MODULE 1: THE DEVELOPMENT OF PHARMACEUTICAL INDUSTRY

1. Disease has been recognized as an enemy of humankind, it is an affliction by the gods.

2. Egyptian therapies focused on purging the affliction, appeasing deities.

3. Greeks became essentially theoretical following four basic concepts: humours: black bile, yellow bile, blood, phlegm became the framework of health and disease.

4. Greek medicine placed a rather little emphasis on herbal remedies. It was in the mid 19th century that chemistry and biology advanced sufficiently.

WHAT HAPPENED DURING THE EARLY YEARS? (4)

1. (Lind, 1793)

2. (Jenner, 1798)

3. (Semmelweis, 1861)

4. (1864)

19th Century

1. Control of scurvy

2. Vaccination

3. Surgical infection using Aseptic Techniques

4. British Pharmacopoeia

1. Evolving science of biomedicine

2. Emergence Of Synthetic Organic Chemistry

3. Development Of Chemical Industry In Europe

In the late 19th century, three essential strands come together: (3)

Rudolf Virchow

Cell Theory

Rudolf Buccheim, Magendie and Claude

Birth of pharmacology As scientific Discipline

Louis Pasteur

Germ theory of disease

Airborne infection was the underlying cause

What is Germ Theory of Disease?

Louis Pasteur

Immunization Procedures

Paul Ehrlich

Chemotherapy

Compound 606

A drug for syphilis

Salvarsan or Arsphenamine

Compound 606 is also known as

Salvarsan (Compound 606)

Receptor and Magic bullet

Salvarsan (Compound 606)

Antitoxin for bacteria

Diethyl Ether (1950s)

Sweet oil of vitriol

Nitrous Oxide

StupefyIng agent

Amyl Nitrite

A potent vasodilator

Amyl Nitrite

First therapeutic drug to come from synthetic chemistry (Gunthrie, 1859)

Amyl Nitrite

Vasodilating effects (Brunton, 1864)

Aniline

Precursor For mauveine (an accidental chemical discovery by Perkin for supposedly quinine, 1865)

Quinine

initially antimalarial drug

Kekule, 1865

Benzene

1. Physicians felt the need to issue prescriptions to satisfy patient expectations.

2. Isolation of active substances from plant extracts.

3. Companies start to flourish

4. Synthetic chemistry became the source of new compounds starting with aniline-based dye

5. Separation of apothecaries and medical trade from the dyestuff industry.

APOTHECARIES’ TRADE (5)

Morphnine

First alkaloid

Alkaloids

nitrogen containing compounds

• Kjeldahl Method

1. Morphine

2. : Emetine

3. strychnine

4. caffeine

5. quinine

Isolation of active substances from plant extracts examples (5)

Merck

first local apothecary in 1827

Scheringer and Boeringer

this company flourish in 19th century

Squibb

ether (main product in 1858)

Parke Davis and Eli lilly

manufacturing chemists; purified Adrenaline

Bayer, Hoechst, Agfa, Sandoz, Geigy

dyestuff manufacturers

1. Principles of Biomedicine

2. Principles of Chemistry

To turn this ambitious new industry into a source of human benefit rather than a corporate profit, it required TWO things:

Principles of Biomedicine

Understanding how disease and drugs work respectively.

Principles of Chemistry

Going beyond color, crystallinity, but an understanding of the structure and properties of molecules and how to synthesize them in the laboratory.

1. Antipyretics

2. Chloral Hydrate

3. Barbital

4. Urea

5. Procaine

6. Cocaine

THE INDUSTRY ENTERS THE 20TH CENTURY (6)

Chloral Hydrate

First nonvolatile CNS depressant

Barbital

by von Mering and Fischer (clinical introduction in 1904)

Urea

by Hilaire

Procaine

by Einthorn, first local anesthetic drug

Cocaine

had a local anesthetic action in the eye

Cocaine

used by Sigmund Freud and was relieved of indigestion; offered cocaine to his friends and caused addiction.

1. Synthetic Chemistry

2. Natural Product Chemistry

CHEMISTRY-DRIVEN DISCOVERIES (2)

Synthetic Chemistry

Became the established model in the early part of the 20th century.

Synthetic Chemistry

Key discipline in drug discovery; prevailed for 50 years.

Synthetic Chemistry

Research management was largely at hand of the chemists.

Synthetic Chemistry

Drugs produced benzodiazepines, tranquilizers, antiepileptic drugs, antihypertensive, antipsychotics.

Synthetic Chemistry

Classifications of drugs is based on the chemical structure rather than the site/mode of action

• “Phenobarbital incident”, “Phenytoin”

Natural Product Chemistry

Pharmaceutical companies on "love-hate" relationship and pharmaceutical industry has difficulty in synthesizing structures

1. Penicillin

2. Chloramphenicol

3. Tetracycline

4. Streptomycin

5. Vincristine and Vinblastine

6. Paclitaxel

7. Ciclosporin

8. Tacrolimus

9. Mevastatin

Natural Product Chemistry examples (9)

1. Penicillin - 1929

2. Chloramphenicol - 1947

3. Tetracycline - 1948

4. Streptomycin - 1949

5. Vincristine and Vinblastine - 1958

6. Paclitaxel - 1971

7. Ciclosporin - 1972

8. Tacrolimus - 1993

9. Mevastatin - 1976

YEAR?

1. Penicillin

2. Chloramphenicol

3. Tetracycline

4. Streptomycin

5. Vincristine and Vinblastine

6. Paclitaxel

7. Ciclosporin

8. Tacrolimus

9. Mevastatin

Target-Driven Discoveries

Concept of Chemotherapy

Paul Ehrlich

first modernist who defined the principles of drug specificity in terms of specific interaction between a drug molecule and target molecule.

• magic bullet

Agents only work when they are BOUND

“Corpora non agunt nisi fixata” means?

Target-Driven Discoveries

Chemistry remained empiric for many years

IG Farbenindustrie

Interest in preparing antimicrobial drugs

Prontosil (sulfanilamide)

Saved life of Domagk's daughter

Sulfonamide

this structure proved to be a rich source of molecules with many pharmacologic properties.

Prontosil (1932)

First antibacterial drug

Sulfanilamide (1935)

Active metabolite of Prontosil

Carbutamide (1955)

First oral hypoglycemic drug

Acetazolamide (1949)

First carbonic anhydrase inhibitor

Chlorothiazide (1957)

Major improvement in diuretics

Diazoxide (1961)

Novel hypotensive drug

Furosemide (1962)

First loop diuretic

Antimetabolite principles

By Hitching and Elions in 1944

Antimetabolite principles by Hitching and Elions in 1944

Interest in the synthesis of folic acid, purines, and pyrimidines as chemotherapeutic agents.

Antimetabolite principles by Hitching and Elions in 1944

Identified dihydrofolate reductase which is necessary for DNA synthesis. Pyrimidine analogues inhibited the enzyme.

1. Pyrimethamine

2. Trimethoprim

3. 6-mercaptopurine

4. Azathioprine

5. Acyclovir

6. Zidovudine

Emergent drugs in antimetabolite principles include: (6)

1. Ligand-receptor interactions

2. Beta-adrenoreceptor blocking agent

3. H2-receptor antagonist

JAMES BLACK AND RECEPTOR- TARGETED DRUGS (3)

Ligand-receptor interactions

• Drug antagonism

• Classes of receptors have varied effects

Beta-adrenoreceptor blocking agent

• Pronethalol| (1960) - toxic

• Propranolol (1964)

H2-receptor antagonist

• Burimamide (1972) - first to have an action on H2 receptors in healthy human volunteers

• Cimetidine (1977) - at Smith, Kline and French Laboratories

Burimamide (1972)

first to have an action on H2 receptors in healthy human volunteers

1. Pronethalol| (1960)

2. Propranolol (1964)

3. Burimamide (1972)

4. Cimetidine (1977)

YEAR?

1. Pronethalol|

2. Propranolol

3. Burimamide

4. Cimetidine

1. Digitalis - in treating dropsy

2. Antidysrhythmic effect of quinine

3. Amphetamine to treat ADHD

4. Laborit's discovery of Phenothiazine

5. Promethazine causing sedation

ACCIDENTAL CLINICAL DISCOVERIES (5)

1. 1900s

2. 1937

3. 1960

4. 1963

YEARS OF EVENTS LEADING TO ESTABLISHMENT OF REGULATORY PROCESS (4)

1990s

YEAR

• System of "prescription only" medicines

• What info should be on the label

• System of "what cures”

• Controlling of addictive substances

1937

YEAR

• Diethylene glycol caused death

• Demonstrated the need for safety

1960

YEAR

• Thalidomide disaster

• Chemie Grunenthal

• UK began to follow US regulatory laws in safety

• Urgent reappraisal because of the incident

1963

YEAR

• Establishment of Commission on the Safety of Drugs.

• A new drug has to be submitted for approval before clinical trials and market release.

Medicines Act

• Closed the loophole

• Added efficacy

Rational Drug Design

Ability to predict the appropriate molecular structure of a drug based on information about its biological receptor.

1. receptor

2. druggable

3. active substance

Vaccine → COVID-19 (1. ________) → Target (2. _________) → Lead compound (3. ______ ________)

Computational Chemistry and Computer-Aided Drug Design

CADD means?

Computational Chemistry and Computer-Aided Drug Design (CADD)

are the current trends in drug discovery.

1. yellow bile

2. black bile

3. phlegm

4. blood

Greek’s framework of health and disease in early years (4)