Pharmacology Review: Basic Principles. Presented by: A Nelson Avery, MD

Transcription

1 Pharmacology Review: Basic Principles Presented by: A Nelson Avery, MD Board Certified in Toxicology, Preventive Medicine and Internal Medicine Clinical Professor and Director Preventive Medicine Residency Program navery@medicine.tamhsc.edu

2 Chirality A drug molecule must have the proper shape to permit binding to its receptor site. Chirality (stereoisomerism) exists for over half of all drugs;; they are enantiomeric pairs. In the majority of cases, one of these enantiomers will be more potent. Ex: potency of (S)(+) methacholine 250x greater than (R)(-) A. Nelson Avery, MD 2

3 Permeation Permeation is the movement into and within the biological environment, through various barriers: Aqueous diffusion: passive flow between blood and extravascular space;; direct relationship to electrostatic charge (ionization, polarity) of the molecule;; governed by Fick s law: Drug absorption is faster from organs with large surface areas (small intestine > stomach) Absorption faster through thin membranes (lung > stomach) Lipid diffusion, special transport, endocytosis next slide A. Nelson Avery, MD 3

4 Permeation Lipid diffusion: passive movement of molecules thru membranes and other lipid structures;; lipid solubility is inversely related to charge;; governed by Fick s law, the lipid:aqueous partition coefficient, & ph Transport by special carriers: capacity limited and not governed by Fick s law ex: P-glycoprotein, MDR1 transporter Endocytosis: permits very large or lipidinsoluble chemicals to enter cell A. Nelson Avery, MD 4

5 Henderson- Hasselbalch Equation ph of medium governs fraction of molecules charged (ionized) vs. uncharged (non-ionized) Henderson-Hasselbalch equation: Log ( protonated form ) = pka - ph (unprotonated form) Ex: if pka-ph = log of 1 (10 1 ) = ratio of protonated to unprotonated of 10:1 (= ~90% protonated) = log of 2 (10 +2 ) = ratio of 100:1 (= ~99% protonated) = log of 1 (10 1 ) = ratio of 1:10 (= ~10% protonated) = log of 2 (10 2 ) = ratio of 1:100 (= ~ 1% protonated) Note: quaternary amines are permanently charged and cannot undergo reversible protonation, so are always poorly lipid soluble. A. Nelson Avery, MD 5

6 Water and Lipid Solubility of Drugs Weak bases are ionized when protonated à more polar and water soluble. Get trapped in acidic media (become more protonated) neutral base + proton + cation + RNH 2 + H + RNH + 3 (lipid soluble) (trapped) Weak acids are not ionized when protonated à so are less water soluble, more lipid soluble. Get trapped in alkaline media (become less protonated) anion + proton + neutral acid RCOO + H + RCOOH (trapped) (lipid soluble) Protonated form A. Nelson Avery, MD 6

7 Water and Lipid Solubility of Drugs Weak Base Weak Acid more protonated if ê ph more charged, more water soluble more uncharged, more lipid soluble less protonated if é ph more uncharged, more lipid soluble more charged, more water soluble A. Nelson Avery, MD 7

8 Ion Trapping of Drugs Ex: Stomach: aspirin is a weak acid;; so in stomach with very low ph it is more protonated à less charged, more lipid soluble à can absorb from stomach à then in higher ph of blood does not diffuse back Ex: Kidney: overdose of aspirin can be more quickly eliminated by alkalinizing urine à less protonated, more water soluble à decreased reabsorption from urine A. Nelson Avery, MD 8

9 Example of Ion Trapping: Gastric Absorption of an Acidic Drug Acid drug pk a =4.4 Stomach ph=2.4 Blood ph=7.4 1 RCOOH RCOOH RCOO - RCOO H + + H + Total drug conc.: 1.01 Total conc.: 1001 A. Nelson Avery, MD 9

10 Pharmacokinetics Refers to what the body does to the drug. It is the study of changes in a drug or its metabolites in the body from the time it enters the body until it is fully eliminated. It is a mathematical description of change in body drug concentration, related to processes of drug: absorption (including bioavailability), distribution (body storage, protein binding), elimination with metabolism (biotransformation to metabolites), & excretion (into urine and bile) A. Nelson Avery, MD 10

11 Absorption Absorption is the extent and rate of a substance movement from outside the body to the intravascular compartment (central compartment). Ideally, for absorption to occur, a drug must be in solution, lipophilic, and in a nonionized (non-polarized) state. Other factors: concentration, blood flow, absorbing area, contact time, ph (weak acids pass thru membranes best in acidic environments;; e.g., aspirin in stomach). A. Nelson Avery, MD 11

12 Bioavailability Bioavailability is the measure of amount of drug entering systemic circulation divided by the total dose. IV drugs are 100% bioavailable (= 1). For oral drugs, bioavailability = fraction appearing in the portal circulation times the fraction remaining after any first-pass elimination (bioavailability is <1). Examples of drugs with high first pass elimination: propranolol (so have to give in high oral dose compared to IV) lidocaine (given IV) nitroglycerin (given IV or SL) A. Nelson Avery, MD 12

13 Area Under the Plasma Concentration Curve (AUC) Represents amount of drug that enters the systemic circulation during distribution phase;; it is serum concentration plotted against time. An indicator of total drug absorption and reflects bioavailability. More appropriate than peak serum levels, which are dependent on the rate of absorption. A. Nelson Avery, MD 13

14 Area Under the Curve In this example, the value of AUC is the same regardless of the rate of absorption. 10 Blood level 5 AUC = (red) or (blue) Time j A. Nelson Avery, MD 14

15 Distribution Phase The distribution phase (alpha phase) is the time required to distribute to peripheral/ tissue compartments and equilibrate;; usually lasts ~ 30 mins. to 2 hrs. During alpha phase, concentrations in the plasma ê more rapidly than during 2 nd phase (elimination/ beta phase). Drugs initially distribute to high blood flow areas (heart, liver, kidney and brain), then to slower blood flow areas (muscle, bone, middle ear, skin, and fat). α β A. Nelson Avery, MD 15

16 Plasma Protein Binding Medications are transported by protein molecules in the plasma to the site of action. Albumin binds acidic substances Can decrease with severe liver disease and protein losing syndromes (ex: nephrotic syndrome) α1- acid glycoprotein binds basic substances Can increase 3-4 fold as acute phase reactant (acute MI, arthritis, cancer);; decreased levels with severe liver disease and protein losing syndromes A. Nelson Avery, MD 16

17 Plasma Protein Binding Any unattached drug is termed free drug. Only the free, non-protein bound substances are able to diffuse through cell membranes and equilibrate with receptor sites in tissues resulting in pharmacologic and/ or toxicologic effects. In general, substances that are extensively plasma protein-bound tend to have a small volume of distribution (V d ), whereas drugs or toxins with a high affinity for peripheral tissues have larger V d. A. Nelson Avery, MD 17

18 CNS and Cerebrospinal Fluid Brain capillary endothelial cells have continuous tight junctions. The more lipophilic a drug is the more likely it is to cross the blood-brain barrier. There are specific uptake transporters and efflux carriers (P-glycoprotein). Meningeal and encephalic inflammation increase local permeability. A. Nelson Avery, MD 18

19 Volume of Distribution (V d ) V d (L/kg) = amount of drug in body (in mg). plasma drug concentration (mg/l x kg body wt.) This is a theoretical volume into which a substance distributes in the body at equilibrium. It is the volume that would be required to dissolve total drug at same concentration as found in blood. It is not a real volume. A. Nelson Avery, MD 19

20 Volume of Distribution (V d ) Highly water-soluble (hydrophilic) drugs possess small volumes of distribution (V d ) and have high blood concentration levels. Highly fat-soluble (lipophilic substances penetrate most membrane barriers, including both fenestrated and closed capillaries (can quickly cross the blood brain barrier), and therefore have a large V d and have low blood concentration level. A. Nelson Avery, MD 20

21 Volume of Distribution (V d ) V d <1 L/ kg suggests the drug is not distributed beyond vascular compartment (can be removed by dialysis) (ex: aspirin, ethanol, theophylline) V d >1 L/ kg indicates that the drug distributes outside the plasma compartment into other tissues or fluids (so cannot remove significant amount by dialysis) (ex: digoxin) V d ~42 L/ kg indicates drug distributed throughout total body water (small lipophilic drugs binding to extravascular tissues in body) (ex: amitriptyline) A. Nelson Avery, MD 21

22 Volume of Distribution (V d ) Basic drugs are quickly taken up by tissues and fat have a large V d Acidic drugs are not taken up by fat usually small V d In summary, drugs that are fat-soluble and basic will have the largest V d, and drugs that are highly water-soluble and acidic will have the lowest V d. A. Nelson Avery, MD 22

23 Compartment Models One compartment model: Used for drugs that are usually highly water soluble, rapidly distribute throughout the body, and have small volumes of distribution (not distributed beyond the vascular compartment). Predominantly renal elimination A. Nelson Avery, MD 23

24 Compartment Models Two compartment model: Used for drugs that are usually fat soluble, have a slower distribution in the body, have larger volumes of distribution. They have a central compartment and a peripheral compartment (central = blood volume, heart, brain, kidneys, liver;; peripheral (or tissue compartments) = poorer perfused areas). Elimination requires liver metabolism A. Nelson Avery, MD 24

25 Elimination Elimination = metabolism (usually liver) + excretion (usually renal, bile) Metabolism of a drug sometimes terminates its action, but its metabolites may be active (or toxic). (ex: benzodiazepines, TCAs, acetaminophen) First-pass metabolism: ingested drugs can be metabolized in the gut wall or liver before reaching the systemic circulation. Prodrugs are inactive and must be metabolized. (ex: levodopa) A. Nelson Avery, MD 25

26 Phase I Liver Biotransformation: Cytochromes Convert lipophilic chemicals à hydrophilic (more polar, more water soluble) by oxidation, reduction, deamination, and hydrolysis. These unmask or insert a polar function group such as OH, SH, NH 2. Oxidative reactions can occur in the mixed function oxidase system mediated by cytochrome P450 located in the smooth endoplasmic reticulum (= microsomal enzymes). Most common for drug metabolism is P450-3A4. A. Nelson Avery, MD 26

27 Drug Interactions Inducers of P450: (note: 3 common anticonvulsants and a TB drug) phenobarbital phenytoin carbamazepine rifampin also chronic alcohol abuse and polycyclic hydrocarbons (PAHs, cigarette smoke) à Faster drug metabolism à ê drug effect [think of an cigarette smoking alcoholic with a seizure disorder & TB] A. Nelson Avery, MD 27

28 Drug Interactions Inhibitors of P450: cimetidine -azole antifungals macrolides (erythromycin, clarithromycin) fluoroquinolones (ciprofloxacin) metronidazole ritonavir (HIV drug) and many other medications furanocoumarins in grapefruit juice (also inhibit intestinal P-glycoprotein) acute alcohol abuse à Slower drug metabolism à é drug effect A. Nelson Avery, MD 28

29 Phase I Liver Biotransformation: NAD, NADP dehydrogenases Reactions can also occur in hepatic parenchymal cells, independent of P450. Some of these are in the soluble fraction of the cytoplasm = cytosolic enzymes. (ex: ethanol dehydrogenase) A. Nelson Avery, MD 29

30 Phase II Liver Biotransformation Conjugation reactions to é polarity and water solubility and inactivate drug à é kidney and bile elimination Common conjugations include: glucuronic acid, acetate (= acetylation), glutathione, glycine, sulfate, methyl groups A. Nelson Avery, MD 30

31 Toxic Metabolism Some chemicals are metabolized to more toxic substances. Ex: Acetaminophen is predominantly conjugated as the glucuronide or sulfate. P450 converts some acetaminophen to a toxic product N-acetyl-p-benzoquinone-imine (NAPQI) which is detoxified by glutathione (GSH). In an overdose, GSH levels fall to <30% normal, and high levels of NAPQI à liver necrosis;; treatment is N-acetylcysteine A. Nelson Avery, MD 31

32 Summary Slide Absorb à Distrib. à Metab. à Elim. Water soluble cmpd. Gut Lipid soluble cmpd. Small V d, <1L/ kg Large V d, >1L/ kg Liver é P-450: Rifampin + the anticonvulsants phenytoin, phenobarbital, and carbamazepine ê P-450: Cimetidine, -azole antifungals, erythromycin, etc. Kidney Bile A. Nelson Avery, MD 32

33 First Order Elimination Decline in drug levels equal to a constant percentage of the remaining amount of drug or toxin in the plasma per unit of time (the t ½ is independent of the dose). Rate of elimination (= quantity of drug or toxin removed per unit of time) is proportional to drug concentration. Accounts for most drug metabolism. A. Nelson Avery, MD 33

34 First Order Elimination The plasma concentration decreases exponentially with time (= log linear plot) Drug concentration time v x First- Order Drug concentration 10 1 time v A. Nelson Avery, MD 34

35 Zero Order Elimination Rate of elimination (quantity of drug or toxin removed per unit of time) is constant and is independent of concentration, but the t ½ is dose dependent. Ethanol is classic example (decrease blood alcohol level by ~one drink, 25 mg/dl, per hour);; also toxic dose of aspirin or phenytoin Michaelis-Menten elimination is a mixture of first- and zero-order elimination. A. Nelson Avery, MD 35

36 First vs. Zero Order Elimination linear plot curvilinear log plot linear Log linear plot Firstorder Zeroorder linear curvilinear A. Nelson Avery, MD 36

37 Clearance Clearance measures body s ability to eliminate a substance from blood over time. It represents a theoretical volume of blood or plasma cleared. The 2 major sites of clearance are kidneys and liver. Add various organ clearances together (renal + hepatic + other) Clearance (CL) = rate of elimination plasma drug conc. (C) Rate of elimination = CL x C When clearance is first-order, it can be estimated by CL = dose/ AUC A. Nelson Avery, MD 37

38 Half- Life Half-life indicates the time required to attain 50% of steady state or to decay 50% from steady state conditions. Half-life is directly proportional to V d and inversely to total body clearance. t ½ = 0.7 x V d / CL therefore CL = 0.7 x V d / t ½ Q: if a drug has ½ life of 24 hrs and V d of 40 L, what is the total body clearance (CL)? CL = 0.7 x V d / t ½ (have to convert to ml per minute) = 0.7 x 40,000 ml / 1440 mins = 19.4 ml/min A. Nelson Avery, MD 38

39 Half- Life # half-lives concentration 50% 75% % ~100% Factors that é half-life: heart failure, hepatitis, ê P-450, renal disease, vasoconstriction of afferent arteriole in renal glomerulus Factors that ê half-life: é P-450, é GFR, vasoconstriction of efferent arteriole in glomerulus A. Nelson Avery, MD 39

40 Dosage Calculations Loading dose = target plasma conc. x Vd (L/kg x body kg wt.) bioavailability Q: What is loading dose to achieve 3.5 mg/l conc. when V d is 0.5 L/kg in 70 kg person? A: Dose = 3.5 mg/l x (0.5 x 70) = mg Maintenance dose = target plasma conc. x clearance / bioavailability Steady state conc. = rate of infusion / elimination rate x V d Q: Drug has ½ life of 10 hrs, how long will it take to reach 75% of its steady state conc. A: 2 half-lives = 20 hrs A. Nelson Avery, MD 40

41 Plateau Principle As drug enters, the rate of elimination increases. Eventually a level is reached at which elimination equilibrates to administration. The blood level stabilizes at that level;; called the plateau. 200 Drug concentration time plateau A. Nelson Avery, MD 41

42 Plateau: Continuous vs. Intermittent IV Dosing What is happening with curves A, B, & C? A. Nelson Avery, MD 42

43 Ex: Continuous vs. Intermittent Dosing Curve A represents the kinetics of a steady state concentration when there is continuous infusion of drug at the rate of 2 units per day. After an exponential rise, the curve approaches steady state as the rate of infusion and the rate of elimination reach equilibrium. In curve B, the drug is administered twice daily as 1 unit. The fluctuations are less extreme, but the same end is achieved. Curve C: When the drug is given daily as a single 2 unit bolus, there is a sharp peak when the first dose is given, followed by exponential decay as the drug is eliminated. However it takes more than 1 day for all of the drug to be eliminated. Therefore, when the second bolus of 2 units is given on day 2, there is a second high peak followed by exponential decay. The amount of drug fluctuates widely about the steady state level. A. Nelson Avery, MD 43

44 Pharmacodynamics Refers to what a drug does to the body. It is the study of concentration response relationships at the level of the receptor site. Studies the biochemical and physiologic action and effects of drugs on target cells thought to work with a receptor at their site of action A. Nelson Avery, MD 44

45 Potency Potency = measure of dose required to produce a desired effect (relation between dose and intensity of effect). Ex: morphine vs. fentanyl takes less fentanyl to achieve pain relief it is more potent narcotic than morphine. A. Nelson Avery, MD 45

46 Potency (EC 50, ED 50 ) Usually chosen is 50% of maximal effective concentration (EC 50 ) or dose (ED 50 ) Related to the affinity of the receptor for the drug Measured by graded or quantal dose-response curves Clinical effectiveness of a drug depends on its maximal efficacy, not the potency. response more potent dose A. Nelson Avery, MD 46

47 Affinity (K d ) Affinity = propensity of a drug to bind to a given receptor 10 LDR Curve Conc. of drug to bind 50% of receptor sites = K d ;; the smaller K d, the greater the affinity One agonist may bind more strongly to the receptor than another agonist, but have the same maximum effect. The lower the required concentration, the greater the potency. Response 5 0 log Dose agonist agonist with lower affinity A. Nelson Avery, MD 47

48 Efficacy (E max ) Efficacy = maximum response obtainable by a drug treatment (ability to achieve full response, regardless of the concentration) A. Nelson Avery, MD 48

49 Efficacy (E max ) efficacy ê E max E max Measured by a graded doseresponse curve Partial agonists always have lower E max than full agonist In the presence of a full agonist, a partial agonist acts like a competitive inhibitor A. Nelson Avery, MD 49

50 Antagonists Physiologic antagonist: drug counters the effects of another by binding to a different receptor and causing opposing effects. Ex: corticosteroids à é glucose;; use insulin to ê glucose Chemical antagonist: drug counters the effects of another by binding the drug and preventing its action. Ex: use protamine to counter effects of heparin by binding to it A. Nelson Avery, MD 50

51 Pharmacologic Antagonist (Pharmacologic) antagonist = drug that binds to a receptor but does not activate it;; generally they inhibit agonists from binding to and activating the receptor;; it may be reversible or irreversible antagonists and agonists may compete A. Nelson Avery, MD 51

52 Irreversible (non- competitive) Antagonists Irreversible (non-competitive) antagonist: cannot be overcome by increasing the dose of agonist They cause a downward shift in the maximal effect (ê E max = ê efficacy). Ex: NorEpi + phenoxybenzamine on α-receptors. A. Nelson Avery, MD 52

53 Agonist + Non- Competitive Antagonist r e s p o n s e ê efficacy w/ non-competitive antagonist dose Agonist + non-competitive (irreversible) antagonist (B) à ê level of response;; usually by an irreversible acting drug, or a heavy metal. It shifts the curve downward (ê efficacy). A. Nelson Avery, MD 53

54 Agonist + Partial Agonist r e s p o n s e dose (ê efficacy;; +/- potency) Agonist + partial agonist (C) à ê efficacy and variable change in potency of the full agonist (acts like a competitive inhibitor if given with agonist) A. Nelson Avery, MD 54

55 Competitive (Reversible) Antagonist Competitive (reversible) antagonist: pharmacologic antagonist that can be overcome by increasing the dose of agonist Shifts the log dose-response curve to the right (é ED 50 = ê potency) But has the same maximal effect. Ex: diazepam + flumazenil on GABA receptor. A. Nelson Avery, MD 55

56 Agonist + Competitive Antagonist r e s p o n s e ê potency dose w/ competitive antagonist Agonist + competitive antagonist (D) à It competes with agonist for the same receptor. It shifts the curve to the right (ê potency) (requires higher dose for the same response), but does not alter the maximum response. [Ex: vitamin K is antagonist for coumadin/ warfarin] A. Nelson Avery, MD 56

57 Summary: Agonists + Antagonists r e s p o n s e dose A. Nelson Avery, MD 57

58 Summary: Agonists + Antagonists r e s p o n s e (ê efficacy) (ê efficacy;; +/- potency) dose (ê potency) A. Nelson Avery, MD 58

59 Therapeutic Index / Window Therapeutic index = ratio of toxic to clinical dose (ratio of TD 50 (or LD 50 ) to the ED 50 ) High index (safe in high doses): penicillin Low index (dangerous in high doses): warfarin, anti-cancer drugs, digoxin Represents an estimate of the safety of a drug. The therapeutic window = dosage range between the minimal effective therapeutic dose (desired trough) and the minimal toxic dose (permissible peak). A. Nelson Avery, MD 59

60 TI = LD ED Therapeutic Index Fraction of population Therapeutic effect Lethal effect Log dose ED 50 LD 50 A. Nelson Avery, MD 60

61 Receptors A. Nelson Avery, MD 61

62 Intracellular (Transcription Factor) Receptors No specialized transmembrane signaling device is required Have a characteristic lag period of 30 mins. to several hrs;; effects can last for hours or days Ex: steroid hormones à binding to specific DNA sequences near the gene (and releasing of hsp90) à stimulate the transcription of genes in the nucleus Ex: nitric oxide à stimulates intracellular guanylyl cyclase à cgmp A. Nelson Avery, MD 62

63 Receptors located on Membrane- Spanning Enzymes Combine with a receptor on the extracellular portion of the enzymes and modify their intracellular activity When activated, receptors dimerize and phosphorylate specific intracellular protein substrates Ex: insulin (tyrosine kinase), various growth factors, atrial natriuretic peptide (ANP) A. Nelson Avery, MD 63

64 Cytokine Receptors Have extracellular and intracellular domains and form dimers Peptide ligands (cytokine, growth hormone, erythropoietin, interferon) attach to cytokine receptors à activate separate tyrosine kinase molecules (Janus kinases, JAKs) à phosphorylation of STAT molecules à travel to nucleus to regulate transcription of specific genes A. Nelson Avery, MD 64

65 Receptors located on Membrane Ligand- Gated Ion Channels May directly cause the opening of an ion channel or modify the ion channel s response to other agents. The result is a change in transmembrane electrical potential. nicotinic acetylcholine [muscle] GABA A (gamma-aminobutyric acid) [CNS seizures] glutamate (NMDA, AMPA, kainate) 5HT 3 (serotonin) [gag reflex] Glycine [spinal seizures] Response time is very short (milliseconds). These receptors control muscle movements, CNS and spinal seizures, and gag reflex all need to instantly respond A. Nelson Avery, MD 65

66 G Protein Receptors G proteins use a molecular mechanism that involves binding and hydrolysis of GTP, allowing the transducer signal to be amplified and last longer. These receptors are part of a family of 7- transmembrane or serpentine receptors. adrenergic (α,β) muscarinic ACh GABA B glutamate (metabotropic) 5HT (all except 5HT 3 ) dopamine adenosine A. Nelson Avery, MD 66

67 G Protein Receptors G proteins = guanine nucleotide regulatory binding proteins Linked by coupling proteins to intracellular or membrane effectors Components: 1) extracellular ligand detected by cell-surface receptor, 2) receptor triggers activation of G protein on cytoplasmic side, 3) activated G protein changes the activity of an effector element (enzyme or ion channel) à changes the concentration of the intracellular 2 nd messenger (so have slower response). A. Nelson Avery, MD 67

68 Signaling Mechanisms Examples of coupling proteins: Gq, Gs, Gi Receptor type Coupling protein Effector Second messenger Result α1 M1 M3 H1 V1 β1,2 D1 H2 V2 α2 M2 D2 G q G s é phospholipase C é adenylyl cyclase é G i ê ê é IP3 é Ca ++ é DAG camp & protein kinase A é protein kinase C é Ca ++ influx and enzyme activity ê Ca ++ influx and enzyme activity A. Nelson Avery, MD 68

69 Receptors: Ion Channel vs. G Protein ion channel ACh Nicotinic GABA- A Glutamate AMPA, NMDA & kainate G protein ACh Muscarinic GABA- B Glutamate 8 metabotropic receptors Serotonin 5HT-3 5HT- 1, 2, 4-7 Glycine Adenosine Adrenergic (α and β) Dopamine A. Nelson Avery, MD 69

70 Study Questions 1. Definition of potency? [dose required for certain effect] Definition of efficacy? [maximum response obtainable by a drug treatment] 2. Which state, ionized or non-ionized, favors more rapid absorption? 3. Which state, polarized or non-polarized, favors more rapid absorption? 4. Which state, lipid soluble or lipid insoluble, favors more rapid absorption? 5. A highly water-soluble drug possesses a small or large volume of distribution? 6. Most acidic drugs bind to which serum protein? [albumin] 7. Most basic drugs bind to which serum protein? [alpha 1 glycoprotein] A. Nelson Avery, MD 70

71 Study Questions 8. Which type of drug, hydrophilic or hydrophobic, crosses the blood brain barrier more readily? 9. Name 4 drugs that classically induce P450 enzymes in the liver. [phenobarbital, phenytoin, carbamazepine, rifampin] 10. Name 4 drugs that classically decrease P450 enzymes in the liver. [cimetidine, erythromycin, quinolones, azoles] 11. Based on a log plot, which classic type of elimination is linear? [first order] 12. What kind of drugs have zero order metabolism: water soluble or fat soluble? 13. Liver conjugation reactions are usually phase I or phase II? 14. Liver P450 reactions are usually phase I or phase II? 15. How many half-lives would it take to eliminate 90% of a drug: 1, 2, 3, 4, 5, or 6? A. Nelson Avery, MD 71