Basic Principles Of Adme

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Prototype Drugs

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1. Organic acid drugs (e.g. those containing an ionizable carboxyl group R-COOH)
2. Organic base drugs (e.g. those containing an ionizable amino group R-NH2, R2NH, R3N)
3. Organic neutral non-ionizable drugs
4. Large molecule drugs (e.g. polypeptides and proteins)

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I. Introduction
-Objectives in drug therapeutics
-Drug Disposition

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Objectives
1. Administer a drug
2. Get it to its site of action in sufficient quantity to exert its effect for some useful period of time
3. Terminate its action and remove it from the body

Drug Disposition - what happens to the drug in the above process. Includes ADME

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Definition of drug absorption

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The process of getting the drug into the body. Most often this is synonymous with getting the drug into the blood.

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1. Passive transfer processes (1 of 2)

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a. passive diffusion
1) lipid solubility required to dissolve in membrane (a function of polar and non-polar groups)
a) polar groups (e.g. COOH, NH, OH, charged groups) increase water solubility)
b) nonpolar groups (e.g. CH2, CH3, aromatic rings) - increase lipid solubility
2) Ionization (organic acids and bases) increase polarity
3) requires concentration gradient for net transport

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1. Passive transfer processes (2 of 2)

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b. Filtration
1) Molecular size
2) requires concentration gradient for net transport

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2. Carrier mediated transfer processes (1 of 2)

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a. active transport
1) discrete transporter proteins; finite number, therefore saturable
2) structurally selective; competitive inhibition
3) energy requiring; able to transport against concentration gradient
4) examples:
(a) amino acid transport; amino acid analog drugs
(b) P-glycoprotein; multidrug resistance
(c) acid and base transport in renal tubule

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II. Drug Absorption
A. Movement of drugs across biological membranes
1. Passive transfer processes
2. Carrier mediated transfer processes

B. Absorption of Drugs from G.I. via Oral Dosing
C. Absoption of Drugs Administered via Other Routes

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(Outline)

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Carrier mediated transfer processes (2 of 2)

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b. receptor mediated endocytosis
1) involves membrane receptors
2) transport of large polypeptides and proteins
3) likely to become increasingly important with the use of bioengineered proteins as drugs

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Passive diffusion
-Principle of non-ionic diffusion

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1. Only the nonionezed form of a drug diffuses across the lipid membrane
2. The more lipophilic the drug is, the faster is the diffusion
3. At equilibrium, the concentration of the nonionized form is the same on both sides of the membrane

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pH partition effects (1 of 2)

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If the drug is an ionizable acid or base, the concentration of total drug on each side of the membrane can be vastly different if there is a pH gradient across the membrane.
1. acid drugs tend to concentrate on the high pH side of the membrane
2. basic drugs tend to concentrate on the low pH side of the membrane

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pH partition effects (1 of 2)

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3. the ionization tendency of a drug is indicated by its pKa.

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definition of pKa

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The pH at which the drug is half ionized. (Note - the pKa does not tell you if a drug is an acid or a base; it only tells you how strongly it tends to ionize)

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What does pH = pKa mean

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equal concentration of ionized and nonionized (ratio 1:1)

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Acid drugs are increasingly ionized as ________

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pH goes up

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Basic drugs are increasingly ionized as _________

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pH goes down

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For each unit away from the pH, the ration ______

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increases tenfold

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pH has no effect on __________

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neutral, nonionizable drugs

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B. absorption of drugs from G.I. via oral dosing (1 of 4)
1. the drug must first dissolve in the gastric and intestinal fluids

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a) the pharmaceutical preparation can affect dissolution
b) different salt forms of a drugs have different solubilities
c) other materials present can render dissolved drug nonabsorbable

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B. absorption of drugs from G.I. via oral dosing (2 of 4)
2. properties of the drug affect its absorption

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a) lipophilicity
b) ionization

For drugs with very low nonionized:ionized ratios (<1:1000) and which are not very lipophilic, absorption will be poor

There is very poor absorption of complete charged drugs, e.g. quaternary ammonium compounds

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B. absorption of drugs from G.I. via oral dosing (3 of 4)
3. properties of the absorbing surface which affect absorption:

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a) area of surface
b) blood circulation to absorbing surface

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B. absorption of drugs from G.I. via oral dosing (4 of 4)
4. other factors which affect absorption:

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a) concentration of dissolved drug
b) contact time with the absorbing surface

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C. Absorption of drugs administered via other routes (1 of 5)

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1. alimentary tract
a. oral mucosa - rapid absorption, small surface area (used for potent drugs to relieve anginal pain); avoids immediate exposure to liver
b. rectal mucosa - suppository dosage; alternate route for nauseated patient; only ca. 50% passes immediately through the liver

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C. Absorption of drugs administered via other routes (2 of 5)

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2. parenteral routes - bypassing G.I. tract and immediate exposure to the liver
a. routes which still entail an absorption process: (absorption rate can vary depending upon vehicle)
1) subcutaneous
2) intramuscular

b. routes which bypass the absorption process:
1) intravenous
2) intraarterial
3) intrathecal (into the spinal subarachnoid space)

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C. Absorption of drugs administered via other routes (3 of 5)

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3. pulmonary endothelium (volatile anesthetics, aerosols)

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C. Absorption of drugs administered via other routes (4 of 5)

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4. skin
a. few drugs readily penetrate the intact skin
c. controlled-release topical patches
e.g. for highly potent antihypertensive drug clonidine

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C. Absorption of drugs administered via other routes (5 of 5)

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5. mucous membranes (systemic absorption of drugs used for local effects)

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III. Drug distribution
A. Differential distribution of drugs into different body compartments
B. Distribution of drugs within the blood
C. Distribution of drugs in other tissues (cont.)
D. Distributino across some specific barriers

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(outline)

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A. Differential distribution of drugs into different body compartments
-how can we examine drug distribution in man when only blood concentrations can readily be measured?

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(refer to slide)
apparent volume of distribution (Vd) - the volume the drug appears to be distributed in, at the same concentration as in blood

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What is the use of Vd?

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1. Quantitative representation of distribution - is the drug mainly in tissues or in blood
2. Estimation of amount of drug in body and the proportion readily available for therapeutic manipulation
3. The larger the Vd, the longer the drug wills tay in the body

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B. Distribution of drugs within the blood (1 of 5)

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1. Drug is present both free in solution and bound to plasma proteins; protein binding is a reversible process. An equilibrium is established which depends upon the affinity of the drug for the binding sites
a. only free drug can cross membranes to enter other tissues
b. only free drug can bind to receptors.

Thus, a change in free drug blood concentration can lead to a transient change in pharmacological response and in the Vd.

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B. Distribution of drugs within the blood (2 of 5)

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2. The free drug concentration is determind by binding to plasma proteins.
-Acidic drugs bind mainly to albumin.
-Basic drugs bind mainly to alpha1-acid glycoprotein
-Lipophilicity also important.

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B. Distribution of drugs within the blood (3 of 5)

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3. There are a finite number of binding sites on these proteins. Thus, saturation as well as competition can occur.

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B. Distribution of drugs within the blood (4 of 5)

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4. historically, textbooks have emphasized plasma protein binding displacement interactions as clinically significant. Most such clinical effects are now recognized as due primarily to other interactions, e.g., inhibition of metabolism.

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B. Distribution of drugs within the blood (5 of 5)

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5. binding interactions likely to be clinically significant only in few cases, particularly where:
a. drug is very highly bound > 90%
b. drug has very low therapeutic index (toxic conc./therap. conc.)
c. drug has a low hepatic extraction
d. drug is given IV

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C. Distribution of drugs in other tissues (1 of 6)

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1. binding can be functional (e.g. to receptors) or nonfunctional sequestration to tissue proteins.

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C. Distribution of drugs in other tissues (2 of 6)

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2. binding to tissue proteins is reversible, but may be rate limiting in elimination. Highly lipophilic drugs tend to be highly bound.

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C. Distribution of drugs in other tissues (3 of 6)

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3. intracellular distribution - pH partition between plasma (pH 7.4) and intracellular space (pH 7.0) is small but favors movement of basic drugs into cells.

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C. Distribution of drugs in other tissues (4 of 6)

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4. basic drugs can also accumulate at more acidic intracellular sites (e.g. lysosomes, storage granules)

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C. Distribution of drugs in other tissues (5 of 6)

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5. fat as a storage depot - highly lipid soluble drugs accumulate in adipose tissue (important for toxic chemicals, e.g. polychlorinated organics)

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C. Distribution of drugs in other tissues (6 of 6)

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6. time course of tissue distribution (drug "redistribution") - distribution equilibrium occurs in stages due to differences in perfusion of different tissues:
a. highly vascularized tissues (e.g. brain, visceral organs) equilibrate first (e.g. for the short acting anesthetic, thiopental, peak concentration in brain is reached 30 sec after intravenous dose.)
b. less vascularized tissues (e.g. muscle, skin) equilibrate more slowly (for thiopental, 15-30 min.)
c. poorly vascularized tissues (adipose tissues (adipose, bone) equilibrate last (may require several hours).
d. some drug effects may be terminated by redistribution rather than actual elimination (biotransformation or excretion) of the drug.

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D. Distribution across some specific barriers

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1. blood brain barrier

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1. blood brain barrier (1 of 3)

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a. there are tight junctions between endothelial cells of brain capillaries and few transendothelial channels - thus, passage of drugs from the blood into the central nervous system is severely restricted.

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1. blood brain barrier (2 of 3)
b. drugs cross the blood brain barrier by:

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i) passive diffusion - highly lipid soluble drugs cross rapidly (peak concentration reached in minutes). Very polar, highly water soluble drugs do not cross at all.
ii) active transport - e.g. transport of amino acid type of drugs (methyldopa, L-dopa)
iii) endocytosis - engineered chimeric proteins can exploit Alzheimer's disease therapy uses transferrin receptor antibody conjugated to nerve growth factor).

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1. blood brain barrier (3 of 3)
c. strategies for delivery of highly water soluble drugs:

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i) invasive - intrathecal or intraventricular injection.
ii) transient disruption of the barrier with mannitol
iii) prodrugs - metabolized to active form within the CNS.

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definition of prodrug

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an inactive form of a drug that is converted to active form in the body.

prodrugs are used to achieve more desirable absorption/distribution when the actual active form is deficient in desired properties.

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2. Placental "barrier"

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a. exhibits all modes of transfer of molecules across membranes. Passive diffusion due to lipid solubility is probably most important. Thus, there is no protective barrier.

b. drug exposure is especially risky to the fetus due to susceptibility to teratogenic effects in early development.

Metabolites can accumulate in the fetus due to lower lipid solubility of the metabolites compared to parent drug.

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IV. Biotransformation (drug metabolism)
A. Drugs often undergo two step ("biphasic") metabolism
B. Drug metabolizing enzymes
C. Significance in biotransformation
D. Variability in biotransformation

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(outline)

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Definition of biotransformation (drug metabolism)

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Biotransformation leads to structural alteration of the drug molecule by the action of a variety of enzymes. This alteration generally facilitates excretion of lipid soluble drugs by making them more water soluble.

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A. Drugs often undergo two step ("biphasic") metabolism

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1. Phase I biotransformation reactions
2. Phase II biostransformation
3. Many drugs undergo both phase I and phase II metabolism

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1. Phase I biotransformation reactions

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chemically modify the drug via oxidation, reduction, hydrolysis, etc. which, in addition to changing the physical properties of the molecule (e.g. water solubility), results in:
a. inactivation ("detoxification") of the drug. A portion of the chemical structure, essential tot he pharmacological effect, has been altered.
b. conversion of active drug to active drug metabolite. A portion of the chemical structure, not essential to the pharmacological effect, has been altered.
c. conversion of inactive drug compound (e.g. prodrug) to active drug.
e.g. enalapril (an inactive ester with good absorption properties_ is hydrolyzed to a biologically active carboxylic acid metabolite).
d. generation of a chemically reactive metabolite (reactive intermediate).
e.g. the anesthetic halothane iso oxidized to trifluoroacetyl chloride which can subsequently react chemically to form a covalent bond to proteins.

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Phase I reactions yield

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Phase I reactions yield metabolic products which are generally more polar than the parent drug and are therefore more easily excreted.

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2. Phase II biotransformation reactions

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add a conjugating group to the drug molecule which (almost always) results in:
a. pharmacologically inactive metabolites
b. highly ionized, polar, water soluble metabolites
c. exception: acetylation (e.g. of sulfonamides) yields less soluble metabolites

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3. Many drugs undergo both Phase I and Phase II metabolism

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e.g. propranolol

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D = ?

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distribution coefficient between organic and aqueous phases, a measure of lipophilicity.

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B. Drug metabolizing enzymes

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1. metabolic sites
2. liver microsomal metabolism
3. nonmicrosomal enzymes

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B. Drug metabolizing enzymes
1. metabolic sites

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a. liver (most important site of drug metabolism) - factors affecting hepatic clearance of drugs include:
i. activity of the drug metabolizing enzymes
ii. hepatic blood flow

In some cases, hepatic clearance can be sufficiently high to remove most of the drug from the blood passing through the liver. This effect is called "presystemic" or "first-pass hepatic elimination."

(refer to slide for Extraction Ratio)

b. drug metabolism also occurs in many other tissues (e.g. intestine, lung, kidney)

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B. Drug metabolizing enzymes
2. liver microsomal metabolism

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microsomes are isolated smooth endoplasmic reticulum

The smooth endoplasmic reticulum contains two particularly important drug metabolizing enzyme systems: the cytochrome P450 (CYP) complex and the UDP-glucuronyl transferase system.

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a. CYP complex

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i. iron-heme monooxygenase enzyme with associated NADPH - CYP oxidoreductase; require molecular oxygen and NADPH
ii. large number of CYP isoenzymes; gene superfamily
iii. wide range of substrates - isoenzymes oxidize particular structural types
iv. CYP's also involved in endogenous metabolism e.g. steroids.

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b. UDP-glucuronyl transferase

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forms glucuronic acid conjugates

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B. Drug metabolizing enzymes
3. nonmicrosomal enzymes

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in liver, other tissues and in plasma

a. phenolsulfotransferases - form sulfate conjugates
b. alcohol dehydrogenase
c. mitochondrial monoamine oxidase (MAO)
d. esterases
e. amidases

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C. Significance of biotransformation

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1. biotransformation is responsible for termination of pharmacological effects of lipophilic drugs
2. large variability in biotransformation yields large variability in drug response

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D. Variability in biotransformation

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1. variability among individuals

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D. Variability in biotransformation
1. variability among individuals
(1 of 5)

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a. genetic differences
i. cyp isoenzymes
Drug oxidations - bimodal distribution (refer to slide)

there are multiple cases of known genetic polymorphism with respect to CYP genes for drug metabolizing enzymes. The classical test for CYP2D6 phenotype is the debrisoquin polymorphism test wherein the ratio of parent drug to metabolite is determined in patients following a test dose of debrisoquin. Gene chip tests are now available to determine genotype of multiple CYP genes.

Different population groups exhibit different genetic distributions.

ii. some other drug metabolizing enzymes are known to exhibit genetic polymorphism:
a) N-acetyl transferase; bimodal or trimodal distribution
b) pseudocholinesterase (hydrolysis of muscle relaxant succinylcholine) - trimodal distribution

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D. Variability in biotransformation
1. variability among individuals
(2 of 5)

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b. age differences
i. biotransformation enzyme activities low in neonates. Newborns are often deficient in glucuronidation ability.
ii. elderly are heterogeneous due to different rates of deterioration of enzyme and elimination systems. No blanket statement can be made regarding dosage adjustment.

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D. Variability in biotransformation
1. variability among individuals
(3 of 5)

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c. sex differences. Females metabolize many drugs slower than males. Metabolism rate of some drugs is correlated with testosterone levels.

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D. Variability in biotransformation
1. variability among individuals
(4 of 5)

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d. pathology. e.g. liver disease

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D. Variability in biotransformation
1. variability among individuals
(5 of 5)

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e. species differences - important in new drug development.

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D. Variability in biotransformation
2. variability within a given individual
(1 of 2)

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a. enzyme induction
i. stimulation of metabolism by other substances (very common). Somking, alcohol, pesticides, other drugs, diet (brussel sprouts, charcoal-broiled meat, high protein)

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D. Variability in biotransformation
2. variability within a given individual
(2 of 2)

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ii. stimulation of drug's own metabolism (autoinduction) - blood levels fall during chronic therapy (tolerance). Induction is a slow process.

Examples:
-cimetidine (anti-ulcer) inhibits the metabolism of warfarin (antigcoagulant)
-some antifungals and antibiotics inhibity CYP3A4 which oxidizes terfenadine leading to excessive blood levels and arhythmias.
-fluoxetine (prozac) is an inhibitor of microsomal oxidation (CYP2D6)
-grapefruit juice inhibits metabolism of cyclosporin

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D. Variability in biotransformation
3. variability with regard to the drug itself

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differential metabolism of optical isomers (enantiomers)

(refer to slide for figure)

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V. Drug Excretion
A. Renal Excretion
B. Biliary Excretion

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outline

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Definition of drug excretion

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Elimination of drug and metabolites from the body - since excreta (e.g. urine) are more "waterlike" than the body as a whole, water soluble forms of the drug are required.

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A. Renal Excretion

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1. glomerular filtration
2. proximal tubular transport
3. distal tubule

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A. Renal Excretion
1. glomerular filtration

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only unbound (free) drug in blood

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A. Renal Excretion
2. proximal tubular transport

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secretion into urine.

a. two systems involved:
i. one for organic acids
ii. one for organic bases

b. competition for transport mechanism
e.g. probenecid and penicillin, to retain penicillin in the body

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A. Renal Excretion
3. distal tubule

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a. reabsorption by passive diffusion
b. can be modulated by pH or urine
i. enhance excretion of acids by increasing urine pH
ii. enhance excretion of baes by decreasing urine pH

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B. Biliary Excretion

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1. active transport of polar molecules, especially anionic (e.g. negatively charged) molecules, into bile.
2. drug metabolites eliminated by biliary excretion tend to be comparatively large (mol. wt. >300) molecules, e.g. glucuronic acid conjugates
3. Enterohepatic recirculation
a. tends to prolong duration of drug in the body
b. can be interrupted by diarrhea, antibiotic therapy

(refer to slide)

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VI. Summary of Clinical Significance of Drug Disposition Effects
A. Some clinically significant drug disposition effects which can lead to variability in drugs blood levels and therefore variability in pharmacological response:
B. Treatment of Drug Overdose

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outline

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A. Some clinically significant drug disposition effects which can lead to variability in drugs blood levels and therefore variability in pharmacological response:

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1. binding to materials in GI tract (reabsorption)
2. plasma protein binding (protein concentration, competition effects)
3. biotransformation (induction, inhibition, genetic variation)
4. renal active transport competition
5. hepatic and renal blood flow effects
6. urinary pH effects
7. hepatic and renal disease effects
8. alterations of gut flora

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B. Treatment of drug overdose

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1. supportive treatment - treating the patient, not the poison
2. antidotal treatment - available for relatively few drugs
3. treatment based on altering drug disposition:
a. retard absorption by
i. emesis
ii. gastric lavage
iii. charcoal
iv. catharsis
b. alter distribution - little can be done
c. alter biotransformation - retard formation of toxic metabolite
d. enhance urinary excretion
i. diuresis
ii. alter urine pH

-Acidify urine (ammonium chloride) to enhance excretion of basic drugs.
-Alkalinize urine (sodium bicarbonate) to enhance excretion of acid drugs.

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Don't forget to do the review questions in the packet!

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Don't forget to do the review questions in the packet!