周宏灝【英文】藥理學(xué)之總論

1、1．Simple diffusion,Passive process, concentration gradient dependent, requires no energyMolecules move from area of high to low concentrationRate of diffusion is proportional to:lipid solubility, the greater t

2、he lipid solubility the faster the rate of diffusionpKa of moleculesConcentration difference between both sides,Diffusion through lipid bi-layer,,,Acidic drug:HA ? H+ + A? (ionized) Basic drug: BH+ ? H+ + B (union

3、ized),Ion trappingCell membranes are less permeable to ionized compounds,,Ka =,[ H+ ] [ A? ][HA],,pKa = pH - log,[ A? ][HA],,[ A? ][HA],,10 pH-pKa =,Acidic drug：,Ionization depends on pH and pKa,,,,Basic drug：,,,,A

4、? + H+?HA,HA?H+ + A?,[ A? ][HA],,10pH-pKa =,Plasma：pH=7,Stomach：pH=4,1,1,102,105,Cromolyn Sodium (色甘酸鈉) pKa=2, Acidic,= 107-2 = 105,[ A? ][HA],,10pH-pKa =,= 104-2 = 102,,,Total,Total,Example,101,100001,Small molecule

5、s diffusion through aqueous channels,2. Filtration,Water solubilitySmall molecular Diameter of aqueous channels in Capillary wall: 4-8Å（=10?10m )Only for water, urea filtration >100 not permeable,Intracellu

6、lar cleft: 40Å, all solute in blood are permeable except protein,Intracellular cleft,,,,,Intracellular cleft: big hole,3. Carrier-mediated transport,Active transportAgainst concentration gradient Requires coupling

7、 of energy (hydrolysis of ATP),Facilitated diffusionAlong concentration gradient Requires no energy,Requiring carrier Structure specificSaturable (functional protein molecules are limited)Competitive inhibition,Disp

8、osition of drug in the bodyAbsorption, Distribution, Metabolism and Excretion,Section 2,Ch. 2,Transfer of a drug from its site of administration to the blood stream,Oral ingestion,Major site:,Longer transit time = 3 hou

9、rs Larger surface area of villusAbundant blood flow pH5-8 good for most of drugs,intestine,1．Absorption,Oral cavity 0.5-l .0 m2Stomach 0.1-0.2 m2 Small intestine 100 m2Large intestine 0.04-0.07 m2Rectum 0

10、.02 m2,Fick’s Law of Diffusion,Flux (molecules per unit time),＝(C1－C2)×,Area×Permeability coefficientThickness,,First pass elimination,,,,,,,,,,,,Metabolism,Site of action,Intestine wall,Portal vein,Before dru

11、g reaches the systemic circulation, the drug can be metabolized in the liver or intestine.,Stool,Passive diffusion ＋ FiltrationRapid and complete absorption,Intramuscular & subcutaneous injection,Inhalation,Gaseous

12、or volatile substances and aerosol can reach the absorptive site of the lung.Highly available area of absorption (alveolus area = 100-200m2; pulmonary capillary area = 80 m2Rapid, no first pass effect, directly reach d

13、esired site of action (asthma, COPD),Transdermal,,Transdermal skin patches-Lipid soluble drugs can be absorpted via skin Nifedipine Glycerol trinitrate,Process by which a drug reversibly leaves he blood stream and ent

14、ers the interstitial or cellular fluids of the body.,2．Distribution,Free drug??BoundDrugMetabolites,,,,,,ReceptorFree ? bound,TissueFree ? bound,,,,,,,,,Excretion,Blood,,,,,Physical and chemical characteristics o

15、f the drug (lipid to water partition coefficient)Cardiac outputCapillary permeability in various tissuesLipid content of the tissue Binding to plasma protein and tissue,Factors that affect drug distribution,,,,,,Plas

16、ma protein binding,Reversible equilibriumSaturableDP: Non-permeableNonspecific & competitive,,,Plasma proteins Albumin: Weak acids alpha-acid glycoprotein: Weak basesEffects of plasma protein binding Free fra

17、ction: active, excreted, metabolizedthe more binding, the less active drug the more binding, the less excreted and metabolized: “l(fā)onger half-life”,Drug A: 1000 molecules,99.9% bound,1 molecules free,,,,,100-fold incre

18、ase in free pharmacologically active concentration at site of action. Effective TOXIC,,+ Drug B w/ 94% bound,90.0% bound,,,,,100 molecules free,,Drug interaction of plasma protein b

19、inding,,,,,,,Blood-brain barrier, BBB,Tight junctions Endothelial cells and associated astrocytes are stitched together by structures,The row of capillary epithelial cells that regulates transfer of drug to the brain.,,

20、Only drugs having a high lipid-water partition coefficient will diffuse into the brain.,,,Structure (a number of tissue layers) between fetal and maternal blood.Drugs must be able to diffuse across lipid barriers to ent

21、er the fetus. No barrier effect on drug transport,Placental barrier,,3. Metabolism, Biotransformation,Sites of metabolismMost meds are biotransformed in the liver It can occur in renal tissue, lungs, blood plasma, and

22、 intestinal mucosa,Enzymatic alteration of a drug molecule,,Drug,,,Oxidation(Cytochrome P450),Conjugation (Glucuronidation, etc,,,Conjugation,Stable adducts,Metabolites,,,,No-polar species,,,Billary elimination(St

23、ool),Renal elimination(Urine),Polar species,Phase I,Phase II,Phases of metabolism,,,,,,,,,,,,X (passive diffusion),X,CYP450,X-OH,,,UGT,X-OG,,,Y (actively transported),Y,CYP450,Y-OH,UGT,X-OG,,,,,bile,Blood,Hepatocyte,H

24、epatocyte,,,,,,,Phases of metabolism,,,Influx transports: OATPs, OATs, OCTs, NTCP Efflux transports: MRP2, MDR1, BCRP, BSEP, MDR2,(OAT: organic anion transporter; OCT: organic cation transporter),Oxidation,,Cytochrome P

25、50 superfamily The primary oxidative enzyme system within the liver,,Genetic determined enzyme activity,,,,,,,,,Genes,,Environment,,Speeds up metabolism, increases drug clearance, decreases concentrations of substrates,

26、Enzyme induction,Consequences of Induction,Increased rate of metabolismDecrease in drug plasma concentration Enhanced oral first pass metabolismReduced bioavailabilityIf metabolite is active or reactive, increased dr

27、ug effects or toxicity,,Slows down metabolism, decreases drug clearance, increases concentration of substrates,Enzyme inhibition,Consequences of Inhibition,Increase in the plasma concentration of parent drugReduction in

28、 metabolite concentrationExaggerated and prolonged pharmacological effectsIncreased likelihood of drug-induced toxicity,Routes of excretionKidney (most important)Biliary tract and the fecesOthers: expired air, sweat

29、, saliva, tears and breast milk,4. Excretion,,,,,,,,,,,Filtration Active secretion Reabsorption,,,Acid Base,,99% of H20 +Lipid solubledrugs,Plasma flow650ml/min,Glomerular Filtration Rate (GFR): 125ml/min,Urine

30、1ml/min,The ways by which a drug is excreted by the kidney,organic anion transporting polypeptide, OATP,Organic Cation Transporters OCT,The process by which a drug or metabolite is eliminated from the body,Liver,,Gut,Fec

31、es excretion,Portal vein,Biliary excretion&Enterohepatic recycling,Bile duct,Biliary Secretion,Time course of drug concentration,Section 3,Ch. 2,1. Single dose,,Time (min),Plasma aspirin concentration (mg/L),,Cmax,

32、Tmax,,iv,,orally,,,,,Area under curve (AUC)ng?h/mL,Absorption = elimination,,1-3 h for most of drugs,2. Multiple doseConstant repeated administration of drugs,Css-max < MTC,Css-min > MEC,,,4-5 half-life, 90% of

33、steady-state concentration is reached in 3.3 half-lives,,To produce a Css > MEC and < MTC,,Drug accumulation and elimination,87.5% 94% 97%,,,,,,,Time,Plasma Drug Concentration,,,,,,,MTC,MEC,,,Time,Plasma D

34、rug Concentration,,,,MTC,MEC,,,,Time,Time,Log Concentration,,,,,,,Loading dose,,Utilized when a therapeutic level is desired quickly and an initial larger dose is administered followed by substantially smaller maintenanc

35、e doses (may increase risk of toxicity and adverse effects).,Elimination Kinetics,Section 4,Ch. 2,Elimination kinetics,First order elimination kineticsn = 1 dC/dt = - kC,Zero order elimination kinetics n

36、= 0 dC/dt = k,dC/dt = - kCn,Rate constant for elimination,,,First order and zero order elimination,Comparison,First Order Elimination[drug] decreases exponentially w/ timeRate of elimination is proportional to [d

37、rug]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

38、 of [drug]No true t 1/2,,Low concentration (10mg/L): Zero orderSaturation of metabolizing enzyme,Mixd elimination kinetics,Important Parameters in Pharmacokinetics,Section 5,Ch. 2,Time it takes for drug concentrations

39、to decrease by one half,1. Half-life, T1/2,Zero order elimination: t1/2 = 0.5 ? C0/k,First order elimination: t1/2 =0.693/Ke,,,t1/2,t1/2,t1/2,t1/2,,t1/2,,,Slope = -Ke/2.303,Time（h）,Time（h）,Plasma Concentration,,? `Ra

40、te of elimination proportional to plasma concentration. ? `t1/2 is dependent on drug amount,,,? `Constant rate of Elimination irrespective of plasma concentration? `t1/2 is constant regardless of drug amount,Plasma Co

41、ncentration,Volume 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,2. Clearance，CL,,,3. Volume of distribution, Vd,,Volume in

42、 which drug appears to distributeVd not physical volume.Vd = Dose (known)/Cp (known)Vd is proportionality constant,plasma 4 L,Intercellular 10 L,Intracellular 28 L,,,,,Acidic drugs,Basic drugs,Amphoteric drugs,Neutral

43、 drugs,Basic drugs accumulate in tissue ? high Vd,Total：42 L,Estimate of how well the drug is distributed. Value 50 L/ (70kg) indicate the drug has accumulated in specific tissues. e.g. digoxin 5mg?0.78 ng/ml ?Vd = 645

44、 L, mainly in lipid tissue and muscle including cardiac muscleCalculation of dosage to be given: Vd=D/C,Application of Vd,4. Bioavailability,,,,,,,,,,Dose,Destroyed in gut,Notabsorbed,Destroyed by gut wall,Destroyed

45、by liver,To systemiccirculation,,,,,4. Bioavailability,,Relative BioavailabilityCompurgation of two different drugs or different dosage forms of same drugF = (AUCtest x Dstand)/(AUCstand x Dtest),Absolute Bioavailab

46、ilityThe fraction of the dose of a drug (F) that enters the general circulatory system,F = (AUCev x Div)/(AUCiv x Dev) ev: extravascular,,Oral administration of digoxin 0.5mg,,Pharmaceutical Co. A,Pharmaceutical

47、Co. B,,,Relative Bioavailability,Chapter 3 Pharmacodynamics,Drug Action and Mechanism,Section 1,Ch. 3,1. Therapeutic effects,Expected desirable and beneficial pharmacological effectEtiological treatmentSymptomatic tr

48、eatmentSupplementary treatment or substitution treatment,2. Adverse drug reactions, ADR,,All the reactions that can bring out the uncomfortable or painful reaction, and have no relationship with the aim of administratio

49、n.ADR are a large problem: ~ 5% of hospital admissions are as a result of an ADR.,Reactions unrelated to the therapeutic aim and occurred at therapeutic dose.,1. Side effect,,,,,Dry mouth,Inhibition of salivary secret

50、ion,,Dilated pupils Blurred vision,,Inhibition of pupillary constrictor muscle,,Tachycardia,,Vagal block,,,Spasmolysis,,Blocked effects on motility,,Atropine Muscarinic antagonist,,,,,,,,,,,,Too high dosage or too long

51、 usageHarmful functional or morphous damage,Acute toxicity，LD50Chronic toxicityTeratogenesisCarcinogenesisMutagenesis,2. Toxic effect, Toxicity,LD50 and toxicity classification,Developed by a German pharmaceutical c

52、ompanyBefore its release, inadequate tests were performed to assess the drug's safety Sold from 1957 to 1961 in almost 50 countries As an antiemetic to combat morning sickness and as an aid to help sleep in pregna

53、nt womenFrom 1956 to 1962, approximately 10,000 children were born with severe malformities, including phocomelia,Thalidomide disaster,,Phocomelia,Francis Kelsey,Phenobarbital ? hypnosis ? dizziness, drowsiness next mor

54、ning Long term administration of glucocorticoid ? adrenal cortex hypofunction, for several months,After stop of drug administrationDrug concentration below the threshold concentrationResidual pharmacological effect,3.