Chemistry of Pharmacology

Therapeutics - Drugs

Traditional drugs

chemical agents

Therapeutics - Biologics

Antibodies & Hormones

Therapeutics - Natural health products

herbals, vitamins, minerals

Canadian Drug Legislation - 3 directories

• therapeutic products directorates

• biologics & genetic therapies directorates

• natural health product directories

Generic Drug Names

• commonly used by pharmacologist

• uniquely identifies molecules

Trade Names

• assigned by company

• problem - too many different names for same drug

Drug Development Process

• take approx 15 yrs & cost - 800 mil

• move thru levels

Drug Discovery / Preclinical Testing

• step 1

• cultured cells, living tissue or animals

• evaluate biological effects, pharmacokinetics & toxicity

• takes 6.5 yrs

Clinical Trial Application

• step 2

• submit to health canada b4 human studies

• LOTS of paper work w pre-clinical data

• Health Canada responds in 30 days

Phase I Clinical Trial

• 20 - 100 healthy volunteers (not pt)

• looks at pharmacokinetics & pharmacodynamics

• takes 1 yr

Phase II Clinical Trial

• 300- 500 pt w disorder

• evaluate therapeutic effectiveness, side effects & dosing information

• takes 2 yrs

Phase III Clinical Trial

• 500 - 5000 pt w disorder

• effectiveness verified

• long side effects assess

• takes 4 yrs

New Drug Submission to Health Canada

• report of effective & safety

  • from preclinical & clinical studies

• approved with Novice of compliant & drug idenficaiton number

• take 1.5 yrs

What is Required to Market Drugs in Canada

• notice of complication (NOC)

• drug identification number (DIN)

Phase IV Clinical Trial

• last stage of drug development

• Health Canada monitors efficacy & safety while being marked

When can drugs be pulled from market

• if not efficacious or safety questioned

  • Vioxx - sept 2004

Route of Administration — Enteral - involves GI

• oral

  • swallow & absorbed in GI

• Rectal

  • in rectum & dissolves in mucosa into blood stream

Route of Administration — Parental - injection

• intravenous

  • injected in blood stream

• intramuscular

• subcutaneous

Route of Administration - Topical

• creams

• patches

Pharmacokinetics - Oral Route

• swallowed & enters small intestine

• carried by portal vein to liver

• Can go into systemic cirucation or bile duct

Most drugs are absorped

in small intestine

oral route - Systemic Circualtion Delivers to

• heart tissue

• brain tissue

• muscle tissue

• kidney & excrete

Bile duct

drugs goes into intestine & then excreted in fecease

Pharmacokinetics - Parenteral route

• absorbed from site of injection & into systemic circulation

• disturbed to heart, brain, kidney

• can also enter liver & intestine & be excreted with bile thru faces

How is parental route different from oral

• parental it doesn’t go to liver before entering systemically

Bodys Barriers to Drug Transport — intestinal villi

• Protect from injested drugs, toxins & nutrients

Bodys Barriers to Drug Transport — special cells

• some cells have tight junctions to prevent passage

• like Brain cells

Golgi

Process & packaging of proteins & lipids

Smooth Endoplasmic Reticulum

Metabolism of drugs, carbohydrates & steroids

Rough endoplasmic Reticulum

Synthesis of cellular proteins

Cell Membrane

• Critical role in separating intracellular & extracellular 

• Major determinants to which drug will pass – has lipid bilayer 

Nucleus

• source of genetic material (DNA)

Mitrochonia

• source of energy (ATP)

Cell Membrane

• made of phospholipids (polar/water soluble) phosphate head

• 2 fatty acid (lipid soluble) tails

• arrangement makes it lipidbilayer

• embedded proteins

How Drugs cross men

• direct penetration

• thru ion channels & pores

• specific transport proteins

direct penetration

• must be lipid soluble (lipophilic)

• composed of primary lipids

• ex. hydrophilic can’t penetrate

Ions channel & pores

• very small & selective

  • small positive charge ions can pass

  • hydrophilic too big

• compounds (<200 Da) can pass

Which compounds can cross the channels

• Sodium Na+

• potassium K+

• lithium Li+

Drug Transporter - Uptake transporter

• bring drug into cell

• help with

  • interstitial absorption, renal excretion & getting to action site in cell

Drug Transporter - Efflux transporter

• remove drug from cell

• Important for protection

• Found in

  • intestine, placenta, kidney & BBB

Polar Molecules

• water soluble

• uneven distribution but no net charge

Examples of Polar molecules

water

glicose

antibotic kananmycin

Water moles

more electron (-) found around O

this causes uneven distribution

Ions

• atoms or molecule number of electrons (-) is not equal to protons (+)

• have net charge (neg or pos)

• charge ions cannot pass through cell membrane

Examples of ions

sodium na+

potassium k+

chloride cl-

lithium li+

Quaternary Ammonium Compounds

• have 1 nitrogen atom & always positive charged

• positive charge makes it unable to cross mem

Ionized Molecules

• can be charged or uncharged

• determination of weak acid or base depends on surrounding pH

Weak Acid

• Will be non-ionized in stomach (acid)

• Will be ionized in small intestine (alkaline)

Weak base

• ionized in stomach

• non-ionized in small intestine

Acidic pH impact on drug movement

• ionized drugs can’t directly penetrate cell membrane

• aspirin (weak acid) can only pass thru acidic somtach acid

Alkaline pH impact on drug movement

• amphetamine (+) weak base can only pass in small intestine

• will ionized in acidic place

• postive charge repels passage

Ion Trapping

• different in pH on different side of mem

• will become stuck once entering place with different environment

• used in OD cases

Parts of body rich in capillary beds

• lung

  • for brining O to blood & delivery

• GI tract

  • allows nutrients & molecules (drugs) to be carried & delivered

• kidney

  • drugs & toxins delivered to kidney for elimination

Fenestations

• within endothelial cells

• allow moles to pass through to be delivered

Hydrophilic Drugs & Capillaries

• cannot penetrate endothelial cell mem

• must pass in fenestration to exit cap

Lipophilic Drugs & Capillaries

• can penetrate endothelial cell mem — bc lipid bilayer

• can pass thru fenestration

Blood Brain Barrier & Capillaries

• capillaries in BBB have tight junctions & no fesntations

• must be lipophilic or have transport proteins to pass