Pharmacodynamics 2024 PDF

Principles of pharmacokinetics/ pharmacodynamics 2: January 18, 2024 Dylan Burger, PhD [email protected] RGN2513 Recap Bioavailability- Sample Question 3 “Pete Mitchell” is an experimental drug used on Russian MiGs. For a 70kg male the IV AUC from a 200 mg dose is 150 mg.hr/L. The Oral AUC from a 2...

Principles of pharmacokinetics/ pharmacodynamics 2: January 18, 2024 Dylan Burger, PhD [email protected] RGN2513 Recap Bioavailability- Sample Question 3 “Pete Mitchell” is an experimental drug used on Russian MiGs. For a 70kg male the IV AUC from a 200 mg dose is 150 mg.hr/L. The Oral AUC from a 200 mg dose is 13.2 mg.hr/L. What is the bioavailability of this drug? What other conclusions might we draw from these data. F = AUC po  dose absorbed AUC iv  dose administered F= 13.2/150 F=0.088 or 8.8% With such a low bioavailability this drug may be better administered parenterally. Low Bioavailability- What does it mean? Low bioavailability less drug enters the blood stream than expected. Could be poor absorption or inactivation or chemical breakdown of the drug If chemical modification: more metabolites of the drug produced (may or may not be reactive) Consequences? Administer more drug to get desired effect 10% bioavailability means you need 10x the dose to get the desired plasma concentration Only possible if there are no side effects Choose an alternate route Intravenous- guarantees 100% bioavailability IM, SC etc… May be sufficient to avoid first pass effect in the liver Chemical modification to drug to change absorption and metabolism patterns Change in drug formulation (i.e. enteric coating) Outline Drug Metabolism Types of reactions Cytochrome P450 Monooxygenase system Drug Metabolism- clinical considerations Drug Excretion Routes of excretion Elimination kinetics Repeated dosing and drug accumulation Pharmacodynamics PHARMACOKINETICS- Drug Elimination Drug Elimination- the irreversible loss of drug from the body o 2 Processes contribute to drug elimination Metabolism (biotransformation)- Enzymatic conversion of a chemical entity (drug) into another Excretion- Elimination of a chemically unchanged drug, or its metabolites, from the body. PHARMACOKINETICS- Metabolism Goal- to increase size and polarity of compounds (more easily excreted) Drugs are mostly metabolized in the liver - also gastrointestinal tract, kidneys, lungs, placenta, skin Phase I: Addition of a reactive group (-OH, -NH2, -SH). Attach a polar group Reactions: oxidation, hydroxylation, reduction Phase II Conjugation of the reactive group with a highly charged, water soluble substrate (e.g. glucuronic acid) Reactions: glucuronidation, acetylation, conjugation with amino acids PHARMACOKINETICS- Metabolism DRUG METABOLISM  Drug metabolizing enzymes may: Convert pharmacologically active compounds to inactive forms Activate prodrugs, - pharmacologically inactive  active forms, e.g tamoxifen Increase therapeutic action of some drugs , e.g codeine  morphine Decrease toxicity (usually)  Occasionally can increase toxicity, eg conversion of acetaminophen [Tylenol] into a hepatotoxic substance. Significant in overdose. PHARMACOKINETICS- Metabolism Result: highly charged, +/- inactive, water soluble compound More readily excreted by the kidneys or in bile Many Phase I reactions are catalyzed by members of the cytochrome P450 family Other Phase I enzymes include: alcohol dehydrogenase (ethanol) aldehyde dehydrogenase low levels = alcohol intolerance Drug Metabolism – Cytochrome P450 enzymes A large superfamily of heme-containing enzymes that metabolize drugs and endogenous compounds. Each enzyme family and its subtypes will have distinct substrate specificities and catalyze distinct reactions (with some overlap) The drug metabolizing enzymes (CYP 1-3) are found at highest concentration in liver. CYP 3A4 – Most common enzyme subtype involved in drug metabolism. CYP2E1 CYP1A2 CYP2C (9,19) CYP3A CYP2D6 Shimada T et al. J Pharmacol Exp Ther 1994;270(1):414. Do NOT Memorize Me! CYP450s can display polymorphisms A trait that demonstrates a different distribution/activity in >1% of the population PM = poor Population metabolizer EM = extensive metabolizer (normal metabolism) Metabolism rate URM= ultra rapid metabolizer *Some textbooks also teach “intermediate metabolizers” which metabolize at a rate between PM and EM CYP 2D6 Displays polymorphism in the population: most EM 4-10% PM 1-2% URM ~30 % URM in Ethiopians and North Africans CYP 2D6 metabolizes -blockers (heart drugs) Tricyclic antidepressants Antipsychotics It is also required for the activation of codeine CYP 2D6 Codeine Morphine CYP 2D6 Poor metabolizers demonstrate decreased responsiveness to typical doses of codeine Ultra-rapid metabolizers have suffered “overdoses” CYP activity can be inhibited substrates inhibitors meds C meds A meds C meds A meds C meds A meds G enzymes CYP3A4 meds G meds G Drug accumulates if it is normally degraded by CYP3A4 Note: the opposite would be true if CYP was normally responsible for activating the medication (like codeine & CYP2D6) CYP activity can be induced enzymes substrates meds C inducer meds A CYP3A4 meds G Drug levels are reduced if it is normally degraded by CYP3A4 Note: the opposite would be true if CYP was normally responsible for activating the medication (like codeine & CYP2D6) CYP Induction and Inhibition Induced cigarette smoke(1A) phenytoin (3A) Inhibited ketoconazole (3A) erythromycin (3A) This can significantly affect drugs that are normally substrates of these CYPs: Inducers decrease therapeutic levels whereas inhibitors result in accumulation of a drug. *For a drug that is active at administration (i.e. not a pro-drug) Sample problem  Drug-metabolizing enzymes in liver A B C D CYP – Inhibitor – Grapefruit juice Grapefruit juice can inhibit intestinal CYP3A4 thereby increasing the amount of drug that reaches the liver and the systemic circulation CYP – Inhibitor – Grapefruit juice Grapefruit juice * Dresser GK et al Clin Pharmacol Ther 2000;68(1):28–34 *NB: felodipine is a vasodilator; the figure (above, right) shows a significant decrease in blood pressure as a result of higher drug levels CYP 2E1: Ethanol ethanol can be metabolized by alcohol dehydrogenase as well as by CYP2E1 chronic ethanol ingestion can increase levels of CYP2E1 acetaminophen is metabolized 95 % by conjugation with glucuronic acid 5 % by oxidation via CYP 2E1 metabolism by CYP 2E1 produces a toxic metabolite for the liver NADQI = N-acetyl-p-benzoquinoneimine NADQI is normally eliminated/neutralized by conjugation with glutathione Do NOT Memorize Me! an alcoholic is at greater risk, as a consequence of excessive drinking levels of CYP 2E1 become elevated… so more acetaminophen can be converted into toxic metabolites levels of glutathione are depleted by the metabolism of alcohol … so fewer defence mechanisms against the toxic metabolite METABOLISM: SPECIAL CONSIDERATIONS  Age o Infants (immature liver) and elderly (reduced liver/kidney function) need drug dosage (or choice) adjustments  Nutritional Status o Drug-metabolism requires a number of co-factors o May be absent in malnourished pt  compromised drug metabolism  First-Pass Effect o Rapid hepatic inactivation of an oral drug o Drug absorbed from GI tract, carried directly to liver (‘first pass’) o Therapeutic effects lost o Drugs with strong first pass effect must be administered parenterally (intravenously [IV]/ intramuscularly [IM] /subcutaneously [SQ]) METABOLISM: SPECIAL CONSIDERATIONS  Stereoselectivity-Drug metabolizing enzymes may act on different stereoisomers selectively.  E.g. Warfarin- generally given as racemic mixture  S isomer is 4x as potent as R isomer (fewer metabolic pathways) PHARMACOKINETICS- Excretion The removal of drugs and their metabolites from the body. Drugs can exit the body in Urine Bile Sweat Saliva Breast milk Expired air Routes of excretion- Urine Major route of elimination of drugs in the body Renal elimination may be of unchanged drug or a polar metabolite (more common) 3 steps Glomerular Filtration- Movement of drugs from blood to urinary filtrate. Only low MW drugs can be filtered. N.B. Albumin is not filtered- so albumin-bound drug is not filtered. Passive Tubular Reabsorption- Due to proximity of blood vessels to tubules lipid soluble drug can move down a concentration gradient back into blood. Active tubular secretion- Certain drug transporters can actively pump drugs into urine (P-glycoprotein, organic acid and base transporters). Routes of excretion- Urine (considerations) Several factors can modify renal drug excretion pH dependent ionization- As passive tubular reabsorption is determined by lipid solubility, changes in the pH of urine can alter the passive reabsorption of drugs. - Can be exploited therapeutically (e.g. aspirin overdose). - Aspirin- weak acid. For overdoses in children one treatment is to increase urine pH (more basic). Increases urinary ionization of aspirin and decreases reabsorption. Competition for active tubular transport- Active tubular secretion has limited capacity. Two drugs can compete for elimination from the same transporter (slows excretion). Decreased kidney function- In newborns the kidneys are not fully developed and therefore have a limited capacity to excrete drugs renally. Similarly, in the elderly or in individuals with chronic kidney disease kidney function may be impaired and renal drug excretion is decreased. Routes of excretion- Bile/Feces Important for elimination of compounds not absorbed in the gut, and for large water soluble compounds. Higher the molecular weight, the greater the biliary excretion Enterohepatic cycling- A process when a drug entering the intestine in bile is reabsorbed into the circulation through the portal blood vessels. Drug in Blood Drug/conjugate in liver Drug/conjugate in bile Enterohepatic recycling Drug/conjugate in intestine Bile released from gall bladder Excretion in feces Routes of excretion- Expired Air Common route of excretion for gaseous drugs (i.e. anesthetics) Less common for soluble drugs Routes of excretion- Breast Milk Certain drugs (generally lipid soluble) may be excreted into breast milk. Polar drugs rarely partition to breast milk Nursing infants may be at risk of exposure to drugs in breast milk Routes of excretion- Skin Small amounts of drug may be excreted through skin via sweat E.g. benzoic acid, salicylic acid, alcohol Certain drugs can cause mild dermatitis when excreted through skin Generally not a major consideration therapeutically Routes of excretion- Hair Small amounts of drug may be excreted through in hair E.g. methamphetamine Generally not a major consideration therapeutically, has been used forensically. Routes of excretion- Saliva The pH of saliva varies from 5.8 to 8.4. Unionized lipid soluble drugs are excreted passively. Bitter after taste in the mouth of a patient may be an indication of drug excreted in saliva. Some basic drugs inhibit saliva secretion and are responsible for mouth dryness. Examples- Caffeine, Phenytoin, Theophylline. Typically only small amounts of drug are excreted in this fashion, little therapeutic significance. PHARMACOKINETICS- Elimination Kinetics First order kinetics- Rate of elimination is dependent upon the concentration of the drug - A constant FRACTION of the dose is eliminated in a given time period - Most drugs are eliminated in this way Zero order kinetics- Rate of elimination is independent of the concentration - A constant AMOUNT of the dose is eliminated in a given time period - E.G. Ethanol, Aspirin (at high doses) PHARMACOKINETICS- Elimination Kinetics PHARMACOKINETICS- Drug Clearance Clearance- A measure of the removal of drug from the body. Typically expressed as the volume of plasma from which all drug is removed in a given amount of time. i.e. ml/min or L/hr Knowledge of a drug’s clearance allows for prediction of rates of elimination. Drug Clearance- Sample Problems Biff Tannen is given a 1000 mg of GeorgeMcFly’sHaymaker. Biff has a blood volume of 1 L. After 1 hour 900 mg of the drug remains in Biff? What is the clearance? Clearance= amount of plasma cleared of all drug/ unit time. 100 mg of drug was removed in 1 hour. Drug concentration 1000 mg/L 100 mg/hr / 1000 mg/L= 0.1 L/hr or 100 ml/hr Bonus: If Biff’s clearance rate remains the same (i.e. first order kinetics) how much drug will be left after 2 hours? New plasma concentration- 900 mg/L 0.1 L/hr* 900 mg/L= 90 mg removed in 1 hour (i.e. the second hour) 900- 90= 810 mg remaining after 2 hours Bonus Bonus: If GeorgeMcFly’sHaymaker was eliminated via zero order kinetics, then how much drug will be left at 2 hours? Zero order kinetics- consistent amount of drug is removed. Amount of drug removed will be the same as the first hour (100 mg) Therefore 800 mg remaining after 2 hours. Other measures of drug elimination  Drug Half-Life o Time required for the amount of drug in the body to decline by 50%. o Drugs with a short half-life must be administered more frequently than drugs with a long half-life o When drug administration is discontinued, most of the drug will be eliminated over five half-lives For first order kinetics, the half life will be the same for any two points on a drug elimination curve. For zero order kinetics, the half life will NOT be the same for two points on a drug elimination curve TIME COURSE OF DRUG RESPONSES  Plasma Drug Levels Q. What would a graph for an IV drug look like? o Minimum effective concentration (MEC): plasma drug level below which therapeutic effects will not occur o Therapeutic range of a drug lies between the MEC and the toxic concentration Drugs with a wide therapeutic range are relatively easy to use safely. Drugs with a narrow therapeutic range (i.e. digoxin) require careful monitoring. Repeated dosing and drug accumulation Drugs often need repeated doses (chronic administration) Results in drug accumulation Plateau- When amount of drug eliminated (metabolized/excreted) equals the amount administered. o For a consistent dose/interval (and first order elimination kinetics) this will be ~five half lives. Loading dose: Large initial dose used to achieve immediate therapeutic effect when time to plateau is too long Maintenance dose: Smaller dose given after loading dose to maintain drug concentration in the therapeutic range (equivalent to amount of drug lost since last administration). Sample Problems- Loading doses Diane Court is sick. She needs a dose of “InYourEyes”. She needs to rapidly achieve a plasma concentration of 7.5 ug/L. Given a weight of 80 kg, an apparent volume of distribution of 0.5 L/kg, a clearance of 0.04 L/hr, calculate the loading dose required. Loading dose= plasma concentration X volume of distribution Loading dose= 7.5 ug/L X [0.5 L/kg X 80 kg] Loading dose= 300 ug Sample Problems- Maintenance dose The initial dose of “InYourEyes” worked for Diane. But in order to ensure that her plasma levels remain within the therapeutic range she will require a maintenance dose. Given a weight of 80 kg, a volume of distribution of 0.5 L/kg, a clearance of 0.04 L/hr, calculate the maintenance dose required to sustain a plasma concentration of 7.5 ug/L. Maintenance dose- Must match the amount cleared in a given period of time. Clearance= 0.04 L/hr x 7.5 ug/L= 0.3 ug/hr Maintenance dose= 0.3 ug/hr PHARMACODYNAMICS - - The study of the biochemical and physiologic effects of drugs and the molecular mechanisms by which those effects are produced The study of what drugs do to the body and how they do it Dose-Response Relationship o Relationship between dosage and intensity of the response produced o Determines: Minimum amount of drug to produce a response Maximum response How much to increase dosage to produce desired increase in response Dose-response curves Generally plotted as Response vs log[dose] Two characteristic properties of drugs are revealed in doseresponse curves: Maximal efficacy The largest effect that a drug can produce Relative potency The amount of drug that must be given to elicit an effect Implies nothing about maximal efficacy; refers to dosage needed to produce effects 42 Drug targets Most drugs produce their effects by interacting with protein targets (exceptions: antacids, osmotic diurectics [i.e. mannitol], or nucleic acid targeting drugs [i.e. cyclophosphamide]) The most commonly targeted proteins are receptors (proteins that recognize an extracellular signal, enabling the cell to react to changes in its environment). – Drugs may also target enzymes, structural proteins, membrane transporters phospholipids etc… These may be considered “drug receptors”, but the term receptor is typically reserved for cell surface or intracellular regulatory proteins within the major superfamilies of receptors (i.e. GPCRs, ion channels, hormone receptors, kinase-linked receptors). Ligand: a substance that forms a complex with a biomolecule (generally a drug receptor) to achieve a biological effect. The general formula for ligand-receptor interactions is as follows (where L = ligand [drug] and R = receptor): L + R ⇌ L-R COMPLEX → RESPONSE Four Primary Receptor Families Cell membrane–embedded enzymes/kinase receptors (1) Ligand-gated ion channels (2) G protein–coupled receptor systems (3) Transcription factors (4) More on this from Dr. Pratt Drug-receptor binding The first step in the reaction of a biological system to a drug occurs when the drug binds to its receptor. Receptor responses tend to be observed over a wide range of drug concentrations Affinity: a measure of how tightly a drug binds to its receptor If a drug does not bind tightly, then the action of the drug will be shorter and the chance of binding will also be less. Typically expressed through the equilibrium dissociation constant (KD). KD: the concentration of drug required for 50% of the receptor binding sites to be occupied It is also the concentration at which ligand dissociation from the receptor is equal to ligand association with the receptor. KD KD Affinity is just one determinant of drug effect Efficacy- a measure of the action of a drug once binding has occurred (pharmacology). Determines maximal response to a drug. Measures of what a drug does to the body: EFFICACY vs POTENCY Efficacy: largest effect drug can produce Potency: amount of drug needed to produce a given effect  Meperidine has greater efficacy than pentazocine: more pain relief  Morphine is more potent than meperidine: effect achieved at lower dose o For moderate pain relief (below green line), meperidine also has greater potency than pentazocine: lower dose  same pain relief  Potency of a drug implies nothing about its maximal efficacy! o Drug’s potency much less clinically relevant than its efficacy. Why? Increasing dose can often overcome lower potency Types of Receptor Interactions  When a drug binds to a receptor, it can act in several manners: o Agonists mimic action of endogenous regulatory molecules eg Norethindrone, in oral contraceptives, acts by “turning on” receptors for progesterone o Antagonists block receptor action eg Antihistamines suppress allergy symptoms by binding to receptors for histamine, released by the body in response to allergens o Partial agonists produce a submaximal response o Can mimic agonist effects but also appear to antagonize the effect of full agonists eg buprenorphine is a partial agonist of opioid receptors (predominantly u-opioid receptor) Can be used to treat pain, but also antagonizes effects of full opioid agonists Types of Receptor Interactions o Inverse agonists bind to a receptor and induces the opposite effect as an agonist. o Allosteric modulators: Indirectly influence the effects of an agonist or inverse agonist at its receptor protein target. Allosteric modulators bind to a site distinct from that of the orthosteric binding site where a receptor agonist would normally bind. Usually they induce a conformational change within the protein structure. o Biased agonists: When receptor binding leads to multiple, distinct responses (i.e. g-protein coupled receptors), biased agonists preferentially activate one of those pathways. Types of Receptor Interactions Biased agonism (TRV067) Trends in Pharmacological Sciences 2014 35, 308-316DOI: (10.1016/j.tips.2014.04.007) Copyright © 2014 Elsevier Ltd Terms and Conditions Antagonism: Antagonism can be competitive or non-competitive. Noncompetitive antagonists Bind irreversibly to receptors Reduce the maximal response that an agonist can elicit (fewer available receptors) Impact not permanent (cells are constantly breaking down “old” receptors and synthesizing new ones) but it is long-lasting Competitive antagonists Compete with agonists for receptor binding Bind reversibly to receptors If the drugs have equal affinity then the receptor will be occupied by whichever agent is present in the highest concentration RECEPTOR REGULATION   Receptors can undergo dynamic changes with respect to their density (number per cell) and their affinity for drugs and other ligands Continuous/repeated exposure to agonists can desensitize receptors, particularly in the case of G protein-coupled receptors. o Reduces the G protein–coupling efficiency/alters binding affinity o Short-term effect is called desensitization (tachyphylaxis) and is due to phosphorylation Phosphorylation also signals cell to internalize membrane receptor Through internalization and regulation of receptor gene expression, number of receptors decreases o This longer-term adaptation is called down-regulation    Continuous/repeated exposure to antagonists initially can increase response of the receptor. o This is called supersensitivity o Chronic exposure to antagonists can increase the number of receptors via upregulation DRUG TOLERANCE  When same dose of drug given repeatedly loses its effect  Or when greater doses needed to achieve a previously obtained effect  Pharmacodynamic tolerance: due to receptor down-regulation o Describes adaptations to chronic drug exposure at the tissue and receptor level  Pharmacokinetic tolerance: due to accelerated drug elimination o Usually from up-regulation of enzymes that metabolize drug DISEASES AFFECTING RECEPTORS  Response to drugs also affected by disease states that alter number and function of receptors o Eg myasthenia gravis, autoimmune disorder in which antibodies destroy nicotinic receptors in skeletal muscle, leads to impaired neurotransmission and muscle weakness Drug efficacy vs safety There is considerable variation in drug response amongst the population.  ED50: The dose that is required to produce a defined therapeutic response in 50% of the population o Considered a “standard” or “average” dose and is frequently the dose selected for initial treatment  LD50: Typically determined using laboratory animals, it is the average lethal dose, ie dose that kills 50% of the animals given that dosage. DEFINITION: THERAPEUTIC INDEX OF A DRUG  Therapeutic Index: Measure of a drug’s safety.  Ratio: LD50 / ED50  Large: drug relatively safe / Small: drug relatively unsafe o Drug “X”: average lethal dose >> average therapeutic dose – safe o Drug “Y”: average lethal ~= 2 X average therapeutic dose – unsafe Sample Question Egon Spengler Low Dose 100 Egon Spengler Med Dose % Binding 80 60 Egon Spengler High Dose The figure to the left depicts the binding of an experimental drug named “Zuul” in the absence (red tracing) and presence (blue, green, purple) of another drug “Egon Spengler”. Based on the information presented what can we conclude about Egon Spengler? 40 20 0 1 -0 00 01 02 03 04 05 06 07 0 10 10 10 10 10 10 10 10 × 1. 0×. 0×. 0×. 0×. 0×. 0×. 0×. 0× 0 1 1 1 1 1 1 1 1 1. D A. B. C. D. E. The drug is a competitive antagonist The drug is a partial agonist The drug is an inverse agonist The drug is a non-competitive antagonist “Dogs and Cats Living Together, Mass Hysteria” No conclusions can be drawn about the efficacy of the drug from binding curves (B or C). Since the maximal binding is reduced (green and purple curves) the drug cannot be a competitive antagonist (which only shifts the curves rightward). Sample Question InigoMontoya Low Dose 100 InigoMontoya Med Dose % Max Response 80 60 The figure to the left depicts the response of a tissue to an experimental drug named “Westley” in the presence and absence of another drug “Inigo Montoya”. Based on the information presented what can we conclude about Inigo Montoya? InigoMontoya High Dose 40 20 InigoMontoya Alone 0 1 -0 00 01 02 03 04 05 06 07 0 10 10 10 10 10 10 10 10 × 1. 0×. 0×. 0×. 0×. 0×. 0×. 0×. 0× 0 1 1 1 1 1 1 1 1 1. A. B. C. D. E. The drug is a competitive antagonist The drug is a partial agonist The drug is an inverse agonist The drug is a full agonist Inigo is now the Dread Pirate Roberts B When administered alongside Westley, Inigo Montoya appears to act as an antagonist (or possibly an inverse agonist). It could not be a full agonist (with lower potency) since it reduces the maximum response (purple). The curve of Inigo Montoya alone (black) shows a small induction of response suggesting it is a partial agonist. E is probably true but not relevant to the question Thank you for your attention! Questions? [email protected] RGN 2513