Pharmacology Review…Intro?
• Pharmacokinetics
• Pharmacodynamics
• Drug Interactions
• Tolerance
Pharmacokinetics
• Pharm - drug, kinetics - movement
• The interaction of drugs with the body
• Primarily: Absorption, distribution and
elimination of drugs and the factors that
affect this process(s).
Absorption
Factors affecting absorption of drugs
– Route of Administration
– Physical properties of the drug and the tissues
(organs)
Absorption
Factors affecting absorption of drugs
Routes of Administration
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Topical: Skin & Eyes
Oral: Gastrointestinal & Sublingual
Rectal
Nasal
Inhalational (Lungs)
Parenteral: Intra- venous or muscular (IV, IM)
Intrathecal
Absorption
Factors affecting absorption of drugs
Physical properties of the drug and the tissues
(organs)
• Solubility of the drug; solubility coefficient
– Lipophilic versus Hydrophilic
• pH of the solvent (drug is the solute)
– Degree of Ionization (pKa)
• Concentration of the drug
Absorption
Factors affecting absorption of drugs
Physical properties of the drug and the tissues
(organs)
• Permiability of the tissue and size of the
drug molecule
• Surface area of the tissue/organ
• Blood supply (vasculature) of the route
tissue/organ
Absorption
Factors affecting absorption of drugs
Routes
Absorption
Factors affecting absorption of drugs
Liver Circulation
Liver
GI Tract
IV
Absorption
Factors affecting absorption of drugs
Routes of Administration
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Topical: Skin & Eyes
Oral: Gastrointestinal & Sublingual
Rectal
Nasal
Inhalational (Lungs)
Parenteral: Intra- venous or muscular (IV, IM)
Intrathecal
Distribution
• Most drugs are not distributed evenly
throughout the body
• Circulatory system is the primary route for
distribution
• Physico-chemical properties of the drug will
determine its distribution
Distribution
Factors that affect Distribution
• Solubility (Polarity & Lipophilicity)
– distribution in water versus fat compartments
• Binding to serum albumin proteins
• pKa
• Molecular size
Distribution
Volume of Distribution
• Relationship of Dose to Drug Concentration
depends upon the Volume
C=D
V
• Drug concentrations are measured in blood
(serum) only, but drugs are usually
distributed into other compartments as well
Distribution
Volume of Distribution
• Volume of Distribution therefore refers to
the apparent distribution from blood alone
C=D
Vd
• Blood has a very high water content
• Blood represents only about 6% of the total
body water.
Distribution
C=D
Volume of Distribution
Vd
• Volume of Blood, Interstitial Fluid and
Tissue Fluid = Total Body Water
– Plasma = 2.8 L (4%)
– Interstitial Fluid = 9.2 L (12 L; 20%)
– Intracellular Fluid = 30L (42 L; 60%)
• TBW: Males = 60-70 % / Females 50-60 %
Distribution
Volume of Distribution
C=D
Vd
• A drug which is poorly distributed beyond
the blood will have a lower Vd than a drug
which distributes throughout the body,
which will have a lower Vd from a drug that
distributes in fat
• Barbiturates : Vd << 1 L/kg
• Ethanol : Vd = 0.53 L/kg
• THC: Vd = 4 to 14 L/kg
Distribution
Factors that affect Distribution
• Solubility (Polarity & Lipophilicity)
– distribution in water versus fat compartments
• fat soluble drugs pass through membranes
and low water tissues more rapidly
• may be distributed/stored in fat
• may be poorly taken up in the blood/need a
carrier
Distribution
Factors that affect Distribution
• Binding to serum albumin proteins
• Drug distribution to other compartments is
reduced and slowed
• eg. Barbiturates. ~ 99% protein bound.
• Apparent distribution is in 2.8 L; blood
concentrations are much higher than target
tissues (eg. Brain cells).
Distribution
Factors that affect Distribution
• Solubility (Polarity & Lipophilicity)
– distribution in water versus fat compartments
• Binding to serum albumin proteins
• pKa
• Molecular size
Distribution
Factors that affect Distribution
• pKa (Ionization)
• CH3-CH3-COOH
CH3-CH3-COO• Ionized forms are more polar, thus retarded
by cell membranes, but more soluble in
water
Distribution
Factors that affect Distribution
• Molecular Size
• Small molecules (Ethanol) CH3-CH20H
pass rapidly through cell membranes
without uptake mechanisms
• Larger molecules (Mannitol) are retarded
and may be excluded from some
compartments
Elimination
• Definition
• Removal of the drug by either
– metabolism (conversion) to another subtance
– excretion of the drug in unchanged form
Elimination
Routes
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Liver
Kidney
Lungs
Sweat
Hair
Elimination
Liver
• Major site of metabolism
• Enzymatic
• Type I - modification of the drug by
hydrolysis, methylation, oxidation etc.
• Type II - conjugation to a large polar
molecule (eg glucuronidation)
Elimination
Liver
• “Goal” to make the drug more
– soluble in water (excretion via Kidneys)
– soluble in bile (excretion via feces).
• Liver takes 100% of blood from stomach
and intestines and 40% total circulation
• Major metabolic and de-toxifying organ
Elimination
Kidneys
• Major site of water and salt balance and
nitrogen (urea) elimination.
• Filters the blood
• Polar drugs and metabolites will pass into
the urine with water
• Ionization status will also affect excretion
Minor Routes of Elimination
• Lungs
– Drug must be volatile (eg. Inhaled anaesthetics
and alcohols)
• Sweat
– polar, water soluble drugs will pass into the
sweat
• Hair
– deposition from growing end, drugs
sequestered in dead hair cells outside of body
Elimination Kinetics
• Enzymatic elimination of drugs primarily
First Order Kinetics (Michaelis-Menton)
C =Coe-kt
• Elimination half life
t 1/ = 0.693/k
2
Elimination Kinetics
(Michaelis-Menton)
Actual change in concentration over time
Logarithimic change in concentration over time
Elimination Kinetics
• Elimination is dependent upon concentration, but
almost 97% will be eliminated after 5 half-lives
Initial concentration 1 mg%
One half life
0.5 mg%
Two half lives
0.25 mg%
Three half lives
0.125 mg%
Four half lives
0.0625 mg%
Five half lives
0.03125 mg%
or 0.96875 mg% (97%) eliminated
Non-Enzymatic Breakdown
• Some drugs are unstable at physiological
pH or in either acid or base conditions
• These drugs will breakdown to products
over time (the equivalent of metabolism and
elimination)
• The problem for Forensic Toxicology is that
these processes can occur postmortem and
especially in-vitro.
Non-Enzymatic Breakdown
Example Cocaine
• Cocaine is metabolized to ecgonine
methylester (EME) by an esterase in the
blood (pseudocholinesterase)
• Cocaine also breaks down over time to
Benzoylecgonine (BE), especially at
physiological and alkaline pH
Non-Enzymatic Breakdown
Example Cocaine
• Preservatives (chemicals which bind
enzymes and prevent postmortem
enzymatic changes and tissue breakdown)
will stop the metabolism of cocaine to
EME, but not the breakdown of cocaine to
BE.
• Thus some or all of the BE detected in a
sample may have been cocaine prior to
death
Steady State
• At therapeutic concentrations drugs taken
over a period of time attain Css Steady state
concentration
Blood concentration
Mean Css
Time
Kinetics in Overdose
• Absorption, Distribution and especially
elimination of drugs can change in overdose
• Large amounts of drugs in the stomach
cause ‘concretions’ which reduces
absorption
Kinetics in Overdose
• Distribution may be altered, for example
protein binding sites in the blood may
become saturated - Vd may change
• Elimination kinetics may change; often
dramatically, when enzymes become
saturated and enter zero-order kinetics, an
increase in dose will now lead too much
greater blood concentrations with an
altered half-life
Pharmacodynamics
The Site of Drug Action
• Agonist -a molecule that ‘fits’ a receptor by
either its spacial and/or ionic properties
• Antagonist - a molecule which blocks a
receptor by either binding to a nonactivating site or physically blocking the
site (or causing only very weak activity).
• Most drugs mimic natural agonists
Pharmacodynamics
The Site of Drug Action
• Lock and Key
Natural Agonist
Drug Agonist
Antagonist
Pharmacodynamics
The Site of Drug Action
• Antagonist effects
• Blocking metabolism - re-uptake inhibitors
allow the natural molecule (cocaine dopamine; Prozac etc - serotonin) to remain
longer at the site of action
• May have beneficial or detrimental effects
• May also act as an antidote
Pharmacodynamics
The Site of Drug Action
• Some drug families are based on receptor
binding eg. Opioids- related to morphine;
all opioids bind to one or more of the three
classes of opioid receptors
• Receptors may activate inhibitory
pathways; thus agonists may produce
inhibitory responses while antagonists may
produce excitatory responses (e.g. GABA
pathways).
Drug - Drug Interactions
Kinetic Effects
• Drugs may be metabolised by the same
enzyme system(s).
• Consequence: Induction or inhibition of
metabolic pathways by one drug resulting in
increasing or decreasing blood
concentrations of the other drug (Has
implications for the drug with the lowest
therapeutic index/greatest disease impact).
Drug - Drug Interactions
Example Warfarin
• Warfarin is taken as an anticoagulant to
combat thrombosis (blood clots) which may
break free and damage the heart or lungs.
• Warfarin is highly protein bound
• Warfarin is metabolised by P450 enzyme
system (more about this later).
Drug - Drug Interactions
Example Warfarin
• Phenobarbital is also highly protein bound
and induces the P450 system.
• Consequence of someone on warfarin who
takes a course of phenobarbital:
– Increased free warfarin offset by increased
metabolism; net result is increased dose of
warfarin needed to achieve anticoagulation.
– If dose not lowered at end of phenobarbital
treatment, bleeding due to warfarin may result
Drug - Drug Interactions
Kinetic Effects
• Drug Interactions may also be beneficial,
e.g. probenecid blocks movement of
penicillin into the urine resulting in higher
blood concentrations at lower doses and
more effective antibiotic treatment.
Drug - Drug Interactions
Target Effects
• Drugs may have similar (synergistic) effects
(e.g. sedation) which may be additive
(similar recptors) or supra-additive (two or
more targets) or infra-additive (similar
receptors; agonist and antagonist)
A+B = C
A+B > C
A+B < A or B
Drug - Drug Interactions
Pharmacokinetics
• Absorption
– Chemical incompatability of two drugs
– Prevention of absorption or delay (e.g.
decreased gastric motility by opioids)
• Distribution
– Changes in protein binding
– Inhibition in Liver uptake
– Change in circulatory flow
Drug - Drug Interactions
Pharmacokinetics
• Elimination
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Enzyme Induction
Enzyme inhibition or competition
Inhibition of recirculation from the bile
Changes in Renal processes
• acidic urine facilitates the uptake of bases (and vice
versa) into the urine
• Reabsorption of some drugs back into the
circulation may be blocked
Tolerance
• Two primary aspects of tolerance are
Metabolic and Functional
• Metabolic (primarily hepatic).
• Functional (CNS)
Tolerance
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Metabolic
Dispositional
Kinetic
Primarily Liver
Can involve all drugs
Change in [blood]
enzyme induction
no abstinance
(withdrawl) syndrome
Functional
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CNS
Dynamic (receptor)
Brain
CNS drugs only
No Change in [blood]
learning-like/change in
excitation status
• abstinance syndrome
Tolerance
• Cross tolerance for
drugs using the same
• Tolerance level is
moderate (up to 35%
increase in dose)
• Cross tolerance for
drugs with the same
effect
• Tolerance level is high
(up to 200% increase
in dose)
Tolerance
Stimulants
• Functional tolerance develops rapidly and
large increases in dose can occur over one
drug session e.g. crack cocaine binges
• however metabolic tolerance dose not
develop as rapidly; deaths due to non-CNS
effects, especially cardiac or vascular and/or
thermoregulatory causes are common.
Tolerance
CNS Depressants
• Functional tolerance develops more slowly
and is lost over a shorter period than
acquisition.
• One major problem is respiratory
depression; the respiratory centre is located
in the medulla and most if not all sedatives
depress respiration - tolerance to this effect,
especially for opioids, dose not occur
References
• Principles of Medical Pharmacology
(Kalant & Roschlau eds.) 6th ed., Oxford
Publ., 1998.
• Goodman and Gilman’s The
Pharmacological basis of Therapeutics
(Hardman & Limbird eds-in-chief) 9th ed.,
McGraw-Hill, 1996