L1 Introdction

一、Introduction to Molecular Pharmacology

Objectives to pharmacology:

1. Definition of the four basic terms (drug, pharmacology, clinical pharmacology, and therapeutics) for the study of pharmacology.
2. Properties of an ideal drug
3. Therapeutic objective of drug therapy.
4. Factors that determine how an individual will respond to a specific drug and dosage

Four basic terms:

• Drug: any chemical that can affect living processes
• Pharmacology: the study of drugs and their interactions within living systems
  • Physical and chemical properties
  • Biochemical and physiological effects
  • Knowledge of the history, source, and use of drugs
  • Absorption, distribution, metabolism and excretion
• Clinical Pharmacology: study of drugs in humans
• Therapeutics: use of drugs to diagnose, prevent and treat illness( and/or pregnancy)=medical use of drugs

The Defination

1. Pharmacology

DEFINITIONS:

• Pharmacology is the study of how drugs exert their effects on living systems.
  • Pharmacologists work to identify drug targets in order to learn how drugs work. Pharmacologists also study the ways in which drugs are modified within organisms.
  • In most of the pharmacologic specialties, drugs are also used today as tools to gain insight into both normal and abnormal function.
• Pharmacologist
  • Pharmacologists work to identify drug targets in order to learn how drugs work. Pharmacologists also study the ways in which drugs are modified within organisms
  • In most of the pharmacologic specialties, drugs are also used today as tools to gain insight into both normal and abnormal function.

Pharmacy and pharmacist

• Pharmacy is a medical science concerned with the safe and effective use of medicines
  • the study of techniques involved in the preparation compounding, dispensing, preservation and storage of the drugs for medical use
• Pharmacist: who is qualified and licensed
  • Functions:
    • to prepare and dispense drugs
    • to responsible for the manufacture of the dosage form of drugs (e.g. tablets, capsules, etc)

2. Drugs

Drugs can be defined as chemical agents that uniquely interact with specific target molecules in the body, thereby producing a biological effect.

• Drugs can be stimulatory or inhibitory
• Drugs, as well as hormones, neurotransmitter, autocoids（自分泌物） and toxins can make possible the transfer of information to cells by interaction with specific receptive molecules called “receptors“
  • 
• Drugs interact with biological systems in ways that mimic, resemble or otherwise affect the natural chemicals of the body
• Drugs can produce effects by virtue of their acidic or basic properties (e.g. antacids（抗酸剂）, protamine（鱼精蛋白）), surfactant properties (amphotericin（两性霉素）), ability to denature proteins (astringents（收敛剂）), osmotic properties (laxatives（泻药）, diuretics(利尿剂)), or physicochemical interactions with membrane lipids (general and local anesthetics(麻醉剂))

3. Receptors

Most drugs combine (bind) with specific receptors to produce a particular response. This association or binding takes place by precise physicochemical and steric interactions between specific groups of the drug and the receptor.

Classification:

1. Proteins
   1. Carriers
   2. Receptors
      1. G protein coupled
      2. Ligand gated channers
      3. Intracellular
   3. Enzymes
2. DNA

Divisions of Pharmacology

1. Pharmacognosy 生药学

What is Pharmacognosy？

• the branch of pharmacology dealing with the economic, biological and chemical aspects of natural drugs and their constituents
• study of the sources of drugs and the physical characteristics of crude or unrefined drugs
• study of drugs derived from herbal and other natural sources and how the body reacts to them
• Simply: the study of natural( plant and animal)drug sources

2. Pharmacokinetics 药物动力学

Pharmacokinetics Is what the body does to the drug

• The magnitude of the pharmacological effect of a drug depends on its concentration at the site of action.

It studies:

• Absorption
• Distribution
• Metabolism
• Elimination

3. Pharmacodynamics 药效学

Pharmacodynamics Is what the drug does to the body

• Interaction of drugs with cellular proteins, such as receptors or enzymes, to control changes in physiological function of particular organs

Drug-Receptor Interactions

• Binding

Dose-Response:

• Effect

Signal Transduction:

• Mechanism of action, pathways

4. Pharmatherapeutics 药物遗传学

Area of pharmacology concerned with unusual responses to drugs caused by genetic differences between individuals

Responses that are not found in the general population, such as general toxic effects, allergies, or side effects, but due to an inherited trait that produces a diminished or enhanced response to a drug.

Differences in Enzyme activity:

• Acetylation polymorphism 乙酰化多态性
• Butylcholinesterase alterations 丁基胆碱酯酶改变
• Cytochrome P450 aberration 细胞色素P450畸变

5. Pharmacogenomics 药物治疗学

What is Pharmacotherapeutics

• study of how drug may be used in the treatment of disease
• which among the drugs would be most effective or appropriate for a specific disorder or what dose would be required
• Use of drugs and clinical indications of drugs to prevent and treat disease

6. Toxicology 毒理学

Toxicology was defined as the basic science of poison, now defined as the quantitative and qualitative study of the adverse effects of toxicants on biological organisms

Toxicant is a chemical or physical agent that produces adverse effects on biological organisms.

How toxicants enter, effect, and being eliminated from the organism

All substances are toxic if taken in the wrong quantities

二、Drug Classifications

Molecular nature:

• Chemical agents
• Biologics 生物制剂
• Complementary therapies （补充疗法、辅助疗法）、

Methods of distribution:

• OTC drug
• Prescription drug

Classified by Molecular Nature

1. Traditional Drugs Are Chemical Agents

Synthesized in a laboratory

Produce biological responses in the body

• If desirable response—therapeutic
• If undesirable response—adverse

2. Examples of Biologics

1. Hormones
2. Monoclonal antibodies
3. Natural blood products and components
4. Interferon 干扰素
5. Vaccines

3. Complementary and Alternative Therapies

Natural plant extracts, herbs, vitamins, minerals, dietary supplements

Acupuncture, hypnosis, biofeedback, massages

针灸，催眠，生物反馈，按摩

Classified by Methods of Distribution

1. Advantages and Disadvantages of Prescription Drugs

Advantages

• Health-care provider examines the client and orders proper drug
  • Amount and frequency of drug is controlled
  • Instructions on use and side effects of drug are discussed

Disadvantages

• Require a prescription to obtain
• Need for health-care-provider appointment

2. Advantages and Disadvantages of OTC Drugs

Advantages

• No health-care provider appointment required
• Often less expensive than prescription drugs

Disadvantages

• Client may choose wrong drug
• Client may not know reactions or interactions
• Ineffective treatment may
• result in progression of disease

Properties of Ideal Drug

1. Important properties

1. Effectiveness

   • A drug that elicits the response it was meant to. It is the most important property.
   • No effect=no justification of use (FDA approved with appropriate experiments)

2. Safety:

   • Pharmakon = poison in Greek

   • Safe even at high concentrations and for long periods of administration (no such thing as a safe drug

     • Reduced by proper administration (iv, ip im, sc, etc,.)
     • NO habit forming aspects
     • No side effects

3. Selectivity

   • One that elicits only the response for which it is given

   • Selective for specific reaction with no side effects(there Is no such thing)

     • Drowsiness can be caused by antihistamines 抗组胺药

     • Morning sickness, cramps, and depression can be caused by oral contraceptives

       • 口服避孕药可以引起孕吐、痉挛和抑郁症

     • Constipation, urinary hesitance, and respiratory depression can be caused by morphine

       • 吗啡可引起便秘、尿潴留和呼吸抑制

2. Additional Properties of Ideal Drug

1. Reversible action
   • Effects be reversible, i. e, removal /subside w/i specific time (1/2 life is short but potent during that time)
   • Example: General Anesthetic; Contraceptives
2. Predictability
   • Know how patient will respond Ease of Administration
3. Ease of Administration
   • Number of doses should be bw and easy to administer
   • (1) increase compliance & (2) decrease errors
     • Diabetic patient Multiple daily injection of insulin
     • Intravenous infusion
4. Freedom from drug interactions
   • Should not augment or decrease action of other drugs or have adverse combined effects
     • Respiratory depression caused by diazepam (valium) which is normally minimal, can greatly be intensified by alcohol
     • Antibacterial effects of Tetracycline can be greatly reduced by taking ron or calcium supplements
5. Low cost
   • Easy to afford (especially with chronic illness)
     • Growth hormone (somatrem)costs between $10, 000 ad 20000
     • Lifelong medication: hyper tension, arthritis, diabetes
6. Chemical Stability
   • No lose of effectiveness with storage
7. Possession of a simple generic name
   • Easy to remember and pronounce
     • Example: Viagra (sildenafil); Tyleno (acetaminophen)

Ideal Drug should also have ideal Name

• Each drug has at least three names
  • Chemical
    • Description of the drug using chemical nomenclature
  • Generic
    • Non‐proprietary name
  • Trade
    • Proprietary or brand names
    • Created by companies to sell drugs

三、Principles of Drug Action

Drugs do not produce new function

No drug has a single action

• have both therapeutic and adverse actions
• Or have multiple therapeutic effects

Drug vs poison: dose related

Therapeutic actions are interchangeable

• Actions can be considered therapeutic in one case and adverse in another
• e.g. acetaminophen (anti-fever, but causes liver toxicity)

Drug’s effects are variable?

• It depends
• Many sources of variability
  • Disease state, age and sex
  • route of drug administration, dose, drug interactions
• Deciding to use a drug
  • weigh benefits vs. risks
  • there are always risks

Therapeutic Objective

To provide maximum benefit with minimum harm

Factors that determine Intensity of Response:

• Administration- dosage size and route
  • Because of errors in administration routes and dosage and at wrong time there are many discrepancies（差异） in what patient gets and could cause more harm than good
  • Errors could be made by pharmacists, physicians, or nurses
  • Should give patients complete instruction about their medication and how to take it
• Pharmacokinetic processes
  • Determines how much of an administered dose gets to its sites of action
    • drug absorption
    • drug distribution
    • drug metabolism
    • drug excretion
• Pharmacodynamics
  • Once a drug has reached is site of action, pharmacodynamic processes determine the type of response and intensity
    • Drug must first bind to its specific target site at (RECEPTOR) that may be a chemical, a protein on a cell or in blood or tissue spaces, or on a bacteria or virus (i.e., heparin, antibody, leukotriene receptor (new), penicillin, etc…)
    • Followed by a sequence of events that result in response (inhibition of clotting, inhibition of peptidoglycan synthesis, inhibition of inflammation, blocking of virus, etc …).
  • Functional state of the patient is also important Tolerance to morphine will cause less of a response & placebo effects may help determine response
• Individual Variations
  • Each patient is unique in ability to respond and to how they each respond, but formation of “IDEAL DRUG” will lessen this variation
    • Age- very important factor
    • Sex- due to hormonal differences
    • Weight - less effective and longer lasting in obese individuals (storage in fat)
    • Kidney & liver functions elimination of drug
    • Genetic variables tolerance, allergy (though not always genetic)

Factors that determine the intensity of drug response

Prescribed dose → Administered dose: Administration

• Medication errors
• Patient compliance（病人的配合度）

Administered dose → Concentration at sites of action: Pharmacokinetics & Sources of Individual Variation

• Pharmacokinetics
  • Absorption
  • Distribution
  • Metabolism
  • Excretion
• Source of individual variations
  • physiological variables
  • pathological variables
  • genetic variables
  • drug interactions

Concentration at sites of action → Intensity of Responses: Pharmacodynamics

• drug-receptor interaction

• patient’s functional state

• placebo effects

四、Modern Pharmacology

Began in Early 1800s

Chemists isolated pharmacological substances from natural substances

Effects on animals studied

Early researchers used themselves as test subjects

• Pharmacology Recognized as Distinct Discipline

First department of pharmacology established at Estonia in 1847

John Jacob Abe

• Father of American pharmacology
• Founded first pharmacology department in United States at University of Michigan in 1890

United States Pharmacopoeia (USP), 1820

• First comprehensive publication of drug standards
• Summarized standards of drug
  • Purity
  • Strength
  • Directions for synthesis

Food and Drug Administration (FDA)

Officially established in 1988

Agency of US Department of Health and Human Services in 1988

1. Center for Drug Evaluation and Research

• Branch of FDA
• Determines safety and efficacy of drugs
• Pharmaceutical laboratories must solicit approval from FDA before marketing a drug

2. Center for Biologics Evaluation and Research (CBER)

• Branch of FDA
• Regulates use of biologics (serums, vaccines, and blood products)
• 1986 Childhood Vaccine Act result of CBER work

3. Four Stages of Approval for Therapeutic and Biologic Drugs

Step1: Preclinical investigation 临床前研究

Involves laboratory research

Tests done on cells and animals

Determines drug-dose range

Examines adverse effects

Results are considered inconclusive

Step2: Clinical Investigation 临床研究

Longest part of approval process

Termed ―clinical-trials phase

Evaluates human benefits

Step3: Review of New Drug Application (NDA)

Average review time 17–24 months

Drug approved: process continues

Drug rejected: process suspended

Step4: Post Marketing Surveillance 上市后监管

New drug placed on market

Surveyed for harmful effects in larger population

FDA holds annual public meetings

Introduction to the CTA & NDA process in China

1. China Food and Drug Administration(CFDA)

Main responsibilities

• The implementation and enforcement of pharmaceutical rules and laws
• Regulations for all drug, food, supplement, medical device, and cosmetics in China
• The inspection, sales, research, and advertisement of drug, food, supplement, medical device, and cosmetics products
• Drug approvals