phase 1: Reactions of functionalization – Phase 2: Reactions of conjugation Can occur in succession or standalone Metabolites can be active or inactive 26  Pharmacokinetic Principles – Metabolism Phase 1 biotransformation typically involves cytochrome P450 group of enzymes – Heme-containing enzymes – CYP 3A4 most prevalent – Non-drug compounds also broken down by CYP enzymes (e.g. alcohol is metabolized by CYP 2E1) Drug-drug interactions often occur at this stage – Via inhibition or induction of CYP enzymes – Warfarin is a substrate of CYP enzyme – Fluconazole is a CYP inhibitor – Rifampicin is a CYP inducer 27  Pharmacokinetic Principles – Metabolism Phase II reactions add a molecule to the drug to increase hydrophilicity – Glucuronidation, sulphation, acetylation, methylation 28  Pharmacokinetic Principles – Metabolism Factors affecting drug metabolism: Drug Delivery Factors Intrinsic Factors Blood flow to liver Metabolizing capacity Protein binding Concomitant interacting drugs Genetic polymorphism 29  Pharmacokinetic Principles – Excretion Metabolites and parent drugs are eventually eliminated from the kidneys and excreted in the urine Good kidney function is required – Drugs may accumulate in patients with kidney dysfunction – Dosage reduction or switch to alternative agents 30  Pharmacokinetic Principles – Concept of half-life Half-life (T1/2): time taken for concentration of drug in body to reduce to half – The shorter the half-life, faster the drug clearance Important implications in drug dosing: – Dosing interval for drugs depends on T1/2, more frequent dosing required for short T1/2 e.g. Q8Hly or Q6Hly 31  Plasma Concentration-Time Curve Elimination Cpeak Cmin Area under curve Steady State Absorption 32  Clinical Use of Pharmacokinetics Understand how the body handles a drug Aids in design of dosing regimen i.e. how to give (route), how much to give, how frequent to give – Determine therapeutic index for safe and effective drug dosing Therapeutic drug monitoring for narrow therapeutic index drugs Explain drug interactions and its consequences 33  Dose and Drug Response The ideal therapeutic dose of a drug for a patient maximizes efficacy while minimizing toxicity (side effects) Dose-response relationships: EC50 (or ED50) refers to concentration of drug that produces 50% of clinical effect Drug A > potent than drug C Drug A > maximal efficacy than drug B Drug D steeper curve than A, B, or C (aka michaelis-menten relationship) à may have narrower therapeutic index 34  Dose and Drug Response Therapeutic index reflects the min effective concentration and min toxic concentration Lower doses à ineffective Higher doses à unacceptable toxicity Narrow therapeutic index drugs (e.g. vancomycin) require close drug level monitoring (aka therapeutic drug level monitoring) 35  Patient Case A 62 year old male patient presents to the emergency department complaining of dyspnea and a crushing chest pain while at work. He has a history of hypertension (high blood pressure), dyslipidemia and Type 2 diabetes but has defaulted medical treatment for 2 years. An ECG performed revealed an ST-segment elevation. Laboratory markers performed showed elevated cardiac enzymes. A diagnosis of a myocardial infarction was made. He was immediately sent to the cath lab whereby a blockade in his coronary arteries was found. A stent was deployed to open up his coronary arteries. The attending cardiologist How should then ordered to start the patient on I clopidogrel, dose an antiplatelet to it and how long prevent stent thrombosis. does it stay in the body? 36  Clinical Use of Pharmacokinetics - Clopidogrel Absorption: rapid and complete – Bioavailability > 90%, not affected by food intake Distribution: Vd is large Metabolism: Pro-drug (inactive) à CYP2C19 into active metabolite Excretion: 50% metabolite unchanged in urine T1/2 is short at 6-8 hours (parent and metabolites) – Irreversible binding to platelets, duration of action is associated with turnaround time of platelets = 7 days 37  Variations in Drug Responsiveness Given the same dose and formulation of drugs, individual patients may not respond the same way (inter-patient variation) – Daily warfarin dose required to produce the same anticoagulation effect can range from 1mg to 10mg/day – Some patients tolerate high doses of amlodipine (antihypertensive) while others experience side effects at low doses Given the same dose and formulation of drug, the same patient may not respond the same way (intra-patient variation) 38  Mechanisms for Variations in Drug Responsiveness 1) Differences in drug concentration that reaches receptor site – Attributed to differences in ADME – Alteration to amount of drug reaching receptor site à different clinical response – Multidrug Resistance genes (MDR) à active pumping of drugs out of cells e.g. Tumor cell resistance to cancer drugs 2) Variation in concentration of endogenous receptor ligand 39  Mechanisms for Variations in Drug Responsiveness 3) Alterations in number or function of receptors – Genetic factors lead to difference in number and function – Excessive growth factor signaling due to mutations in cancer cells à drug targets e.g. tyroxine kinase inhibitors – Tolerance and tachyphylaxis: progressively diminished response to drug at a certain dose following repeated exposure E.g. change in function of opioid receptors – Dependence: compulsive need for an individual to use a drug to function normally 40  Mechanisms for Variations in Drug Responsiveness 4) Changes in components of response distal to the receptor – Post receptor processes influence drug response – Age and general health of patient, severity of disease state – E.g. compensatory increases in sympathetic nervous tones during blood pressure reduction and fluid retention in kidney may lead to resistance to antihypertensive drugs – Presence of interacting drugs that produce antagonistic actions 41  Pharmacogenomics 42  Pharmacogenomics The study of genetic factors that underlie variations in drug response Important to know the frequency of alleles in local population à explains differences in drug response and side effect profile between ethnic groups 43  Pharmacogenomics 44  Examples of genetic polymorphisms Phase I: CYP 3A4/5 – The cytochrome P450 enzyme CYP 3A4/5 metabolizes wide variety of drugs including tacrolimus – Some patients express CYP 3A5 genes à increased metabolism of drugs – In kidney transplant patients, tacrolimus dose requirement is higher in CYP 3A5 expressors à potentially increased risk for organ rejection – Higher rates of CYP 3A5 expression in Asians 45  Examples of genetic polymorphisms Phase II: TPMT (Thiopurine S Methyltransferase) – Enzyme responsible for methylation of thiopurine group of drugs – Example is azathioprine, drug used in transplant and treatment of immunological conditions – Metabolized by TPMT into TGNs (active metabolites) – 3 clinical phenotypes: high, intermediate and low enzymatic activity – Low level of TPMT activity leads to higher risk for toxicities including myelosuppression 46  Examples of genetic polymorphisms Drug induced hypersensitivity reactions – Genetic polymorphisms not limited to metabolic processes – May also increase risk for hypersensitivity to drugs – Routine check for presence of HLA-B*1502 before starting patients on carbamazepine (anti-epileptic drug); HLA- B*5701 before starting abacavir (antiviral drug for HIV) – Risk for Steven-Johnson’s syndrome (SJS) or Toxic Epidermal Necrolysis (TEN) which are life-threatening 47  Patient Case A 62 year old male patient presents to the emergency department complaining of dyspnea and a crushing chest pain while at work. He has a history of hypertension (high blood pressure), dyslipidemia and Type 2 diabetes but has defaulted medical treatment for 2 years. An ECG performed revealed an ST-segment elevation. Laboratory markers performed showed elevated cardiac enzymes. A diagnosis of a myocardial infarction was made. He was immediately sent to the cath lab whereby a blockade in his coronary arteries was found. A stent was Is the drug effect deployed to open up his coronary arteries. The attending cardiologist predictable for this then ordered to start the patient on clopidogrel, an antiplatelet patient? to prevent stent thrombosis. 48  Clinical Application of pharmacogenomics – Clopidogrel Heterogeneity in platelet inhibition achieved by patients on clopidogrel – 20-55% of patients exhibit impaired response to the drug – Potential factors include drug interactions, non- adherence to medications, pharmacogenomics 49 50  Clinical Application of pharmacogenomics – Clopidogrel CYP 2C19 is an important pathway in the activation of drug actions Many variants of the gene encoding for CYP 2C19 – CYP2C19*1: Normal enzyme activity – ︎CYP2C19*2 –*8: No or reduced enzyme activity – ︎CYP2C19*17: Increased enzyme activity Being a poor metabolizer (PM) means unable to activate the drug 51  Patients who are poor metabolizers have a higher concentration of parent clopidogrel 52  Clinical Application Patients undergoing PCI Standard therapy: Genotype guided Prasugrel or Ticagrelor therapy Poor metabolizers à Prasugrel or Ticagrelor Normal à clopidogrel 53 54 55  Clinical Application of pharmacogenomics – Clopidogrel 56  Take Home Messages Pharmacodynamics explains what the drug does to our body, describes mechanism of action of drugs. Pharmacodynamic also explains the side effect profile of drugs Pharmacokinetics explains how our body handles a drug and provides rationale for drug dosing and dosage adjustment in organ failures Drug interactions can be both pharmacodynamic or pharmacokinetic Pharmacogenomics explains variability in drug response across different populations. Genotype guided therapy has been recommended for some drugs to improve patient outcomes 57  Thank you! 58