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Definitions
Physiology- science which treats the functions of the living
organism & its parts
Pharmacology- science of the effect of drugs in all aspects
a- A/D/M/E
b- effects & mechanism of action
c- toxicity & drug interactions
Pharmacognacy - (neutraceuticals/herbs)
Pharmacy- science of preparation, compounding & dispensing
of drugs
Therapeutics- application of pharmacology to the therapy of
disease
agonist (A) ↔ (A) (receptor) ↔ response
Agonist: stimulus (ex. specific ligand for receptor mediated response)
experimental value:
reveals potential for response.
however, endogenous agonist may not exist.
Antagonist: (ex. specific inhibitor of receptor mediated response)
experimental value:
response indicates blockade of endogenous
functional agonist
Placebo:
inert medication
essential component of experimental analysis
30% response to placebo in some situations
Test Question: (resource text- Lippincott; Chapters 1 & 2)
Discuss the relevant pharmacokinetic and
pharmacodynamic characteristics of a theoretically ideal
antagonist to be applied in the following specific situation.
The goal is to employ the antagonist (antibiotic) to cure a
bacterial infection in the prostate gland fluid, and that the pH of
infected prostate fluid is basic relative to plasma. Assume that
the mechanism of antagonist action will be to prevent a
requisite endogenous cell-cycle specific ligand-receptor
interaction in the bacterial cell wall. The antagonist will be
administered to an individual suffering from vascular pathology
associated with long-standing poorly controlled diabetes
mellitus.
please limit your answer to 3 single sided pages
think: Specificity
“tissue Space” Vracko: Am J Pathology 77;313,1974
think:
GIliverbloodGU(prostateprostate fluidbacteria)
Absorption:
- generally viewed as absorption from site
of administration into blood
Absorption:
think: Specificity
routes of drug administration: key factors in absorption into vascular system
- perfusion of site
- chemistry of drug preparation
- disintegration/dissolution for solid
- dissolution for suspension
- solutions
- diffusion:
- lipid/water partition
- size/molecular weight
- transport systems
“enteral vs. parenteral”
“via intestine vs. other”
Oral route of administration
Advantages:
- convenient, human acceptance
(other species?)
- relatively safe
Issues:
- bioavailability (fraction of dose appearing in blood)*
- inert with respect to GI acid, enzymes & food
- lipid/water partition & size
- resistance to hepatic metabolism
(i.e. minimal “first pass effect”)
- super-infection in GI tract with antibiotics
ideal bioavailability & mechanisms ??
Oral route of administration
Advantages:
- convenient, human acceptance
(other species?)
- relatively safe
Issues:
- bioavailability (fraction of dose appearing in blood)
- inert with respect to GI acid, enzymes & food
- lipid/water partition & size*
- resistance to hepatic metabolism
(i.e. minimal “first pass effect”)
- super-infection in GI tract with antibiotics
drug penetration through cell
membranes:
- aqueous channels <100 mw
- most important process:
passive diffusion due to
lipid/water partition & size
- methodology for partition
coefficient
impact of size & partition coefficient (olive oil/water) on permeability
Oral route of administration
Advantages:
- convenient, human acceptance
(other species?)
- relatively safe
Issues:
- bioavailability (fraction of dose appearing in blood)
- inert with respect to GI acid, enzymes & food
- lipid/water partition & size
- resistance to hepatic metabolism
(i.e. minimal “first pass effect”)*
- super-infection in GI tract with antibiotics
“first pass” effect, hepatic metabolism & bioavailability:
Oral route of administration
Advantages:
- convenient, human acceptance
(other species?)
- relatively safe
Issues:
- bioavailability (fraction of dose appearing in blood)
- inert with respect to GI acid, enzymes & food
- lipid/water partition & size
- resistance to hepatic metabolism
(i.e. minimal “first pass effect”)
- super-infection in GI tract with antibiotics*
relevant to super-infection in GI tract if unabsorbed active drug
normal GI flora: relevance to potential superinfection
Distribution:
think: Specificity
Drug Distribution
Generally implies initial distribution from blood to
tissue space (fluids & cells) & epithelium
- protein binding in plasma
- organ perfusion
- specialized capillary barriers
- lipid/water partition & size for diffusion
- transport systems
- ion trapping in cellular/extracellular fluid*
- protein binding in cells (host or bacteria)*
drug distribution
ideal ? total body water? (think specificity)
“tissue Space” Vracko: Am J Pathology 77;313,1974
think:
GIliverbloodGU(prostateprostate fluidbacteria)
Metabolism & Excretion
think: Specificity
Understanding constant
half-life with first order
kinetics:
- oral dosing @ half-life intervals
- steady state (peak/trough) @ 4-5 half-lives
- note: rate of decline should be slower at lower blood levels
ideal?
ideal plasma kinetics?
first order:
- constant half-life
- predictable dosing regimens
(therapeutic vs. toxic range)
t1/2 = practicality (? hours)
- oral dosing @ half-life intervals
- steady state (peak/trough) @ 4-5 half-lives
- note: rate of decline should be slower at lower blood levels
Consider a Loading Dose
good & bad of hepatic metabolism
- hepatic portal vein from intestine
- portal venous & arterial blood perfuse into
capillary spaces (sinusoids) between
cells (hepatocytes)
- hepatocytes form bile & water soluble
metabolites primarily for
renal excretion
- selective active secretion into bile;
little diffusion
- central vein to vena cava
Hepatic metabolism* to increase water solubility & enhance
excretion by kidney/urine & liver/bile/intestine
Phase I (oxidation/reduction) in smooth ER
- oxidation via cytochrome P450 enzymes
- other
Phase II (conjugation) in cytosol with:
- sulfate
- glucose
- acetate
- glutathione
- amino acids
* primarily in liver (smooth ER & cytosol)
Cytochrome P450:
- hydroxylations
- hydrophilic
- isozymes
Hepatic endoplasmic reticulum:
- smooth ER
- site for P450 oxidation
- surface area & enzymatic activity may
double in 2-3 days in response to drug substrate
Metabolism to Enhance Excretion:
superinfection with GI antibiotics: issue of GI-hepatic recycling
GI-hepatic recycling:
Bile
Liver: conjugated
water soluble steroids
Plasma: E 2and P
Intestinal lum en
Bacter ial deconjugation
and reabsor ption
Oral adm inistration
Fecal excr etion
isoniazid (INH)
toxicity via
metabolism
hepatic metabolism & biliary excretion:
ideal? (inert as a substrate)
avoid issues of :
- bioavailability (first-pass effect)
- plasma t1/2 variations (genetics, age, other drugs)
- toxic metabolites
- secretion of antibiotic into intestine
Renal Excretion:
ideal?
- GFR
Theoretical mechanisms for selective concentration at site of action:
ion trapping; bio-activation; receptor binding
Pharmacokinetics:
- tissue fate (effect of target on agonist/antagonist)
- ion trapping
- bioactivation
- receptor specificity (tissue & chemical)
Ion trapping
plasma pH = 7.4
infected prostate fluid pH = 8.2
weak acid antibiotic
- equal plasma-prostate fluid concentrations of
non-ionized drug
- greater ionization of drug in basic fluid than plasma
- greater total drug in basic fluid then plasma
ion trapping & differential total drug
concentration based on pH difference
relevant if ionized & non-ionized are each
biologically active
weak acid drug concentrated in basic (pH
8.2) fluid of infected prostate relative to
plasma (pH 7.4)
- due to greater ionization (A-) at
basic pH
- ionized form (A-) “trapped”
pH = pKa + log [A-]/[HA]
calculating total drug concentrations:
- know pH, pKa & total plasma concentration
- calculate [A-]/[HA] at plasma pH
- calculate [HA] at plasma pH, assume same at prostate fluid pH
- calculate [A-]/[HA] at prostate fluid pH
- use [HA] to determine [A-] at prostate fluid pH & sum
ideal fate in prostate fluid?
specificity & concept of
bioactivation
• theoretical application to specificity of
antibacterial action ?
- site of bioactivation
- pharmacodynamic action of substrate
vs. product
- kinetics of product
note: precedent for testosterone action
E. Jensen et al.: Fate of s.c. 3H-estadiol in the female rat
- significance of the organ-specific estrogen receptor
(accumulation/retention in estrogen-dependent organs)
- significance of competitive antagonism by an anti-estrogen (PD)
predict much greater accumulation/retention of PD vs. estradiol
think: potential analogy to bacteria & antibiotic
Estrogen(E) + Receptor(R)  ER  response

anti-estrogen
receptors: general concepts
- tissue specificity
- chemical specificity & high affinity
- requisite interaction with ligand for response
think: antibiotic interaction with bacterial receptor
(blocks interaction of endogenous bacterial ligand with its receptor)
administration of 3 different drugs acting on same receptor
- potency @ ED50
- intrinsic activity @ maximum
- drug “c” is a partial agonist
Affinity vs. Efficacy
Drug + Receptor
Complex  Response
affinity
efficacy
Affinity vs. Efficacy
Drug + Receptor
Complex  Response
affinity
efficacy
Insulin resistance in Type II diabetes:
- reduced receptor concentration with obesity
Consider the changes in the dose response curve with these abnormalities
Understanding the dose response curve:
- affinity
- efficacy
Affinity vs. Efficacy
Drug + Receptor
Complex
affinity
Agonist-
Antagonist (ideal?) -
Response
efficacy
Competitive antagonism:
effect of agonist (a) alone & in the presence
of increasing doses (b-d) of an antagonist
antagonism:
a) doses of agonist alone
b-d) agonist dose response the presence of increasing concentrations of
irreversible, competitive antagonist (note same ED50)
advantages of irreversible antagonist: (t1/2 &  maximum @
saturation)
plasma concentrations with oral dosing @ plasma half-life
- consider fate in bacteria from ion trapping of antibiotic
in prostate fluid & longer t1/2 in bacteria due to receptor binding
ideal? bacterial receptor saturation due to selective accumulation
Vascular Pathology (angiopathy) in Diabetes
macroangiopathy: not diabetic-specific, but accelerated rate and greater incidence
- atherosclerosis of coronary & peripheral arteries
- occlusive lesion due to abnormal smooth muscle proliferation
& migration toward lumen; fatty deposits & calcification
microangiopathy: specific to uncontrolled diabetes (hyperglycemia)
- impairment of microcirculation (arterioles & capillaries)
- notable in skin (ulcers), retina (blindness), glomerulus of kidney (renal failure)
and peripheral nerves (sensory systems & organs innervated by voluntary/motor
& involuntary/autonomic neurons)
- initially non-occlusive, subsequently occlusive → ↓ perfusion
- ↑ intra-capillary pressure (endothelial damage, ↓NO, inability to
dilate/autoregulate on efferent side of capillary beds)*
-↑
permeability/leakage of plasma proteins/growth factors
- ↑ capillary basement membrane thickening
* supportive evidence: less pathology in capillaries distal to
an arterial stenosis (reduced perfusion pressure to downstream capillaries)
Consider the impact of atherosclerosis & capillary basement
membrane thickening of diabetes on:
Dosing regimen (?)
Fick’s Law of Diffusion:
rate =
(concentration gradient) (permeability) (surface area)
__________________________________________
(molecular weight) (thickness)
Choice of a cell-cycle specific or cell-cycle-independent
antagonist (?)
Antagonist (antibiotic):
cell-cycle specific: constant drug (antagonist) exposure to
maximize chance for interaction during susceptible
phase
cell-cycle independent: potential for maximal lethal effect
with short-term occupancy
Ideal? Cell-cycle specific of independent?
Ideal plasma kinetics for cell-cycle dependent?
Method of administration?
Loading dose?
pharmacodynamics:
- effect of agonist/antagonist on target tissue
- think: specificity for desired effect & safety
i.e. bacterial cell wall perturbation via
interaction with bacteria-specific receptormediated process
Therapeutic Index
toxic or lethal dose 50 / therapeutic or effective dose 50
LD50 / ED50
Therapeutic Index:
theoretical dose-response curves for ideal drug?
ED50 vs TD50 or LD50
Consider the theoretical adjustments required in the doseresponse curve with diabetic-induced impaired perfusion/drug
diffusion.
Advantages of 24 hour constant release transdermal (patch)
route relative to oral (4 doses/day)
• Bioavailability ?
• Superinfection ?
• Need to increase dose with impaired
perfusion?
• Cell-cycle dependent action?