PCL201 STUDY NOTES
LECTURE 1: Intro
Pharmacology = study of drugs, how substances interact with biological systems, fates+actions in body
Drug = substance used in diagnosis, treatment, mitigation, prevention of disease/disorder
Pharmacokinetics (PK): what body does to drug; ADME: absorption, distribution, metabolism, excretion
Pharmacodynamics (PD): what drug does to body; actions/effects of drug
Drug Nomenclature
1. Chemical Name - recognized worldwide, used in early development
2. Drug Company Code Name - used by companies during early development
3. Non-Proprietary (Generic) Name - official or approved name in pharmacopoeias
4. Proprietary (Brand) Name - assigned by manufacturer, registered trademark
5. Street Name - assigned by public; useful for physicians to know these
Drug Development + Regulation in Canada
A. Synthesis of a compound (up to 4 yrs)
B. Preclinical Testing (3-5 yrs) - animal studies, structure-activity relationships, in vitro assays
C. Clinical Trial Application - must be approved by Health Canada
D. Clinical Trials
1. Phase I (6-9 months) - first human subjects, healthy volunteers, establish pharmacokinetic
parameters + some examination of safety
2. Phase II (6m - 3 yrs) - first patients (usually male), proof-of-concept, dosing adjustments, some
examination of safety
3. Phase III (1-5 yrs) - thousands of patients, comparisons with placebo or standard drug,
examination of safety + efficacy
E. New Drug Submission (NDS) to Health Canada
-contains information about safety, efficacy, and quality of product
-results from preclinical + clinical tests, production, packaging + labelling, adverse effects
F. (Abbreviated NDS)
-generic companies don’t need to show drug efficacy, just need to prove product is the same as
the approved brand-name drug
G. (Supplemental NDS) - used when manufacturer wants to change drug already authorized for sale
(change dosage, intended effects, etc.)
H. Notice of Compliance - NOC+DIN needed to sell product in Canada (if failed, will receive NON)
Note: DIN = drugs in Canada, NPN = natural health products
I. Patented Medicine Prices Review Board (PMPRB) - establishes max price of patented drug, no
regulation over generic drugs
J. Phase IV - post-marketing surveillance, looking mostly for safety
-Patent Act: gives manufacturers 17 years patent protection from date of issue, or 20 years from filing date
Study Design
-Cohort Design: prospective; following groups with different exposure and want to see outcome
-Case-Control Design: compare unaffected and affected populations, look at differing exposures
,LECTURE 2: Drug Properties and Permeation
Concentration-Time Curves
Focus: Oral Drug Absorption
-mainly absorbed by small intestine; very large surface area + rich blood flow
-intestinal barriers: stomach pH very acidic, may destroy drugs
-drugs can be given enteric coating to protect from this environment (intestine made of enterocytes)
-intestinal epithelial cells have tight junctions
Factors Affecting Rate of Drug Diffusion
-properties + concentration of drug, surface area for permeation, contact time, blood flow
, LECTURE 3: Drug Absorption
Mechanisms of Drug Permeation
-Passive Diffusion: water-soluble drugs through aqueous pore, or lipid-soluble drug dissolved in membrane
-Facilitated Diffusion: harder for charged drugs
-Active Transport: requires ATP
-Transcytosis: large drugs typically endocytosed
Drug Properties that affect Permeability
-Size + Structure: water soluble (250-450 Da can diffuse), lipid soluble (<1000 Da can diffuse)
-Water + Lipid Solubility: determined by partition coefficient (P)
-P: (oil/water) or (membrane/buffer); value of P increases with hydrophobicity (lipid solubility)
-lipophilic drugs generally more soluble, but still need to cross unstirred water layer of membrane
-Ionization: uncharged form of drug better able to cross cell membranes
-acidic drugs: pH > pKa = more drug in charged form (A-), reduced absorption
-basic drugs: pH > pKa = more drug in uncharged form (B), increased absorption
-Drug Transporters: often found on basal/apical membranes of hepatocytes, enterocytes, renal tubular cells,
brain capillary cells
-uptake transporters: SLC superfamily (OATs, OATPs, OCTs, OCTNs)
-efflux transporters: ABC superfamily (MDRs, MRPs, BCRP)
Example: P-glycoprotein (MDR1) -known substrate: Digoxin
-part of ABC superfamily; removes drugs from tumour cells (often overexpressed in cancer patients)
-also expressed in numerous healthy cells; need inhibitor that only targets cancer cells
LECTURE 1: Intro
Pharmacology = study of drugs, how substances interact with biological systems, fates+actions in body
Drug = substance used in diagnosis, treatment, mitigation, prevention of disease/disorder
Pharmacokinetics (PK): what body does to drug; ADME: absorption, distribution, metabolism, excretion
Pharmacodynamics (PD): what drug does to body; actions/effects of drug
Drug Nomenclature
1. Chemical Name - recognized worldwide, used in early development
2. Drug Company Code Name - used by companies during early development
3. Non-Proprietary (Generic) Name - official or approved name in pharmacopoeias
4. Proprietary (Brand) Name - assigned by manufacturer, registered trademark
5. Street Name - assigned by public; useful for physicians to know these
Drug Development + Regulation in Canada
A. Synthesis of a compound (up to 4 yrs)
B. Preclinical Testing (3-5 yrs) - animal studies, structure-activity relationships, in vitro assays
C. Clinical Trial Application - must be approved by Health Canada
D. Clinical Trials
1. Phase I (6-9 months) - first human subjects, healthy volunteers, establish pharmacokinetic
parameters + some examination of safety
2. Phase II (6m - 3 yrs) - first patients (usually male), proof-of-concept, dosing adjustments, some
examination of safety
3. Phase III (1-5 yrs) - thousands of patients, comparisons with placebo or standard drug,
examination of safety + efficacy
E. New Drug Submission (NDS) to Health Canada
-contains information about safety, efficacy, and quality of product
-results from preclinical + clinical tests, production, packaging + labelling, adverse effects
F. (Abbreviated NDS)
-generic companies don’t need to show drug efficacy, just need to prove product is the same as
the approved brand-name drug
G. (Supplemental NDS) - used when manufacturer wants to change drug already authorized for sale
(change dosage, intended effects, etc.)
H. Notice of Compliance - NOC+DIN needed to sell product in Canada (if failed, will receive NON)
Note: DIN = drugs in Canada, NPN = natural health products
I. Patented Medicine Prices Review Board (PMPRB) - establishes max price of patented drug, no
regulation over generic drugs
J. Phase IV - post-marketing surveillance, looking mostly for safety
-Patent Act: gives manufacturers 17 years patent protection from date of issue, or 20 years from filing date
Study Design
-Cohort Design: prospective; following groups with different exposure and want to see outcome
-Case-Control Design: compare unaffected and affected populations, look at differing exposures
,LECTURE 2: Drug Properties and Permeation
Concentration-Time Curves
Focus: Oral Drug Absorption
-mainly absorbed by small intestine; very large surface area + rich blood flow
-intestinal barriers: stomach pH very acidic, may destroy drugs
-drugs can be given enteric coating to protect from this environment (intestine made of enterocytes)
-intestinal epithelial cells have tight junctions
Factors Affecting Rate of Drug Diffusion
-properties + concentration of drug, surface area for permeation, contact time, blood flow
, LECTURE 3: Drug Absorption
Mechanisms of Drug Permeation
-Passive Diffusion: water-soluble drugs through aqueous pore, or lipid-soluble drug dissolved in membrane
-Facilitated Diffusion: harder for charged drugs
-Active Transport: requires ATP
-Transcytosis: large drugs typically endocytosed
Drug Properties that affect Permeability
-Size + Structure: water soluble (250-450 Da can diffuse), lipid soluble (<1000 Da can diffuse)
-Water + Lipid Solubility: determined by partition coefficient (P)
-P: (oil/water) or (membrane/buffer); value of P increases with hydrophobicity (lipid solubility)
-lipophilic drugs generally more soluble, but still need to cross unstirred water layer of membrane
-Ionization: uncharged form of drug better able to cross cell membranes
-acidic drugs: pH > pKa = more drug in charged form (A-), reduced absorption
-basic drugs: pH > pKa = more drug in uncharged form (B), increased absorption
-Drug Transporters: often found on basal/apical membranes of hepatocytes, enterocytes, renal tubular cells,
brain capillary cells
-uptake transporters: SLC superfamily (OATs, OATPs, OCTs, OCTNs)
-efflux transporters: ABC superfamily (MDRs, MRPs, BCRP)
Example: P-glycoprotein (MDR1) -known substrate: Digoxin
-part of ABC superfamily; removes drugs from tumour cells (often overexpressed in cancer patients)
-also expressed in numerous healthy cells; need inhibitor that only targets cancer cells
