1、药理学总论-绪言 Pharmacology A Very Basic Intro,What is a drug?any chemical agent whichaffects any biological process,Sources of Drugs,Animals Plants Minerals Synthetic Microbes Genetic engineering drugs,基因工程药物过程示意图,从细胞中分离出DNA,限制酶截取DNA片断,分离大肠杆菌中的质粒, DNA重组,用重组质粒转化大肠杆菌,培养大肠杆菌克隆大量基因,A goal of Genomics is to f
2、ind and express genes that code for unknown peptides with significant biological properties, like receptors or enzymes. In a reverse Pharmacology approach this peptide, e.g. a receptor, is then used to “fish“ for a natural ligand . With receptor and ligand in hand the biological role of the receptor
3、 needs to be determined. Finally, screening for synthetic ligands as well as lead optimization can lead to new drug candidates. In contrast, the classical approach to drug discovery starts with the identification of a ligand that has biological activity that in turn is used to “fish“ for the corresp
4、onding receptor.,One example for a Genomics strategy aims at identifying drug targets based on molecular homology within Gene-families. One of the most important families of drug-targets for the pharmaceutical industry is the family of G-protein coupled receptors (GPCRs). Of the top 200 best selling
5、 prescription drugs, more than 20% interact with GPCRs, providing worldwide sales of over $20 billion. The characteristic motif of the GPCR family is the seven distinct hydrophobic regions, each of 20 to 30 amino acids that form the transmembrane domain of these integral membrane proteins. This key
6、amino-acid sequence motif can be found within all types of GPCRs and can be used to identify DNA-sequences that code for GPCRs.,What is pharmacology ?the study of how drugs effect biological systems,What is Pharmacology ?,Pharmacology,Pharmacokinetics PharmacodynamicsWhat the body does to drug What
7、the drug does to body,Pharmacotherapeutics PharmacocognosyThe study of the use of drugs Identifying crude materials as drugs,Toxicology,Pharmacokinetics What the body does to the drug- Absorption - Distribution - Metabolism (Biotransformation) - Excretion,Half-life (t1/2) - the time required for the
8、 plasma concentration of a drug to be reduced by 50 %,DRUG CLASSIFICATION Based on the chemical structure - Based on the main effect (e.g. analgesics). - Based on the therapeutic use (e.g. antipsychotic 安定药). Based on mechanism of action (e.g. serotonin agonist).,From Chemist to First In Man approxi
9、mately 7 10 yearsHow a Drug becomes a drug,H. Haarmann University of Maryland, 2002,Basic & Clinical Evaluation of New DrugsDrug discovery & Drug screeningChemistryIn Vitro StudiesFunction in cells, tissues, and at receptors2. Preclinical safety & toxicity testingIn Vivo - Animal studiesPharmacology
10、 and Behavioral PharmacologyPotency and Efficacy ED50Tolerance and Tachyphylaxis(快速耐受) Toxicity Acute and Chronic LD50Teratogenicity = birth defectsCarcinogenicity = cancerous3. Evaluation of drug in humans,Evaluating Drugs in Humans,The Food and Drug Administration (FDA),Phases of a Clinical Trials
11、 Phase I Phase II Phase III Phase IV,Evaluating Drugs in Humans,Phase I Healthy adult volunteersEvaluation of safety, Pharmacokinetics (PK), side effects?Phase II - PatientsEvaluation of efficacy, safety, PK, and side effectsDouble-blind placebo controlledPhase III Specific patient subpopulationsDet
12、ermine efficacy for specific indicationsLarge sample of specific patients (1,000)Randomized double-blind placebo controlledPhase IV Post FDA ApprovalDetermine efficacy for specific indicationDetermine drug utilization patterns and additional efficacyMonitor rare, severe side effects/toxicity,Drug No
13、menclature,Chemical name（化学名）- *Generic name （非专利名） Trade name （商品名）,Chemical Name: 2-(4-isobutylphenyl)-propionic acidGeneric Name: ibuprofen（布洛芬）Trade Names: Advil, Aches-N-Pain, Brufen, Emodin, Haltran, Medipren,Midol 200, Motrin, Nuprin,Rufen, Trendar, Wal-Profen,*preclinical nomenclature = company abbrev-123456 (e.g. WAY-100635, MK-869),
