Download Introduction to Pharmacology 2 General Principles: Absorption


Introduction to Pharmacology 2
o General Principles: Absorption, Routes of Absorption, Distribution, Metabolism, and
Excretion
 The body is “dynamic”
o Action of the BODY on the DRUG
 Absorption- get into blood stream (blood level more
important than dose!)
 Distribution- to site of action (and across barriers);
everywhere else
 Metabolism-degradation (activation of prodrugs)
 Excretion- removal
 Minor alterations in any of these will affect therapeutics
o Actions of the DRUG on the BODY
 Therapeutic effects- reason for administering drug
 Side effects- undesirable, but hopefully tolerable [patient
compliance], effects on physiological mechanisms
 Toxic effects- usually at higher than therapeutic doses (e.g.,
antihistamines- CV problems and psychoses)
 Watch for both prescriptions AND over-the-counter (OTC)!
o Pharmacokinetics- quantitative description of the biochemical and
physiological effects of drugs and the mechanisms underlying these
effects (body on drug)
o Pharmacodynamics- quantitative description of the biochemical and
physiological effects of drugs and the mechanisms underlying these
effects (drug on body)
 Overview of Pharmacokinetics (ASA orally)
o General Diagram
 1. Disintegrates and dissolves in gastric contents.
2. Must pass GI mucosa, through blood vessel walls and into
bloodstream (ABSORPTION)
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In the bloodstream, the drug can:
 Remain in its free form OR
 Bind to blood elements or plasma proteins (albumin)
 Drug binding is a reversible equilibrium process,
shifting between free drug and bound drug
 As free drug is metabolized (concentration
decreased) the bound form becomes free
(reversible equilibrium)
 Binding to plasma proteins varies from drug to drug,
some not binding at all, some having > 95% binding
Only free drug is available to tissues, since proteins cannot typically
penetrate into extracellular space and into circulation
Free drug will be distributed, via circulation, to site of action to
produce effect (ASA to head for headache; joints for arthritis, etc.).
 But, distribution also includes tissue reservoirs and other
sites (side effects).
Can you give other examples of gradients?
Lipid Solubility
 Body fat is patient reservoir for lipid soluble drugs
 Lipid soluble drugs move within body fat and stay there,
e.g., THC (marijuana) produces effects in CNS, but
accumulates in tissue reservoirs for a long period, producing
no effect; same with anesthetics and other lipid soluble
drugs (“latent” reactions)
 (Heroin = 2 morphine)
Biotransformation (usually active to inactive)
 Helps reduce effects of foreign compounds
 Metabolites usually less active, more water soluble (lipid
soluble = absorption; water soluble = excretion)
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o
o
o
o
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Drug is metabolized into more water soluble form for
excretion (but ability for receptor interaction is decreased)
 A few drugs are excreted unchanged
Pharmacokinetics studies the factors which influence the blood
level of free drug
Importance of blood level of drug
 Shape of curve is determined by rates of absorption,
distribution, metabolism & excretion
 ALL are occurring together!
 Ascending part of curve: absorption more rapid
 Descending part: metabolism & excretion more
rapid than absorption
Plasma concentration (PC) increases as drug is absorbed into
bloodstream
 low PC, too little free drug in blood for equilibrium to drive
drug into tissues where it produces effects
Minimal effective concentration (MEC)- threshold PC.
 Enough drug is present to enter tissues to interact with
receptors and produce effect.
 Desired effect usually seen at level above MEC
 Goal-Achieve desired therapeutic range (exists for all drugs
 Below MEC, no desired effects; above MEC, toxic effects.
 (20 ASA tablets at one time drives the drug into
sites where you don’t want it - toxicity)
 MORE DOES NOT WORK SOONER!!!
 What should you usually recommend if your
patient misses a dose?
Bioavailability- percentage of administered drug reaching systemic
circulation
 Drug’s ability to achieve a systemic level
 Expressed as percentage (80% bioavailability means 80% of
a drug PO will reach systemic circulation)
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Affected by several factors: if drug goes to liver before
systemic circulation, it may be metabolized, decreasing the
amount of drug in systemic circulation as compared to the
amount absorbed from the intestines.
Clinical example: Morphine well-absorbed PO, but ~90%
metabolized on its “first pass” through liver

o Bioequivalence- same active ingredients, identical strength or
concentration, dosage form and route of administration
 Bioequivalence vs. Bioinequivalence
 FDA: generic drug is considered bioequivalent if the
bioavailability from the generic product is not
significantly different from the innovator product
 FDA requires bioavailability of drug measured in
80% of subjects to fall within 20% of mean of test
population bioavailability (between 80%-120%)
o “80/20 rule”- study must be large enough
to provide 80% probability to detect a 20%
difference in avg. bioavailability (for both
innovator drug & generic) thus 2 products
may be considered bioequivalent although
they could exhibit a 40% variation!!!
 Generic versus Brand: relates to efficacy & patient
compliance (cost)
Routes of Drug Administration
o Enteral- drug given into the GI tract
 Oral (PO; ingestion)- most common, usually convenient,
absorption from the GI tract (“first pass” effect)
 Limitations- drug not well absorbed from GIT; drug broken
down by digestive enzymes; incompatible clinical conditions
(vomiting, unconsciousness); blood flow; surface area
 How could you give a drug enterally to an unconscious
patient?
 Prolonged release medication- rate of PO absorption
depends upon drug’s rate of dissolution in GI tract
 Theoretical background- produce slow, uniform
absorption of drug for 8 hours or longer; controlledrelease, timed-release, sustained release, prolonged
action
 Advantage- more infrequent administration
o therapeutic effect overnight
o less incidence/severity of side effects
 Disadvantages- greater interpatient variability
o “Dose dumping” - > 50% of total dose
absorbed in < 2 hours
 Mean serum-time concentration curve, immediate- (tid) vs.
control-release (qd) PO med

Absorption of Drugs
o Importance of protein binding: Transport of drugs across biological
membranes
 Passive diffusion- most common
 Facilitated diffusion- carrier-mediated usually down a
concentration gradient; usually carried by a protein
o The epithelial layer must be passed for absorption within the small
intestine, but tight junctions prevent movement of materials so they
must pass through the cells themselves.
o Bottom line: for a drug to be absorbed, it must pass through
biological (or cell) membranes.
o Prodrugs become active when part of the molecule is cleaved off
 Improve bioavailability
 Obscure unpleasant side effects
 Alter solubility for IV use
 Provide site-specific delivery
o Passive diffusion- the way most drugs get through
 Concentration gradient- from high to low area of
concentration
 Molecular weight- lower the MW, more rapid the diffusion
 Lipid solubility- more lipid soluble, better the absorption;
best absorbed drugs have high lipid solubility (may vary
depending on route, e.g., IM)
 Water solubility - more water soluble, less absorption
 Lipid-water partition coefficient (P=CL/CW)- determined
experimentally; measures how well a drug is absorbed,

expressed as ratio of conc in lipid phase over conc in
aqueous phase. Higher P, better absorption
 pH effects- most drugs are weak acids or bases. The degree
of ionization depends on pH.
 Non-ionized forms preferentially cross biological
membranes;
 If drug is to pass through membrane, it must be
dissolved in solution on one side of membrane to
diffuse across
 If not , the molecules may be too large.
Acids, Bases, and Membranes
o Bronstead-Lowry definition: acids = proton donors; bases = proton
acceptors
o For weak acids:
 In aqueous solution, acid can dissociate to release proton.
There is usually a reversible equilibrium
 (COOH Groups)
 R-H  R- + H+
 Charged forms are non-lipophilic, so uncharged
(non-ionized) form is better absorbed through lipid
bilayer
 Equilibrium constant for dissociation
 = Ka = [R ] [H ]
Ka = conc of products

[R-H]
conc of reactants
o Acidic drugs will be non-ionized at high [H+] (low pH, better
absorption) & ionized at low [H+] (high pH)
o Basic drugs will be non-ionized at low [H+] (high pH better
absorbed) and ionized at high [H+] (low pH)
o Base: proton acceptor; in aqueous solution, can pick up proton to
become ionized (less well-absorbed; usually have an amino group)
o Quaternary ammonium compounds- charge is not dependent on
pH; permanent positive charge
o NOTE: most important clinical point is they should be given by
injection, not PO
 Will they cross the blood-brain barrier?
o Quantitative treatment
 It is sometimes useful to represent Ka as its negative log
(pKa).
 The pKa of a drug is equal to the pH at which it is
1/2 dissociated.
 An acidic drug will be non-ionized at pH’s below its
pKa.
 This principle can be described quantitatively by the
Henderson-Hasselbalch equation:
 pKa = pH + log
[protonated drug

[non-protonated drug]
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Relates pH and pKa to concentrations of protonated and
non-protonated forms of the drug
 for an acidic drug, protonated form is the nonionized (uncharged) form
 for a basic drug, protonated form is the ionized
(charged) form
If the pKa of the drug and the pH of the solution are known,
one can solve for the log term and determine the relative
proportions of ionized and unionized drug.
 For an acid:
o pKa - pH = log [non-ionized drug]

[ionized drug]
 For a base:
o pKa - pH = log [ionized drug]

[non-ionized drug]
The HH equation enables you to determine (quantitatively)
the ratio of protonated form of drug to non-protonated
form
 This principle can be treated quantitatively by the
following equations (remember, non-ionized better
absorption):
 For an acid:
o R = 1 + 10 pH1 - pKa

1 + 10 pH2 – pKa
 For a base:
o R = 1 + 10 pKa - pH1

1 + 10 pKa - pH2
 where R is the ratio of the concentration on the side
of the membrane at pH1 to the concentration on
the side of the membrane at pH2
 If a pH gradient exists across the membrane
(somewhat analogous to concentration gradient),
the drug will tend to accumulate on the side of the
membrane where the drug will be most ionized.
 How can you use the HH equation?
o Consider absorption of basic drug (pKa =
6.4) PO in the stomach with a pH of 1.4
 Quantitatively, the proportion of
ionized/non-ionized drug on either
side of the membrane can be
calculated using the HendersonHasselbalch equation.
 Qualitatively, the acidic pH of the
stomach greatly favors the ionized
form of the drug, which cannot pass
through the membrane. Therefore,
the drug would be poorly absorbed.

Of the small amount of the drug
that would be absorbed, the more
basic pH of the plasma would favor
the non-ionized form of the drug,
which could pass through the
membrane.
o Now consider the same basic drug (pKa =
6.4) at the more alkaline pH of the intestinal
tract (intestinal pH = 7.4.)
 Since the drug is primarily nonionized, it will be able to cross the
membrane. As the blood circulates,
the drug will equilibrate between
the intestinal lumen and blood, and
thus be well-absorbed.
 NOTE: Important points to
understand are that pH can affect
drug mobility and that the nonionized form of a drug will typically
be better absorbed.
o Absorption of Drugs from Various Sites
 Oral or nasal mucosa- pH = 6-8;
 neutral drugs or weak bases are absorbed
 by-pass digestion
 Good blood supply and small surface area
 weak bases (cocaine) or neutral (nitro) can be
absorbed
 Stomach- pH = 1-2
 the very acidic environment favors the ionization of
most drugs
 small surface area and low pH allow few drugs to be
absorbed from the stomach
 rate of gastric emptying may be an important factor
(ETOH has some absorption here)
Distribution of Drugs
o Pharmacokinetics -- ADME
 Factors influencing drug distribution
 Blood flow to tissue- high perfusion will enhance
distribution (well-perfused organs get lots of drug liver, kidney, brain, lungs)
o therefore, these organs are sites of action
and toxicity and metabolism
 Mass of tissue- bigger tissue, more drug (fat gets
lipid soluble drugs)
 Passage through capillary walls
 Presence of specialized barriers
o
o
o
Blood-brain barrier (BBB)- highly
impermeable
 prevents passage of large or ionized
molecules
 low MW (200-300) and lipid soluble
drugs may cross
o Placental barrier- similar to BBB but may be
less selective (most drugs pass through and
may affect fetus)
 Regional differences in pH- drugs tend to
accumulate in environment where they are ionized
 Lipid soluble drug may pass into environment in
which it is ionized (stomach at pH 1.4)
o it becomes “trapped”
o The stomach can serve as a “sink”.
 Binding to plasma proteins
o Albumin is the most important plasma
protein
 Binds many types of drugs
 Bound drug cannot distribute into
tissues
o Drug interactions
 displacement of drug from binding
sites
Clinical Significance
 If 10mg of Drug X is injected and 90% becomes bound, then
9mg is bound and 1mg is free;
 Suppose another drug, Drug Y, displaces 10% of a bound
drug, then 8.1mg of Drug X remains bound which means
that 1.9mg of Drug X is now free (almost twice as much!).
 Potential toxicity!
Distribution of drugs to specific tissues
 Liver
 Large blood flow (big organ, well-perfused)
o exposed to many drugs
 Site of drug metabolism (and toxicity)
 Portal-hepatic circulation
o “first-pass” metabolism (esp. PO)
o enterohepatic circulation
 Kidney
 High blood flow (large % of CO)
 NOTE: Anything affecting renal perfusion will affect
drug delivery to kidney, excretion and,
consequently, blood levels
 Site of excretion
 Fat
 Low blood flow (not well-perfused)
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Accumulation of drug
Site of loss- no receptors (usually)
o dead end organ
Redistribution of drug from other sites (after drug
gets to well-perfused organ, it will eventually go to
fat, e.g., barbiturates)
Brain
 Blood-brain barrier
 Small, lipid-soluble drugs can cross
 Fetus
 Placental barrier
Metabolism of Drugs
o Means of terminating drug action
 Excretion- via urine, feces or expired air (excretion of free
drug is difficult
 principles which increase absorption tend to
decrease excretion- lipid vs. water solubility)
 Metabolize drug to inactive form- biotransformation
 free drug to less active metabolite (typical)
 Metabolism and Excretion- most effective and most
common
 forms inactive metabolites and gets rid of them
 Redistribution- distribution and protein binding are in
dynamic reversible equilibrium with the free drug
o Drugs in the tissues must move out to maintain equilibrium, so the
drug effect stops; this is the basis for dose timing (e.g., q8h)
o Overview of drug metabolism
 99% of drugs:
 Active DrugMetabolismInactive Drug
o Active Drug- nonpolar
 Lipid-soluble
 absorbed
o Metabolism- biotransformed
o Inactive Drug- polar
 Water soluble
 excreted
o Types of Metabolic Reactions
 Microsomal oxidations
 Induction and inhibition of microsomal drug
metabolizing system
 Inhibition- ETOH in late alcoholism damages liver,
therefore less enzymes
 Induction- chronic drug exposure (e.g. barbiturates)
induces enzymes, so subsequent doses are quickly
metabolized and less effective
 Non-microsomal oxidations

Time
0-2 hours
2-4 hours
4-6 hours
Some oxidative enzymes not associated with
microsomes
 In hepatic and extra-hepatic tissues
 Examples
o Monoamine oxidase- in neural tissue:
 metabolizes neurotransmitter
amines (NE, dopamine)
o Alcohol dehydrogenase - free in cytosol
unlike microsomal system found in
endoplasmic reticulum
 Reductions
 Hydrolyses
 Conjugations
 Kinetics of Drug Metabolism (2 types)
o First order kinetics (for most drugs)- Enzymatic process
 Exponential relationship- descending end of blood level
curve where metabolism is a rate-limiting factor for blood
level decrease
 Rate of metabolism depends on the concentration of the
drug: more drug, quicker reaction; less drug, slower
reaction
 Fixed half-life- as drug amount decreases, metabolic rate
decreases, BUT % of drug cleared is constant (50%).
 This represents half-life (time to metabolize 50%;
independent of the drug concentration
 In first order kinetics, the actual amount of drug cleared in a
given time (i.e., the rate of clearance) depends on the
amount of drug that is present.
 However, the % of total drug that is cleared in a
given time is constant.
Blood Level Initial Blood Level Final
Amount of Drug
% of Drug Cleared
Cleared
8
4
4
50
4
2
2
50
2
1
1
50
 What is half-life in this example? When will drug be
“gone”?
 Summary:
 dependent on dose
 98% of all drugs
 Work exponentially
 Have half-life [fixed (constant)]
 50% metabolized per t1/2
 e.g., Cp = 10mcg/ml at 2h, Cp = 5mcg/ml at 8h, so
what is t1/2=???
o Zero order kinetics for some drugs (ethanol)

Time
0-2 hours
2-4 hours
4-6 hours
Rate of metabolism does not depend on the concentration
of the drug (rate is constant)
 Linear relationship
 No fixed half-life- amount of drug cleared (rate) is constant
but % drug cleared (half-life) varies
 e.g., ETOH - X# of drinks take Y# of hours to clear relative to
degree of saturation of metabolic enzymes
 Zero order kinetics: actual amount of drug cleared in a given
time is constant & is independent of amt of drug present.
 Metabolism of drug based on enzyme availability
 enzyme saturation = no increase in metabolism
(clearance), so increased blood levels (toxicity),
e.g., person gets drunk (or dies of respiratory
failure).
Blood Level Initial Blood Level Final
Amount of Drug
% of Drug Cleared
Cleared
8
6
2 (max)
25
6
4
2
33
2
2
2
50
 Summary:
 Independent of dose
 Enzymes are saturable; e.g., ASA at large doses > 3
tabs is zero order
 Factors Affecting Drug Metabolism
o Age- very old and very young
o Disease- especially of the liver
o Nutrition- especially malnutrition
o Genetic factors (or differences)
o Other drugs- inducers of hepatic microsomal enzyme system; drug
interactions
o Duration of treatment- microsomal enzyme induction via chronic
use
 Excretion of Drugs
o Renal excretion of drugs- primarily via the kidneys; same factors as
before affect excretion: age, pre-existing renal disease (decrease
GFR), enzyme deficiencies, etc.
 Filtration of drugs (at glomerulus)
 Tubular secretion (at proximal tubule)
 Reabsorption of drugs (into the tubular lumen)
o Urine Formation
o
o
o
o
o
pH effect on acids and bases
 acidic urine: favors excretion of basic drugs
 (…because they are ionized or non-ionized?)
 basic urine: favors excretion of acidic drugs
 (same principles as drug absorption)
 Your patient overdoses on BAYER aspirin. Would it be better
to give an acidifying agent such as ammonium chloride or
Vitamin C, or alkalinizing agent such as sodium bicarbonate
or sodium citrate?
biliary and fecal excretion
 secretion of conjugates in bile
 bile salt residue reabsorbed & excreted in feces
(cholestyramine- QUESTRAN)
pulmonary excretion
 gases & volatile alcohols (BREATHALYZER TEST)
sweat & saliva- less significant
milk- nursing mother/newborn; many mothers do not realize how
much can be transferred to baby