Resources – OPTIONAL textbooks PCTH 325 Pharmacodynamics Dr. Shabbits jennifer.shabbits@ubc.ca September 10, 2013 or any introductory pharmacology textbook Resources – course website Important points from last class http://apt.ubc.ca/pharmacology/documents-downloads/ 1. The pharmacological effect of most drugs occurs as a result of drug-receptor binding 2. Drugs can be endogenous or exogenous molecules that bind to receptors via chemical interactions 3. Drugs can produce both desirable and undesirable effects, both of which must be carefully considered 4. The vast number of receptors in the body can be grouped into 4 main classes based on structure and function 5. Drugs can be categorized as agonists (affinity & intrinsic activity) or antagonists (affinity only) 1
Learning objectives Drug-receptor binding is key to the effect 1. Describe and interpret graded and quantal dose-response WHAT is the response? curves the NATURE of the drug 2. List the common routes of administration, including considerations for use • agonists & antagonists 3. Describe the process of drug absorption and how this is affected by pH HOW BIG is the response? 4. Describe how drugs distribute in the body and the effect of protein binding the AMOUNT of drug at 5. Define V d and describe what it can and can’t tell you about the receptors → DOSE a drug’s properties & distributional characteristics 6. Describe how drugs are metabolized and the significance Dose-response relationships of induction and inhibition can be quantified 7. Name the primary route of drug excretion Graded dose-response curves Generating a graded dose-response curve 1. Give increasing doses of drug to patient experiencing pain A graded dose-response curve relates the dose of drug (amount or concentration) to the degree of pharmacological 2. Measure response (% pain reduction) response (effect) in a specific individual *often see “log” dose 3. Plot dose vs response x-axis y-axis 100 Dose (mg) % Response % Reduction in Pain Degree of Effect 0 0 75 250 25 50 500 60 750 90 25 1000 100 0 Drug Dose 0 1000 Drug Dose (mg) 2
Drugs are characterized by efficacy & potency Determining E max and ED 50 from the graph Efficacy: • The maximal response produced by a drug E max 100 ~90% What is the E max ? How measured? → E max % Pain Relief 75 “maximal effect” What is the ED 50 of this drug? 50 x-axis intercept for 50% maximal Potency: 25 response = ~100 mg • The concentration or dose needed to achieve a (you must include units!) predetermined effect (usually 50% of max) in an individual ED 50 0 0 100 200 300 How measured? → EC 50 or ED 50 Drug Dose (mg) “effective concentration or dose” Using potency & efficacy to compare drugs Limitations of graded dose response curves Drugs A, B, C & D are being marketed as pain relievers. Problems: What conclusions can you make about them? • Data collected for one individual only – does not take into account inter-individuality C • Can’t be used for “all or none” responses Degree of Pain Relief A D B Solution: Quantal dose response curves analyze drug efficacy in a large population • record the number of individuals who meet a particular criteria Drug Dose 3
Quantal dose response curves Quantal dose response curves The frequency distribution of most drugs follows a The plot of cumulative responses gives us a quantal dose normal (Gaussian) distribution pattern response curve ~ analyze like a graded dose-response curve Seizure-free patients at 5 years Seizure-free patients at 5 years % Individuals Responding Number Responding Drug Dose Drug Dose Cumulative frequency distribution Analyzing quantal dose response curves Assessing the SAFETY & EFFICACY of drugs E max : dose at which all patients respond % Individuals Responding 100 ‘steep’ slope ‘shallow’ slope 50 (more population variability) 0 Drug Dose ED 50 : dose that produces a response in 50% of the population 4
The therapeutic index (TI) A quick summary and some questions • the ratio of toxic to What we know: TD 50 /ED 50 = 400mg/100mg = 4 effective drug dose or concentration • drugs are agonists or antagonists Seizure Coma prevention • they bind receptors to produce (or prevent) a response • the larger the • we can measure dose-response relationships therapeutic window the safer the drug What we still need to learn: “large margin of safety” • how does drug get into the body? Pharmacokinetics • how does it know where to go? • how does it get out? Pharmacokinetics – the ADME processes Routes of administration Enteral: ‘GI tract’ a) oral (po) Absorption: gets drug into the body convenient & b) sublingual (sl) inexpensive Distribution: where it goes Parenteral: ‘other than GI tract’ Metabolism: what happens to it a) intravenous (iv) b) intramuscular (im) Excretion: how it gets out rapid onset, good if patient Transdermal unconscious or drug is poorly absorbed or unstable in gut Inhalational Topical 5
Absorption Effect of pH on drug absorption movement of drug from site of administration B + H + BH + HA H + + A - into the blood How? Passive diffusion (>95% of drugs) Weak acid Weak base Depends on: • Size • Lipid solubility – structure, ionization, pH, pKa • Blood flow at site of administration • Total surface area for absorption Predicting absorption Practice calculation 1 ~ Thought Question ~ A pain relief drug (pKa=1.8) is taken in the hopes of relieving a headache. How much of it will diffuse If we know how much drug is given, how across the gastric mucosal barrier and into the can we predict how much of it will be blood when taken orally? absorbed? Henderson–Hasselbalch equation: U pH = pKa + log [unprotonated form] [protonated form] P 6
Practice calculation 2 How does the drug know where to go? Suppose the person taking this drug finds that it It doesn’t. upsets her stomach. She decides to fix this by taking an antacid at the same time. Her drug circulates throughout body stomach is no longer upset but her headache in the blood won’t go away. Why? encounters receptors for which (assume the antacid raises the stomach pH by 2 it has affinity pH units) binds pharmacological response Distribution Distribution depends on: the process by which drug reversibly leaves 1. Blood Flow: highly perfused tissues get drug 1 st the bloodstream & in largest amount (brain, heart, liver, kidney) • drug moves between body compartments • drug reaches the site of action Distribution Absorption FREE DRUG Excretion 2. Lipid Solubility: only unionized drug can diffuse across membranes Metabolism 7
Distribution depends on: Effect of protein binding Non-protein bound drug Protein bound drug 3. Protein Binding • drugs reversibly bind proteins in the blood (collectively called plasma proteins ex: albumin) • proteins are too large to leave bloodstream protein-bound drug can’t reach target receptors Only free drug is pharmacologically active Volume of distribution (V d ) Volume of distribution (V d ) Drug administration: amount (dose) of drug (mg, g) There are several Drug analysis: concentration of drug (mg/L, g/mL) physiological fluid compartments into which we need to know the volume V d drugs can distribute Concentration = dose Total Body Water (TBW) V d • assume a 70 kg ‘man’ • body is 60% water • density of water = 1 kg/L Which volume do we use? 70kg x 1L/kg x 0.6 = 42 L 8
V d ~ a clinical example A clinical example ~ solution A 30mg dose of the antidepressant Nortriptyline ** ALWAYS check your units! is administered to a patient iv. When a sample 30mg = 30,000 g = 30x10 3 g of blood is drawn for analysis a plasma concentration of 25 g/L is obtained. Conc = dose V d = dose = 30x10 3 g = 1200L conc 25 g/L V d What is the volume of distribution of this drug? What does this mean? What is volume of distribution? What V d tells you (& what it doesn’t) NOT a real, physiological volume The magnitude of V d indicates the extent of drug distribution in the body, but not the location IS a proportionality constant that relates the amount of drug in the body to its concentration in the blood Large V d : drug distributes outside blood and body fluids into tissues Small V d : drug has limited distribution, typically What does a large V d like 1200L tell you restricted to blood or physiological fluids about the physicochemical properties of Nortriptyline? Blood/plasma Organs/tissues distributes outside actual fluids distributes to tissues/membranes Small V d Large V d must be a lipophilic drug 9
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