Section Ⅵ. Pharmacological Basis of Therapeutics

Section . Pharmacological Basis of Therapeutics

Chapter 3. Factors influencing drug effect & Principle of rational administration

Part 1. Drug factorsPart 2. Patient factorsPart 3. Principle of rational administration

Part 1. Drug factors1. Dosage form() (1)Injection: iv. im. sc. (2)Oral medicine Powder; Tablet; Capsule, Oral liquid. Bioequivalence()

New dosage form() : (1)Oral controlled release form() (2)Oral slow release form(); (3)Transdermal drug delivery system(); (4)Storage form(); (5)Microcapsule and microsphere(; (6)Nanocapsule ans nanosphere(); (7)Liposomes(); (8)Magnetic guide system().

(1): , . (Osmotic pump tablet): , pH.

1. ()

2. ()

l:

(mini-tablet, 3 mm), , ; , , . l (): (--)(); .

(2): , 8h, , .(3): . : , .

3. ()

4. (Higuchi)

: , .

5.

1000 100 : 1mg/ml pH: , 59

, .

(Nitro-Dur) (mg/h) (cm2) (mg/d) (mg) 0.1 5 2.5 20 0.2 10 5 40 0.3 15 7.5 60 0.4 20 10 80 0.6 30 15 120 : , , , , , , , .

(4) , , , , . : , , ().

(5) : , 5400 m, . : , 0.01300 m, C.

(6) , , (nm), 10100 nm, 250 nm; : iv (), po(). .

(7) (), , , , (nm). : , 200 nm1 m; : , 5 m; : , O/WW/O/W, , .

l : , ,, , ; (, );pH, , . : ; ; . : , ; , B.

(8) , , , , . , ; iv(), . .

2. Methods of administration (1)Dosage(from small dosage ) (2)Administration routes, : iv > inhalation > im> sc > po > pr > transdermal (3)Time of administration, (4)Interval of administration, t (5)Course of treatment.

(1)Aim of drug in combination: more effectively treat disease. (2)Drug-Drug interaction Pharmaceutical interaction Physicochemical reaction incompatibility() Pharmacokinetics interaction Pharmacodynamics interaction3. Drug in combination and Drug-Drug interaction

(3)Outcome of drug-drug interaction Synergism(): enhanced drug effect. Addition(): 1+11 Potentiation(): 1+12Antagonism(): diminished drug effect. Subtraction(): 1+11 Counteraction(): 1+1=0

(4)Mechanism of Drug-Drug interac-tionPharmacodynamics: agonist and antagonistPharmacokinetics: absorption, PPB, enzyme induction and inhibition, excretion.

Part 2. Patient factors 1. Age: (1)Children , ; , , . , , , , , .

, , , . , , , , , . , , , , , .

(2)The aged: , , . . (Phenylpropanolamine, PPA), .

2. Sex: Male, Female , , , . , . . , , . , 3; , 2.

; ;;

3. Genetic factors Individual variation(): quantitative difference hyperreactivity; hyporeactivity qualitative difference anaphylaxis (allergy); idiosyncrasy (genetic factors): G-6-PD deficiency. Pharmacogenetics():polymorphism of oxidation()polymorphism of acetylation()

4. Pathological factors ; ; ; ; , ; t1/2; ;

5. Psychic factors , , ; . Placebo effect().

6. Administration for long time (Drug-induced abnormal responses) (1)Tolerance() Tachyphylaxis, Bradyphylaxis Resistance(, ) (2)Dependence() Habituation(), Addiction(), abstinence syndrome(), (3)Withdrawal syndrome() Rebound phenomenon()

Part 3. Principle of rational administration 1. ;2. 3.4.5.

Lets have a rest !

Chapter 4.Antineoplastics()

Part 2. AntineoplasticsPart 3. The combined treatment principles & toxic reaction of antineoplastics Chapter 4. AntineoplasticsPart 1. The pharmacological basis of antineoplastics

Part 1. The pharmacological basis of antineoplastics:1. Classification of antineoplastics(1)According to chemical structure and source: Alkylating agents(: )Antimetabolite(: MTX, 5-FU)Antineoplastic antibiotic()Antineoplastic plant drugs()Hormones()Others(: )

(2)According to biochemical mechanism: Drugs inhibiting biosynthesis of nucleic acid (MTX, 5-FU, 6-MP, HN2, et al.); Drugs directly destroying DNA structure and function(CTX, DDP, MMC, BLM, et al.); Drugs interfering transcript process and inhibiting RNA synthesis (DACT, ADM, et al.); Drugs interfering protein synthesis and function (VLB, VCR, paclitaxel, et al.); Drugs interfering Hormone balance (prednison, androgen, estrogen, et al.).

The mechanisms and sites

(3)Classification of antineoplastics according to cell generation cycle:

Cell cycle-nonspecific agents(CCNSA): . Alkylating agents (), Antitumor antibiotics(), Preparation of platinum(), etc. Cell cycle-specific agents(CCSA): . Ara-C() and HU() : , S; VLB(): M.

Affection of antineoplastics to cell generation cycle (1)Cell generation cycle: Cell generation cycle can be divided into: G0 phase, G1 phase, S(synthesis) phase, G2 phase & M(mitosis) phase. G0 phase cell is non-proliferating cell population, G1 phase to M phase cell are pro-liferating cell population.

(2)Growth fraction(GF, ):

proliferating cell population GF = Total cell population GF, ; GF, .

Inhibiting biosynthesis of nucleic acid:Antimetabolite ()1): MTX 2): 5-FU 3): 6-MP4): HU5)DNA: Ara-C

Methotrexate(,MTX) dTMP DNA

6-mercaptopurine(,6MP)

5-Fluorouracil(, 5-FU)

Hydroxycarbamide, HU

DNACytarabine, Ara-C DNA

Directly destroying DNA structure and function:1)Alkylating agents(): NH2(), CTX()2)Platinum coordination complexes destroying DNA(DNA): DDP(), CBP()3)Antibiotics destroying DNA: MMC(C), BLM() 4)Inhibitor of DNA-topoisomerase CPT(), VP16()

1)Alkylating agents():DNA

+DNA-DNADNA

Cyclophosphamide, CTX 3.

2 Platinum coordination complexes destroying DNA cisplatin, ,DDP DNA

3Antibiotics destroying DNA:Antitumor antibiotics: .

DNABleomycin, BLM :

4)Inhibitor of DNA-topoisomerase() CPT(), VP16()Camptothecin,CPT DNA: DNAI

Interfering transcript process and inhibiting RNA synthesis:Antitumor antibiotics: DACT(D); ADM(); DNR()

Doxorubicin, ADM RNA

Interfering protein synthesis and function: 1) Affecting the formation of spindle fibers: Vinca alkaloids(): VLB, VCR; 2) Interfering the function of nucleoprotein: Harringtonine(): cephalotoxin 3) Interfering the supply of amino acid: L-Asparaginase (L-).

1) Affecting the formation of spindle fibers:Vinblastin (VLB)Vincristine VCRVindesine,VDS)VinocrelbineNVBMVLB>VCR RNAG1VLB VCRVDSNVB VCR

Paclitaxel (, Taxol)Taxotere, docetaxel()

SHarringtonineHomoharringtonine(:

3) Interfering the supply of amino acid: L-Asparaginase (L-).L-L-ASP

Interfering hormone balance: Adrenocorticoids(), Androgens(), Estrogens().Tamoxifen( TAM)GosereninLeuprorelin)ToremifeneAnastrozole()

3. Resistance and its mechanism: (1)Nature resistance (2)Acquired resistance Biochemical mechanism of resistance: reducing drug in cell, change receptor or target enzyme, alternate metabolism (3)Multidrug resistance, MDR P-gp(P-) drug efflux pump, (mdrl), etc.

4.

1(recruitment) :- :- 2(synchronization) -

1. 2. ++++

::: :

1(1)

(2) (3)

2(1) (2) (3) L- (4) (5) (6) L-

1

2

Miscellaneous anticancer drugs:Tyrosine Kinase Inhibitors BCR-ABL Kinase Inhibitors

Monoclonal AntibodiesEPIDERMAL GROWTH FACTOR RECEPTOR INHIBITORSHER2/neu Inhibitors/ ErbB2 INHIBITORS OF ANGIOGENESISPROTEASOME INHIBITION: BORTEZOMIB mTOR INHIBITORS: RAPAMYCIN ANALOGSMonoclonal AntibodyCytotoxic ConjugatesCytokine: Interleukin-2, Colony-Stimulating Factors

Thanks !

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()

pH()