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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