Pharmacodynamics & Pharmacokinetics 1
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1 PCTH 325 Pharmacodynamics & Pharmacokinetics 1 Dr. Shabbits jennifer.shabbits@ubc.ca September 9, 2014
2 Learning objectives 1. Describe the categories of intended drug action 2. Compare and contrast agonists and antagonists 3. Draw and interpret dose-response curves and describe how they are used to assess drug safety 4. List the common routes of drug administration, including considerations for use 5. Describe the process of drug absorption and how this is affected by ph 6. Describe how drugs distribute in the body and the effect of protein binding 7. Define V d and describe what it can and can t tell you about a drug s properties & distributional characteristics
3 What binds to the receptors? Most receptors have naturally occurring (endogenous) molecules that bind to them Exogenous (foreign) molecules can be designed to bind to the same receptor rational drug design Example ~ Endorphins (endogenous) Morphine (exogenous) Bind opiate receptors in brain EUPHORIA
4 Categories of (intended) drug action 1. Replacement: drug replaces a physiological process insulin therapy for type 1 diabetes estrogen replacement therapy in menopause 2. Interruption: drug interferes with a physiological process antihypertensive (blood pressure) medications relax blood vessels to lower blood pressure 3. Potentiation: drug stimulates a physiological process diuretics promote urine output pitocin strengthens uterine contractions in labour
5 Drugs can be agonists AGONISTS have: 1. AFFINITY for the receptor (they bind to it) 2. INTRINSIC ACTIVITY (binding elicits a response) Agonists can be either 1. Endogenous (ex: adrenalin) 2. Exogenous (ex: dobutamine) Both rate Effect
6 Drugs can be antagonists ANTAGONISTS (aka receptor blockers or inhibitors) 1. have AFFINITY (bind the receptor) 2. LACK intrinsic activity (no response) No Effect
7 Antagonist example Claritin : an antagonist that blocks histamine receptors allergy treatment
8 Pharmacologic effects side effects A drug without side effects isn t really a drug Side Effects/Adverse Effects Mild, tolerable, subside on their own (ex: GI disturbances) Potentially lifethreatening & sustained (ex: seizures) Risks vs benefits must be carefully weighed Therapeutic Index
9 Side effect or not? A matter of perspective may cause drowsiness When taken for seasonal allergies Side Effect When taken as a sleep aid Therapeutic Effect
10 Side effects can lead to new drugs excessive hair growth side effect was noted Marketed in 1992 for the treatment of enlarged prostate DHT + DHT receptors in prostate prostate cell proliferation Marketed in 1998 for the treatment of male pattern baldness DHT + DHT receptors in hair follicle hair loss Testosterone DHT (~10x more potent)
11 The pharmacologic effect is related to dose Drug dose-response curves 5 mmhg decrease in diastolic BP hypotension (fainting) % individuals responding Median Effective Dose % individuals responding Median Toxic Dose log drug dose log drug dose
12 Therapeutic index: a measure of drug safety TI = TD 50 / ED 50
13 Therapeutic index: a measure of drug safety Narrow TI Drugs Digoxin Lithium Phenobarbital Vancomycin Warfarin
14 Routes of drug administration
15 Which route to use? 3 factors to consider 1. Drug characteristics size, water vs lipid solubility, charge, ph stability 2. Patient characteristics consciousness, ability to follow instructions, age, other medications 3. Therapeutic objectives urgency of situation, local vs systemic effects
16 Enteral drug administration (systemic effect) involves the gastro-intestinal (GI) tract oral (po) most common sublingual (sl) rectal (pr) Advantages: convenient, inexpensive, safe Disadvantages: 1 st -pass metabolism, ph stability, variable absorption
17 Parenteral drug administration (systemic effect) does not involve the GI tract (usually injections) intravenous (iv) subcutaneous (sc, subq) intramuscular (im) Advantages: immediate no absorption (iv), avoids stability concerns, unconscious OK Disadvantages: discomfort, potential for infection
18 Other routes Inhalational (systemic or local effect) metered dose inhalers, general anesthetics, nasal decongestants Topical (local effect) cream, ointment, drops Transdermal (systemic effect) patch
19 The drug is now in the body what next?
20 Part 3: Pharmacokinetics
21 Pharmacokinetics the ADME processes Absorption: gets drug into the blood Distribution: where it goes in the body Metabolism: what happens to it Excretion: how it gets out
22 Absorption The movement of drug from site of administration into the blood occurs by passive diffusion Influencing Factors: concentration gradient (hi low) Drug drug size (must be less than 1 kda) lipid solubility / ph Blood
23 Membrane permeability effect of lipid solubility Only uncharged, hydrophobic drugs can passively diffuse across lipid bilayers (membranes) D D + D
24 Membrane permeability effect of ph Most drugs are weak acids or weak bases exist in equilibrium between protonated & unprotonated, charged & uncharged species weak acid drug HA H + + A - weak base drug B + H + BH + ph of environment and pka of drug dictate which of the two forms predominates
25 Weak acid and weak base drugs Total weak acid drug = HA + A - = 100% 99% 50% 12% 1% 50% 88% Total weak base drug = BH + + B = 100% 99% 50% 12% 1% 50% 88%
26 Membrane permeability effect of ph Only the uncharged (unionized) species will cross the membrane (ie be absorbed) Weak acid Weak base
27 Predicting absorption/diffusion We can use the Henderson-Hasselbalch equation to predict the extent to which this will occur ph = pka + log unprotonated form protonated form
28 Practice calculation 1 Piroxicam is a weak acid (pka=1.8) that is used to relieve arthritic pain. How much of it will diffuse across the gastric mucosal barrier and into the blood (plasma) when taken orally?
29 Practice calculation 2 The first dose provides temporary pain relief but also causes stomach upset. The person decides to take a Tums with her next dose. After this her stomach is no longer upset, but now her pain won t go away. Why? (Tums raises the stomach ph by 2 units)
30 Bioavailability (fraction absorbed, F) the fraction of drug that reaches systemic circulation unchanged F = amount of drug in systemic circulation amount of drug administered What can you do to ensure a drug is 100% bioavailable (F=1)? non-iv dosage recommendations take fractional absorption into account useful for comparing routes of administration
31 Question When comparing the iv vs po routes of administration, which would require a larger dose of the same drug in order to achieve the same effect? Why?
32 How does the drug know where to go? drug circulates throughout body in the blood encounters receptors for which it has affinity binds pharmacological response
33 Distribution The process by which drug reversibly leaves the bloodstream drug moves between body compartments drug reaches the site of action (receptors) Influencing Factors: conc. gradient drug size lipid solubility / ph blood flow protein binding
34 Distribution effect of blood flow Drug is delivered to tissues in relation to perfusion
35 Distribution effect of protein binding Drugs reversibly bind plasma (blood) proteins (protein + drug drug-protein complex) weak acids bind serum albumin weak bases bind 1-acid glycoprotein Proteins are large sequester (trap) drug in blood drug can t distribute to target receptors protein bound drug is pharmacologically inactive Concentration of free drug in blood less pharmacologically active drug * Most drug dosing regimens take protein binding into account BUT there are situations where protein profiles are altered (pregnancy; disease) and dosing needs to be adjusted
36 Effect of protein binding Weakly protein bound drug Highly protein bound drug
37 Volume of distribution (Vd) Administration: Plasma analysis: dose or amount (mg, g) concentration (mg/l, g/ml) Concentration = dose Vd Which volume do we use?
38 Volume of distribution (Vd) There are several physiological fluid compartments into which hydrophilic drugs can distribute Total body water (TBW) = 70kg x 1L/kg x 0.6 = 42L hypothetical PK man density of water body ~60% water Examples: Heparin = 3L Plasma Gentamicin = 18L ECF Ethanol = 38L TBW
39 A clinical example A 30mg dose of the antidepressant Nortriptyline is administered to a patient iv and a plasma concentration of 25 g/l is subsequently measured. What is the volume of distribution of this drug?
40 A clinical example ~ solution ** ALWAYS check your units! 30mg = 30,000 g = 30x10 3 g Conc = dose V d = dose = 30x10 3 g = 1200L V d conc 25 g/l What does this mean?
41 What is volume of distribution? NOT a real, physiological volume but rather a proportionality constant that relates the amount of drug in the body to its concentration in the blood The magnitude of Vd indicates the extent of drug distribution in the body, but not the location Large Vd (>42 L): Small Vd ( 42 L): drug distributes outside blood and body fluids into tissues drug has limited distribution, typically restricted to blood or physiological fluids
42
43 Things to do 1. Review learning objectives 2. Check for welcome messages update with SIS if necessary 3. Make sure you completed Lecture 1 readings, concept map overview and course policies 4. Bring a scientific calculator to next class
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