药理学总论 -绪言PharmacologyPharmacology

A Very Basic Intro

What is a drug?

- any chemical agent which affects any biological process

Sources of Drugs

AnimalsPlants

MineralsSyntheticMicrobes

Genetic engineering drugs

基因工程药物过程示意图①① 从细胞中分从细胞中分

离出离出 DNADNA

①①

②②

③③

④④

⑤⑤

⑥⑥

②② 限制酶截取限制酶截取DNADNA 片断片断

③③ 分离大肠杆分离大肠杆菌中的质粒菌中的质粒

④ ④ DNADNA 重组重组

⑤⑤ 用重组质粒用重组质粒转化大肠杆菌转化大肠杆菌

⑥⑥ 培养大肠杆菌培养大肠杆菌克隆大量基因克隆大量基因

A goal of Genomics is to find 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 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 corresponding 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 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 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 Pharmacodynamics

What the body does to drug What the drug does to body

Pharmacotherapeutics Pharmacocognosy

The study of the use of drugs Identifying crude materials as drugs

Toxicology

PharmacokineticsWhat the body does to the drug

- Absorption- Distribution- Metabolism (Biotransformation)- Excretion

Half-life (t1/2)- the time required for the plasmaconcentration 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 …approximately 7 – 10 years

How a Drug becomes a drug…

H. Haarmann University of Maryland, 2002

Basic & Clinical Evaluation of New Drugs

1. Drug discovery & Drug screeningChemistry

In Vitro StudiesFunction in cells, tissues, and at receptors

2. Preclinical safety & toxicity testingIn Vivo - Animal studies

Pharmacology and Behavioral PharmacologyPotency and Efficacy – ED50Tolerance and Tachyphylaxis( 快速耐受 )

Toxicity – Acute and Chronic LD50Teratogenicity = birth defectsCarcinogenicity = cancerous

3. Evaluation of drug in humans

Evaluating Drugs in Humans

The Food and Drug Administration (FDA)

Phases of a Clinical TrialsPhase I Phase II Phase III Phase IV

Evaluating Drugs in HumansPhase I – Healthy adult volunteers

• Evaluation of safety, Pharmacokinetics (PK), side effects???

Phase II - Patients• Evaluation of efficacy, safety, PK, and side effects• Double-blind placebo controlled

Phase III – Specific patient subpopulations• Determine efficacy for specific indications• Large sample of specific patients (1,000)• Randomized double-blind placebo controlled

Phase IV – Post FDA Approval• Determine efficacy for specific indication• Determine drug utilization patterns and additional efficacy• Monitor rare, severe side effects/toxicity

Drug Nomenclature

-Chemical name （化学名）- *Generic name （非专利名）

- Trade name （商品名） Chemical Name: 2-(4-isobutylphenyl)-propionic acid

Generic 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)