2General Principles Chapter 1. Introduction About Pharmacology Chapter 2. PharmacokineticsWhat the body does to a drugChapter 3. PharmacodynamicsWhat a drug does to the bodyChapter 4. Factor affecting drug efficacyHow to use a drug rationally
6What is drugA chemical substance that can modulate the current physiological status quo of a biological system.A chemical which is utilized for the diagnosis, prevention and cure of an unwanted health condition (definition by FDA)
7Source of drugs Ancient Natural products Modern PlantsAnimalsMineralsModernActive principles of natural productsArtificial syntheticsFull syntheticSemi syntheticBiological engineering
8From natural product to active principles Raw opiumOpium tincturePoppyMorphineCodeine…
9From natural product to active principles foxglove digoxin deadly nightshade atropine
10Missions of pharmacology Explore the pharmacokinetic and pharmacodynamic features of drugsProbe the mystery of life processFind and develop new drugs
11Process of Drug Development The Long Road to a New MedicinesynthesisScreenPhase II Clinical trialPhase III clinical trialPhase I clinical trialAnimal PK/PD/ToxDosage formCandidate chemicalsDesignApplicationMarketing25) Idea-to-new medicine road - Full Development phaseIn this Full Development stage, known as Phase lll, several thousand patients with the particular disease receive the drug in carefully controlled studies to test its safety, tolerability, and efficacy. Finally, if the compound has proved its worth in all these tests, it enters the Registration phase in which the data of its entire history are compiled and analyzed in a regulatory submission. This New Drug Application, or NDA, is submitted to the FDA for review. In parallel, a Marketing Authorization Application (MAA) is filed in Europe, followed by a Japanese NDA. Only after a successful regulatory review does the candidate become a new medicine.
12History of medicines Phase I: Using natural products to treat diseases China: Sheng Nong’s Herbal Classic (神农本草经), described 365 TCM; Compendium of Materia Medica (本草纲目), described 1892 TCMGreeks; e.g. Dioscorides: De materia medica (药物 学), described 600 plantsIslamic physicians; e.g. Avicenna: Herbal medicinePhase II: ScientificUsing pure drug compoundsUnderstanding physiopathology of diseases and pharmacology of drugs
13History of pharmacology Modern pharmacology originated in Europe Francois Magendie ( ), a French physiologist， Experimental procedures with animals for determination of drug action.Fredrick Surturner ( ) isolated the chief alkaloid of opium, Morphine – pure chemicals and repeated quantitativelyClaude Bernard ( )，investigated the plant extract curare and proposed a site of action for this agent.Rudolph Buchheim ( ). In 1847 established the first laboratory in the basement of his home in Dorpat which is the cradle of experimental pharmacology.Oswald Schmiedeberg ( ). In 1872 set up an institute of pharmacology in Strasbourg, which became a mecca for training in pharmacology
15Why do me need to know PK? Optimize drug therapy to obtain a predictable response!Drug of choiceHow muchHow oftenFor how longThe dose makes medicine–Paracelsus 1538
16Therapeutic Goal is to: Achieve drug concentrations…at the site of action (target tissue)…that are sufficiently high enough…to produce the intended effect…without producing adverse drug reactions.
17Toxicity Efficacy Pharmacokinetics Pharmacodynamics Drug AdministrationAbsorptionDrug Concentration in Systemic CirculationDrug in Tissues of DistributionDrug Metabolism or ExcretedPharmacokineticsDistributionEliminationDrug Concentration at Site of ActionPharmacologic EffectPharmacodynamicsClinical ResponseToxicityEfficacy
18% of dose Metabolites Excreted drug Time Drug at absorption site 20406080100Drug at absorption siteMetabolitesDrug in bodyExcreted drug
20Transfer of drugs across Membranes ExtracellularCarrier-mediated transportActive transportFacilitated diffusionSimple diffusion(Lipid diffusion)Filtration(Aqueous diffusion)Intracellular
21Diffusion through lipid bi-layer 1．Simple diffusionDiffusion through lipid bi-layerPassive process, concentration gradientdependent, requires no energyMolecules move from area of highto low concentrationRate of diffusion is proportional to:lipid solubility, the greater the lipid solubility the faster the rate of diffusionpKa of moleculesConcentration difference between both sides
22Ion trapping Cell membranes are less permeable to ionized compounds Acidic drug: HA H+ + A (ionized)Basic drug: BH+ H+ + B (unionized)Ion trappingCell membranes are less permeable to ionized compoundsH+HAA-BBH+
23Ionization depends on pH and pKa Acidic drug：Ka =[ A ][HA]pKa = pH - log[ A ][HA]pKa-pH10 pH-pKa =Basic drug：
252. Filtration Small molecules diffusion through aqueous channels Water solubilitySmall molecularDiameter of aqueous channels in Capillary wall: 4-8Å（=1010m )Only for water, urea filtration>100 not permeable
26Intracellular cleft: big hole Intracellular cleft: 40Å, all solute in blood are permeable except proteinIntracellular cleft
273. Carrier-mediated transport Requiring carrierStructure specificSaturable (functional protein molecules are limited)Competitive inhibitionActive transportAgainst concentration gradientRequires coupling of energy (hydrolysis of ATP)Facilitated diffusionAlong concentration gradientRequires no energy
28Section 2 Disposition of drug in the body Ch. 2Disposition of drug in the bodyAbsorption, Distribution, Metabolism and Excretion
291．AbsorptionTransfer of a drug from its site of administration to the blood streamOral ingestionMajor site:intestineLonger transit time = 3 hoursLarger surface area of villusAbundant blood flowpH5-8 good for most of drugs
30Fick’s Law of Diffusion Area×Permeability coefficient Flux (molecules per unit time)Area×Permeability coefficientThickness＝(C1－C2)×Oral cavity l .0 m2Stomach m2Small intestine 100 m2Large intestine m2Rectum m2
31First pass elimination Before drug reaches the systemic circulation, the drug can be metabolized in the liver or intestine.Intestine wallPortal veinSite of actionMetabolismStool
33InhalationGaseous or volatile substances and aerosol can reach the absorptive site of the lung.Highly available area of absorption (alveolus area = m2; pulmonary capillary area = 80 m2Rapid, no first pass effect, directly reach desired site of action (asthma, COPD)
34Transdermal Transdermal skin patches- Lipid soluble drugs can be absorpted via skinNifedipineGlycerol trinitrate
352．Distribution Receptor Tissue Blood Process by which a drug reversibly leaves he blood stream and enters the interstitial or cellular fluids of the body.Free drugBoundDrugMetabolitesReceptorFree boundTissueFree boundBloodExcretion
36Factors that affect drug distribution Physical and chemical characteristics of the drug (lipid to water partition coefficient)Cardiac outputCapillary permeability in various tissuesLipid content of the tissueBinding to plasma protein and tissue
37Plasma protein binding [DP][PT]KD +[D][D]D＋P DPKDReversible equilibriumSaturableDP: Non-permeableNonspecific & competitivePlasma proteinsAlbumin: Weak acidsalpha-acid glycoprotein: Weak basesEffects of plasma protein bindingFree fraction: active, excreted, metabolizedthe more binding, the less active drugthe more binding, the less excreted and metabolized: “longer half-life”
38Drug interaction of plasma protein binding Drug A: 1000 molecules+Drug B w/ 94% bound99.9% bound90.0% bound1 molecules free100 molecules free100-fold increase in free pharmacologically active concentration at site of action.Effective TOXIC
39Blood-brain barrier, BBB The row of capillary epithelial cells that regulates transfer of drug to the brain.Tight junctionsEndothelial cells and associated astrocytes are stitched together by structuresOnly drugs having a high lipid-water partition coefficient will diffuse into the brain.
40Placental barrierStructure (a number of tissue layers) between fetal and maternal blood.Drugs must be able to diffuse across lipid barriers to enter the fetus.No barrier effect on drug transport
413. Metabolism, Biotransformation Enzymatic alteration of a drug moleculeSites of metabolismMost meds are biotransformed in the liverIt can occur in renal tissue, lungs, blood plasma, and intestinal mucosa
42Phases of metabolism Drug Phase I Phase II Oxidation Conjugation (Cytochrome P450)Conjugation(Glucuronidation, etcPhase IPhase IIConjugationMetabolitesStable adductsNo-polar speciesPolar speciesRenal elimination(Urine)Billary elimination(Stool)
43Phases of metabolism Blood Hepatocyte Hepatocyte bile X (passive diffusion)Y (actively transported)BloodHepatocyteHepatocyteXYbileCYP450CYP450X-OHX-OGY-OHX-OGUGTUGTInflux transports: OATPs, OATs, OCTs, NTCPEfflux transports: MRP2, MDR1, BCRP, BSEP, MDR2(OAT: organic anion transporter; OCT: organic cation transporter)
44Cytochrome P50 superfamily OxidationCytochrome P50 superfamilyThe primary oxidative enzyme system within the liverCYP1A1/2CYP1B1CYP2A6CYP2B6CYP2E1CYP3A4/5/7CYP2C19CYP2C9CYP2C8Non-CYP enzymesCYP 2D6
46Clazolimine concentration Enzyme inductionSpeeds up metabolism, increases drug clearance, decreases concentrations of substratesNo inducerphenobarbitonebenzo-pyreneClazolimine concentration（µg/g tissue）Time（hr）In ratsConsequences of InductionIncreased rate of metabolismDecrease in drug plasma concentrationEnhanced oral first pass metabolismReduced bioavailabilityIf metabolite is active or reactive, increased drug effects or toxicity
47Enzyme inhibition Consequences of Inhibition Slows down metabolism, decreases drug clearance, increases concentration of substratesConsequences of InhibitionIncrease in the plasma concentration of parent drugReduction in metabolite concentrationExaggerated and prolonged pharmacological effectsIncreased likelihood of drug-induced toxicity
48The ways by which a drug is excreted by the kidney 4. ExcretionThe process by which a drug or metabolite is eliminated from the bodyThe ways by which a drug is excreted by the kidneyRoutes of excretionKidney (most important)Biliary tract and the fecesOthers: expired air, sweat, saliva, tears and breast milkGlomerular Filtration Rate (GFR): 125ml/minUrine1ml/minPlasma flow650ml/minAcid Base99% of H20 +Lipid solubledrugsorganic anion transporting polypeptide, OATPOrganic Cation Transporters OCTFiltration Active secretion Reabsorption
50Time course of drug concentration Section 3Ch. 2Time course of drug concentration
511. Single dose iv orally Area under curve (AUC) ngh/mL Absorption = eliminationiv20406080100120246810CmaxorallyPlasma aspirin concentration (mg/L)TmaxArea under curve (AUC)ngh/mL1-3 h for most of drugsTime (min)
52To produce a Css > MEC and < MTC 2. Multiple doseConstant repeated administration of drugsTo produce a Css > MEC and < MTC4-5 half-life, 90% of steady-state concentration is reached in 3.3 half-livesCss-max < MTCCss-min > MEC
53Drug accumulation and elimination 90%3.387.5% % 97%
54Plasma Drug Concentration MTCPlasma Drug ConcentrationMECTime
55Plasma Drug Concentration MTCPlasma Drug ConcentrationMECTime
56Loading doseUtilized when a therapeutic level is desired quickly and an initial larger dose is administered followed by substantially smaller maintenance doses (may increase risk of toxicity and adverse effects).Log ConcentrationTimeTime
58Rate constant for elimination Elimination kineticsRate constant for eliminationdC/dt = - kCnPlasma concentrationTimeZero orderFirst orderFirst order elimination kineticsn = dC/dt = - kCZero order elimination kineticsn = dC/dt = k
59Comparison First order and zero order elimination First Order Elimination[drug] decreases exponentially w/ timeRate of elimination is proportional to [drug]Plot of log [drug] or ln[drug] vs. time are lineart 1/2 is constant regardless of [drug]Zero Order Elimination[drug] decreases linearly with timeRate of elimination is constantRate of elimination is independent of [drug]No true t 1/2
60Mixd elimination kinetics Low concentration (<10mg/L): First orderHigh concentration (>10mg/L): Zero orderSaturation of metabolizing enzyme
61Important Parameters in Pharmacokinetics Section 5Ch. 2Important Parameters in Pharmacokinetics
62First order elimination: Zero order elimination: 1. Half-life, T1/2Time it takes for drug concentrations to decrease by one halfFirst order elimination:t1/2 =0.693/KeZero order elimination:t1/2 = 0.5 C0/k `Constant rate of Elimination irrespective of plasma concentration `t1/2 is constant regardless of drug amount `Rate of elimination proportional to plasma concentration. `t1/2 is dependent on drug amountSlope= -Ke/2.303Plasma ConcentrationPlasma Concentrationt1/2t1/2t1/2t1/2t1/2Time（h）Time（h）
63CLtotal=CLrenal＋CLliver＋CLothers 2. Clearance，CLVolume of blood in a defined region of the body that is cleared of a drug in a unit time (mL/min).CLtotal = D/AUCCLtotal=CLrenal＋CLliver＋CLothers
643. Volume of distribution, Vd Volume in which drug appears to distributeVd not physical volume.Vd = Dose (known)/Cp (known)Vd is proportionality constant
65Basic drugs accumulate in tissue high Vd Vd of Selected drugsAcidic drugsBasic drugsAmphoteric drugsNeutral drugsplasma 4 LBasic drugs accumulate in tissue high VdIntercellular 10 LDrugVolume (L/70kg)Mepacrine（阿的平）40000Chloroquine（氯喹）17000Amphetamine（苯丙胺）300Propranolol（普萘洛尔）250Theophylline（氨茶碱）30Tolbutamide（甲苯磺丁脲）6Intracellular 28 LTotal：42 L
66Application of Vd Estimate of how well the drug is distributed. Value < L/kg indicate the drug is mainly in the circulatory system.Values > 50 L/ (70kg) indicate the drug has accumulated in specific tissues. e.g. digoxin 5mg0.78 ng/ml Vd = 645 L, mainly in lipid tissue and muscle including cardiac muscleCalculation of dosage to be given: Vd=D/C
674. Bioavailability Destroyed in gut Not absorbed Destroyed by gut wall by liverTo systemiccirculationDose
684. Bioavailability Absolute Bioavailability The fraction of the dose of a drug (F) that enters the general circulatory system,F = (AUCev x Div)/(AUCiv x Dev)ev: extravascularRelative BioavailabilityCompurgation of two different drugs or different dosage forms of same drugF = (AUCtest x Dstand)/(AUCstand x Dtest)
69Relative Bioavailability Oral administration of digoxin 0.5mgPharmaceutical Co. APharmaceutical Co. B
71Drug Action and Mechanism Section 1Ch. 3Drug Action and Mechanism
721. Therapeutic effectsExpected desirable and beneficial pharmacological effectEtiological treatmentSymptomatic treatmentSupplementary treatment or substitution treatment
732. Adverse drug reactions, ADR All the reactions that can bring out the uncomfortable or painful reaction, and have no relationship with the aim of administration.ADR are a large problem: ~ 5% of hospital admissions are as a result of an ADR.
74Muscarinic antagonist 1. Side effectReactions unrelated to the therapeutic aim and occurred at therapeutic dose.Inhibition of salivary secretionDry mouthDilated pupilsBlurred visionInhibition of pupillary constrictor muscleAtropineMuscarinic antagonistVagal blockTachycardiaBlocked effects on motilitySpasmolysis
752. Toxic effect, Toxicity Too high dosage or too long usage Harmful functional or morphous damageAcute toxicity，LD50Chronic toxicityTeratogenesisCarcinogenesisMutagenesis
76Single oral LD50 dosage in rat LD50 and toxicity classificationToxicity ratingCommonly used termSingle oral LD50 dosage in rat1Extremely toxic<1 mg/kg2Highly toxic1-50 mg/kg3Moderately toxicmg/kg4Slightly toxic0.5-5 g/kg5Practically nontoxic5-15 g/kg6Relatively harmless>15 g/kg
77Thalidomide disaster Developed by a German pharmaceutical company Before its release, inadequate tests were performed to assess the drug's safetySold from 1957 to 1961 in almost 50 countriesAs an antiemetic to combat morning sickness and as an aid to help sleep in pregnant womenFrom 1956 to 1962, approximately 10,000 children were born with severe malformities, including phocomelia
803. Residual effect，after effect After stop of drug administrationDrug concentration below the threshold concentrationResidual pharmacological effectPhenobarbital hypnosis dizziness, drowsiness next morningLong term administration of glucocorticoid adrenal cortex hypofunction, for several months
814. Withdrawal reaction After stop of drug administration, the symptoms of original disease would be aggravated (rebound reaction）Vasodilator nitroglycerol and troxerutin (曲克芦丁) rebound vasoconstriction angina pectoris attacks
825. AllergyDrug-induced allergic reaction (hypersensitivity) is an exaggerated or inappropriate immune reaction and causes damage to the patientType I: anaphylactic reactionType II: cytotoxic reactionType III: Immune complex reactionType IV: cell-mediated immunity reaction
836. Idiosyncrasy Not predictable reactions Not related to pharmacological effectsGeneric factorTake oxidant drugGenetic G-6-PD deficiencyHaemolysise.g. aspirin
84From SwitzerlandFirst physician using chemicals to treat diseaseALL DRUGS ARE POISONSThe only thing that determines if a drug provides a benefit or kills a patient is how WE administer it.
89Efficacy vs Potency A is more _________ than B. Maximal response a drug can producePotency:Measure of dose required to produce a responseA is more _________ than B.A and B are more ______ than C.
90TD50 and LD50 Median toxic dose （TD50 or TC50) Median lethal dose ToxicityDeathMedian lethal dose（LD50 or LC50）TD50
91Therapeutic Index Measure of the safety of a drug Also known as therapeutic ratio or margin of safety.
92Minimum toxic concentration Minimum effective concentration Therapeutic windowThe range of concentration over which a drug is therapeutically beneficial and safe.Therapeutic window may vary from patient to patientMinimum toxic concentrationMinimum effective concentrationTherapeutics windowDrugs w/ narrow therapeutic windows require smaller & more frequent doses or a different method of administration
93Mechanisms of Drug Action Section 2Ch. 3Mechanisms of Drug Action
94Four consequent levels of drug action 1. Molecule (drug target): the immediate and first step of drug action2. Cell: cellular function is physically inhibited or “turned on”3. Tissue：alteration of tissue function (e.g. heart, lung, stomach…)4. System：alteration of system function (e.g. cardiovascular, pulmonary, digestive…)
97Physio-pharmacological effect 1. ReceptorA macromolecular component of the organism that binds the drug and initiates its effect.Second messengerPhysio-pharmacological effect
982. Drug – receptor interaction Characteristics of Drug-Receptor InteractionsChemical Bond: ionic, hydrogen, hydrophobic, Van der Waals, and covalent.SaturableCompetitiveSpecific and SelectiveStructure-activity relationshipsTransduction mechanisms
99Occupation theory of drug-receptor interactions k1D + R <=> DRk2By Law of mass action:[D]•[R]•K1= [DR]•K2Therefore K2 /K1= Kd = [D]•[R]/[DR]If RT = total # of receptors, thenRT = [R] + [DR]Replace [R] by (RT-[DR]) & rearrange:EffectD = 0：effect = 0D>>Kd：DR/RT=100%， max effectKd=D, Kd = Conc at EC50[DR] [D]RT Kd + [D]effect==Max. effect
1003. Affinity and Intrinsic activity The strength of binding between a drug and receptorKD is inversely proportional to affinityIntrinsic Activity :The extent to which the ligand activates the receptorEEmax[DR]=100% 0RT
1014. Classification of drugs Full agonist： = 100％，Efficacy = EmaxPartial agonist: 0% < < 100%， Efficacy < EmaxAntagonist: = 0％ ，Effficay = 0100Drug concentrationFull agonistPartial agonistAntagonist50% Maximum effect
102Competitive antagonist Binds to same site for agonist-binding domainCompetes with an agonist for receptorsHigh doses of an agonist can generally overcome antagonist10-210-1110102103104105Fractional occupancy0.11.0Agonist concentrationAntagonistconcentration
103Noncompetitive antagonist Binds to a site other than the agonist-binding domainInduces a conformation change in the receptor such that the agonist no longer “recognizes” the agonist binding site.Antagonist concentration1101001.00.5Fractional occupancy10-210-1102Agonist concentrationHigh doses of an agonist do not overcome the antagonist in this situation
104Spare receptorsHigh affinity agonist produced maximal response without total receptor occupancy – increase sensitivity of the systemMagnitude of response IS NOT proportional to receptor occupancySpare receptors can bind extra ligand preventing an exaggerated response if too much ligand is presentMAXMAX
1055. Type of receptors Channel linked receptors : Example: the ACh receptor, signal is neurotransmitter, depolarization is signal, Na+ channel is target.
1065. Type of receptors 2. G-protein coupled receptors: Signal through trimeric G proteins.The proteins can alter the function of many proteins.
1075. Type of receptors 3. Enzyme linked receptors: Usually signal through protein kinases or protein phosphatases. Protein modification then alters intracellular enzyme activity.结合区
1085. Type of receptors 4. Intracellular receptors Hormone receptors Signal binds directly to an intracellular protein which then activates transcription.
1096. Second messengersPrimitive signal binds with receptor and then trigger second messengerIntracellular effectReceptorFirst messengersSecond messengersSmall, nonprotein, water-soluble molecules or ionsReadily spread throughout the cell by diffusionTwo most widely used second messengers are:1. Cycle AMP2. Calcium ions Ca2+ （ cAMP,IP3,DG,)
110Signal amplificationAmplificationNoamplificationReceptorG-proteinAdenylylcyclaseCycliccAMPProteinkinasesPhosphatestranferred totarget proteins10-10M Adr in blood blood glucose levels by 50%Results in a tremendous increase in the potency of the initial signal permits precise control of cell behavior
1117. Receptor regulationSensitization （hypersensitization, supersensitivity）or Up-regulationProlonged/continuous use of receptor blockerInhibition of synthesis or release of hormone/neurotransmitterDesensitization or Down- regulationProlonged/continuous use of agonistInhibition of degradation or uptake of agonist
112Receptor regulation Homologous desensitization Affecting responses elicited only by the stimulated receptorCan reflect feedback from a transducer (or effector) unique to the pathway of the receptor (X1) or from an off-pathway component (K) that is sensitive to the activation state of the receptor.Heterologous desensitizationActing on several receptors or on a pathway that is common to many receptors.Initiated by transducers or effectors common to multiple receptor signaling pathways (Y or Z).
115Pharmaceutical Factors 1. Dose, formulation, route of administration2. Drug Interactions（1）Pharmacokinetic interactions：chemical or physical;GI absorption;protein binding/distribution;metabolism (stimulation/inhibition);excretion (pH/transport processes);changes in pH or electrolytes.（2）Pharmacodynamic interactions：receptor (potentiation/antagonism
1181. Age Age related change: 1. liver metabolism; 2. renal elimination; 3. body compositionliver metabolism- less amount of drug metabolizing enzymes in newborn infantsOlder people usually take more drugs, also may have more difficulty following complicated instructions for taking drugs.
119Developmental profile of hepatic drug metabolizing enzymes 1. AgeDevelopmental profile of hepatic drug metabolizing enzymesCYP3A7Most drug-metabolizingenzymesEnzyme levelBirthAdulthoodElderlyAge
1202. Gender Women have more CYP3A in the liver Estrogen and progestin inhibit CYP450 leading to a lower CL of drugs in womenWomen tend to take more medications, including dietary supplements, than men
1266. Variation in response Tolerance is a person's diminished response to a drug, which occurs when the drug is used repeatedly and the body adapts to the continued presence of the drug.Resistancerefers to the ability of microorganisms or cancer cells to withstand the effects of a drug usually effective against them.
1277. Genetic factor Single nucleotide polymorphism wt/wt wt/m m/m GTTC T CTA…CAAGAGAT…GT GCTC TA…CA CGAGAT…wt/mm/m