PMOC M1: Introduction to Pharmaceutical and Medicinal Organic Chemistry

Medicinal Chemistry

Branch of chemistry involved in identification, design, synthesis, and development of biologically active compounds

Medicinal Chemistry - An interdisciplinary science

- Organic Chemistry

- Biochemistry

- Computational Chemistry

- Pharmacology

- Pharmacognosy

- Molecular biology

- Physical Chemistry

Faurerouy and Vauquehin (1793)

Incorporated chemistry into Pharmacy curriculum

Derosome (1803)

Isolation of narcotine by _______

Party drugs (1840)

- Use of _________ to anesthetics

- Ether, chloroform, nitrous oxide

Adophe Kolbe (1845)

______________ synthesized acetic acid

William Henry Perkin (1853)

Functional groups

Pierre Berthelot (1856)

_________________ synthesized methane

Joseph Lister (1867)

Carbolic acid as an antiseptic

Charles Romley Alder Wright (1874)

___________________ synthesized diacetylmorphine

Era of analgesics (1875)

- _____________________

- Isolation of salicylic acid from Spirea ulmaria

Salol (1883)

- Ester of salicylic acid and phenol

- Poor solubility

- Better tolerated by patient

Phenazone (1884)

Antipyrine (NSAID)

Dionin (1898)

- Ethyl ether morphine

- Cough sedative

Dionin (1898)

Safer alternative to morphine

Dionin (1898)

"Heroic drug" hence the name Heroin

Heroin

Elicit drug

Sachiro Hata (1910)

__________ developed salvarsan for treatment of syphilis

Frederick Banting (1922)

___________ discovered insulin

Alexander Fleming (1929)

Discovery of penicillin

Gerard Domagk (1932)

Red dye of prontosil

Florey and Chain (1941)

Purified penicillin

Selman Waksman (1944)

- Streptomycin (RIPES - AntiTB)

- No longer used

Guiseppe Brotzu (1948)

Cephalosporins

Bartz (1948)

Chloramphenicol

Duggar (1948)

Tetracycline

Sulfonamides (1950)

Birth of ________

Hansch and Fujita (1960)

Quantitative Structure Activity Relationship (QSAR)

1970

Cimetidine and ranitidine

Daniel Bovet

Sulfanilamide

Louis Lasagna

Controlled clinical trials and placebo

Early 20th century

Anesthetic agents

Lead Compound

Chemical compounds with pharmacological or biological activity

Lead Compound

Chemical structure is used as a starting point for chemical modifications to improve potency, selectivity, or pharmacokinetic parameters

Drugs

Low molecular weight chemical substances that interact with macromolecular targets in the body to produce effect

Drugs

Chemical compounds used to treat, mitigate, diagnose and prevent disease in both humans and animals

Prodrug

Any compound that undergoes biotransformation prior to exhibiting its pharmacological effects

Why do we formulate prodrugs?

1. Improve absorption and patient acceptance

2. Reduce toxicity

3. Slow release of drugs in the body

Examples of prodrugs

- Carisoprodol -> meprobomate

- Enalapril -> Enalapril (Estarase)

- Valaciclovir -> Acyclovir (Estarase)

- Levodopa -> Dopamine (DOPA decarboxylase)

Codrug

AKA: Mutual prodrug

Codrug

Two synergistic drugs chemically linked together

Codrug

Improves the drug delivery of one or both drugs

Codrug

Examples:

- Sulfapyridine + 5-aminosalicylic acid: Sulfasalazin

- Ampicillin + Sulbactam: Sultamicillin

Orphan Drug

Drug specifically developed to treat a rare medical condition, often called an orphan disease

- Example: Cystic fibrosis

Gaucher's Disease

Cause: Glucocebrosidase

Orphan drug: Miglustat

Fabry's Disease

Cause: Galactosidase

Orphan drug: Galsidase β

Mucopolysaccharidosis

Cause: Lysosomal enzymes

Orphan drug: Laronidase

Tourette's Syndrome

Cause: Motor tics

Orphan drug: Lamotrizine

Crohn's Syndrome

Cause: Unknown

Orphan drug: Infliximab

Wilson's Disease

Cause: Copper deposition

Orphan drug: Trientine

SCID

Cause: Adenosine Deaminase

Orphan drug: Pegadimase

Pharmacophore

Part of the drug with the essential functional group that interacts with the receptors active site

Pharmacodynamics

What the DRUG does to the BODY

Pharmacodynamics

Design a drug that will interact as powerfully and selectively as possible for the target

Endogenous Compounds

- Body's own natural chemicals

- Example: Adrenaline, Oxytocin

Exogenous Compounds

- Foreign substances

- Example: Drugs

Drug

- Target

- Response/Effect

- Therapeutic

- Sub therapeutic

- Toxic

Pharmacokinetics

What the BODY does to the DRUG

Pharmacokinetics

Design the drug so that it is capable of reaching that target

Pharmacokinetics

L - Liberation

A - Absorption

D - Distribution

M - Metabolism

E - Excretion

R - Recycling/Response

Liberation

Conventional dosage forms are administered orally or topically

Liberation

ACTIVE DRUG in the dosage form is immediately RELEASED and ABSORBED into the systemic circulation

Diffusion

Most common mechanism controlling drug release

Absorption

- Oral administration

- Parenteral administration

Oral administration

- The most common and popular route

- Stomach

- Small intestine

Fed state

1.5-2 pH

Fasting state

2-6 pH

Small intestine

Main site of absorption

Unionized

Acidic drug + Acidic medium → ________

Basic drug + Basic medium → ________

Ionized

Acidic drug + Basic medium → ________

Basic drug + Acidic medium → ________

Unionized

At what medium are acidic drugs readily absorbed?

More ABSORBED > _________ → A + A

Ionized

At what medium are acidic drugs readily excreted?

More EXCRETED > _________ → A + B

Parenteral administration

- Direct to systemic circulation

- Rapidly distributed

- 100% Bioavailability

Parenteral Administration

Examples:

IV, IM, SC/SQ, intraspinal, intracerebral, intrathecal, intraarterial, intrasynovial

Blood Brain Barrier (BBB)

Presence of tightly joined epithelial that lines the cerebral capillaries

Blood Brain Barrier (BBB)

Protects the brain from exposure to metabolites and chemical

Distribution

- Blood flow

- Drug movement from the systemic circulation going to different tissue and organs

- Perfusion

Perfusion

- Delivery of drug to tissues

- Controlled by specific blood flow to a tissue

Metabolism

AKA: Biotransformation

Metabolism

Most molecules absorbed from the GIT enter the portal vein and are initially transported to the liver

Metabolism

All substances in the circulatory system (drugs, metabolites, and nutrients) will pass through the liver

Liver

Main site for drug and toxin metabolism

Bioactivation

- Azathioprine (immunosuppressant) → 6-mercaptopurine

- Acyclovir (antiviral) → Acyclovir Triphosphate

First-Pass Effect

Significant proportion of a drug is metabolized by hepatic enzymes during the initial trip through the liver

First-Pass Effect

Drug removal by the liver after absorption

First-Pass Effect

Example: Lidocaine (Anesthetic)

- 60% metabolized

Enzyme Induction

Increase metabolism

Enzyme Inhibition

Decrease metabolism

Enterohepatic Circulation

AKA: Biliary Recycling

Enterohepatic Circulation

Drug reenters the intestinal tract from the liver through bile duct

Excretion

AKA: Elimination

Excretion

Major route of elimination for metabolites and unchanged drugs is via excretion into the urine

Glomerular filtration

Unbound drug is PASSIVELY FILTERED by the GLOMERULUS

Tubular secretion

Drug is ACTIVELY SECRETED

Tubular reabsorption

Drug is PASSIVELY REABSORBED back into the BLOOD