Pharmacokinetics

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Some Factors Influencing Absorption and Bioavailability

Absorption

Absorption Principles:

Permeation:

Passive diffusion (aqueous or lipid environment): most common

Active transport: important for some drugs, particularly larger molecules.

I. Aqueous diffusion

within large aqueous components (e.g.,interstitial space, cytosol)

across epithelial membrane tight junctions

across endothelial blood vessel lining

through aqueous pores: allows diffusion of molecules with molecular weights up to 20,000 -- 30,000.

Driving force: drug concentration gradient (described by Fick's Law ).

The driving force represents a tendency for molecules to move in the direction of higher concentration to lower concentration in accord with random molecular motion. A traditional way of thinking about this is to imagine a fluid-filled container which is two sections divided by an imaginary plane. The solution on one side is more concentrated in terms of some dissolved substance that is the solution on the other side of the boundary plane.

Recall that the molecules move randomly, suggesting that sometimes a molecule initially in the "low concentration" section can move to the "high concentration" section. However, on balance. It is more likely that based on probability molecules will tend to move from the higher concentrations side to the lower concentrations side. Suppose that initially there are 2,000 molecules on side A and 1,000 molecules on side B. After a while we look again and find that there now are 1750 molecules on side A and 1250 molecules on side B-- a new ratio is been established, but the process continues until the ratio is approximately 1:1.

Plasma protein-bound drugs cannot permeate through aqueous pores

Charged drugs will be influenced by electric field potentials {membrane potentials, important in renal, trans-tubular transport}

Fick's Law describes passive movement molecules down its concentration gradient.

Flux (J) (molecules per unit time) = (C1 - C2) · (Area ·Permeability coefficient) / Thickness

where C1 is the higher concentration and C2 is the lower concentration

area = area across which diffusion occurs

permeability coefficient: drug mobility in the diffusion path

for lipid diffusion, lipid: aqueous partition coefficient -- major determinant of drug mobility

partition coefficient reflects how easily the drug enters the lipid phase from the aqueous medium.

thickness: length of the diffusion path

II. Lipid diffusion

Most important barrier for drug permeation due to:

many lipid barriers separating body compartments

Lipid: aqueous drug partition coefficients described the ease with which a drug moves between aqueous and lipid environments

Ionization state of the drug is an important factor: charged drugs diffuse-through lipid environments with difficulty.

pH and the drug pKa, important in determining the ionization state, will influence significantly transport (ratios of lipid-to aqueous-soluble forms for weak acids and bases described by the Henderson-Hasselbalch equation.

uncharged form: lipid-soluble

charged form: aqueous-soluble, relatively lipid-insoluble (does not pass biological membranes easily)

Henderson-Hasselbalch equation

General Form: log (protonated)/(unprotonated) = pKa - pH

For Acids: pKa = pH + log (concentration [HA] unionized)/concentration [A-]
note that if [A-] = [HA] then pKa = pH + log (1) or (since log(1) = 0), pKa = pH

For Bases: pKa = pH + log (concentration [BH+] ionized)/concentration
note that if [B] = [BH+] then pKa = pH + log (1) or (since log(1) = 0), pKa = pH

The lower the pH relative to the pKa the greater fraction of protonated drug is found. Recall that the protonated form of an acid is uncharged (neutral); however, protonated form of a base will be charged.

As a result, a weak acid at acid pH will be more lipid-soluble because it is uncharged and uncharged molecules move more readily through a lipid (nonpolar) environment, like the some membrane, than charged molecules

Similarly a weak base at alkaline pH will be more lipid-soluble because at alkaline pH a proton will dissociate from molecule leaving it uncharged and again free to move through lipid membrane structures

Lipid diffusion depends on adequate lipid solubility

Drug ionization reduces a drug's ability to cross a lipid bilayer.

Drugs that are weak acids or bases

A weak acid is a neutral molecule that dissociates into an anion (negatively charged) and a proton (a hydrogen ion) Example:

C8H7O2COOH < > C8H7O2COO- + H+

neutral aspirin (C8H7O2COOH) in equilibrium with aspirin anion (C8H7O2COO- ) and a proton (H+ )

weak acid: protonated form -- neutral, more lipid-soluble

weak base:a neutral molecule that can form a cation (positively charged) by combining with a proton. Example:

C12H11CIN3NH3+ < > C12H11CIN3NH2 + H+

pyrimethamine cation (C12H11CIN3NH3+) in equilibrium with neutral pyrimethamine (C12H11CIN3NH2) and a proton (H+ )

weak base: protonated form -- charged, less lipid-soluble

III. [b]Special Carriers

Peptides, amino acids, glucose are examples of molecules then enter cells through special carrier mechanisms.

Carriers:

Active transport describes an energy requiring process which is saturable, meaning that transport is probably against the concentration gradient and involves a finite number of carriers, hence the process must be saturable when all carrier sites are filled.

Facilitated diffusion, while not requiring "energy" is also saturable (limited number of carrier sites)

Saturable (unlike passive diffusion) because of limited number of carrier sites--once those sites are filled, transport rates cannot be increased.

A property of carrier systems is that process is subject to inhibition by other small molecules.

IV. Endocytosis and exocytosis:

Entry into cells by very large substances (e.g., iron vitamin B12 -- each complexed with its binding protein -- movement across intestinal wall into the blood)

Neurotransmitter system examples for exocytosis:

Following neuronal electrical activation of nerve endings, two steps may be initiated:

Storage vesicles containing neurotransmitter fuse with cell membranes followed by

release or diffusion of contents into the extracellular region.

Extent of Absorption

Incomplete absorption following oral drug administration is common:

For example -- only 70% of a digoxin dose reaches systemic circulation. Factors:

poor GI tract absorption

digoxin (Lanoxin, Lanoxicaps) --- metabolism by gastrointestinal flora

Very hydrophilic drugs - not be well absorbed --cannot cross cell membrane lipid component

Excessively lipid-soluble (hydrophobic) drugs may not be soluble enough to cross a water layer near the cell membrane.

Ion trapping

Kidney:

Nearly all drugs filtered at the glomerulus:

Most drugs in a lipid-soluble form will be reabsorbed by passive diffusion.

To increase excretion: change the urinary pH to favor the charged form of the drug since charged form cannot be readily reabsorbed (they cannot readily pass through biological membranes)

Weak acids: excreted faster in alkaline pH (anion form favored)

Weak bases: excreted faster in acidic pH (cation form favored)

Other sites:

Body fluids where pH differences from blood pH favor trapping or reabsorption:

stomach contents

small intestine

breast milk

aqueous humor (eye)

vaginal secretions

prostatic secretions

IMPORTANT: Ion Trapping: Anesthesia Correlation:Placental transfer of basic drugs
Placental transfer of basic drugs from mother to fetus: local anesthetics

fetal pH is lower than maternal pH

lipid-soluble, nonionized local anesthetic crosses the placenta converted to poorly lipid-soluble ionized drug

gradient is maintained for continual transfer of local anesthetic from maternal circulation to fetal circulation

in fetal distress, acidosis contributes to local anesthetic accumulation

Routes of Administration

Oral Administration

Most convenient, most economical

Disadvantages:

emesis (drug irritation of the gastrointestinal mucosa)

digestive enzymes/gastric acidity destroys the drug

unreliable or inconsistent absorption due to food or other drug effects

metabolism of the drug by gastrointestinal flora

Factors determining rate of drug effect onset

Primary factor:

Rate & absorption extent by GI tract

Absorption Site:

mainly small intestine because of large surface area

Drug ionization state:

nonionized (lipid-soluble) forms favor absorption

weak acids may be highly ionized in the alkaline intestinal pH (not favoring absorption) but this effect is counterbalanced by the large surface-area effect

drugs which are weak acids are readily absorbed in the stomach

First-Pass Effect

Drugs absorbed from the GI tract passes through the portal venous system then through the liver and finally into the systemic circulation when drugs interact with receptors in target tissues.

Extensive hepatic metabolism/extraction result in minimal drug delivery to the systemic circulation for certain agents.

Drugs with large first pass effect exhibit significant differences in pharmacological effects comparing oral vs. IV administration

Examples:

propranolol

lidocaine

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Transdermal Administration

Advantages:

sustained, therapeutic plasma levels (reduced peaks/valleys associated with intermittent drug administrations)

Avoids continuous infusion technique difficulties

Low side effect incidence (smaller doses)

Generally good patient compliance

Factors contributing to reliable transdermal drug absorption:

molecular weight < 1000

pH range 5-9 in aqueous medium

no histamine-releasing action

daily drug requirement <10 mg

Example of drugs available for transdermal delivery:

scopolamine:-tolerance may eventually occur; resulting in loss of therapeutic action

fentanyl (Sublimaze)

clonidine (Catapres)

nitroglycerin-tolerance may eventually occur; resulting in loss of therapeutic action

Rectal Administration

Proximal rectum administration: Absorption into superior hemorrhoidal veins then enters the portal venous system then to the liver (possible first pass hepatic effect) and finally into the systemic circulation

Low rectal administration of drug may allow the drug to enter the systemic circulation without passing through the liver

Generally unpredictable pharmacological responses for the above reasons

Rectal mucosal irritation possible

Parenteral Administration

Ensures active drug absorption

subcutaneously intramuscular injection: more rapid/predictable than oral administration route

only route of administration acceptable for:

uncooperative patients

unconscious patients

Factors the determine rate of systemic absorption:

absorbing capillary membrane surface area

drug solubility in interstitial fluid

aqueous channels (vascular endothelium) promote high diffusion rates of drugs, independent of their lipid solubility

Advantages of IV administration

rapid/precise blood drug levels obtained (e.g., no first-pass effect)

Irritant drugs: more comfortably administered (blood vessels relatively insensitive); drug rapidly diluted (particularly if administered into large forearm vein)

First Pass Effect

First-pass Elimination:

Transport sequence:

across the gut wall into the portal circulation

portal blood transports of the drug to the liver

the drug may then reach the systemic circulation

bioavailability may be affected by steps 1 -- 3

drug metabolism may occur in the intestinal wall or in the blood

drug metabolism (potentially extensive) may occur in liver

liver may excrete drug into the bile

overall process that contributes to bioavailability reduction is the first-pass lost or elimination

Magnitude of first pass hepatic effect: Extraction ratio (ER)

ER = CL liver / Q ; where Q is hepatic blood flow (usually about 90 L per hour {1500 ml/min})

Systemic drug bioavailability (F) may be determined from the extent of absorption (f) and the extraction ratio (ER):

F = f x (1 -ER)

Extraction Ratios, Routes of Administration, and the First-Pass Effect

Some drugs that exhibit high extraction by the liver are given orally.

Some examples -- desipramine (Norpramin), imipramine (Tofranil), meperidine (Demerol), propranolol (Inderal), amitriptyline (Elavil, Endep), isoniazid (INH).

Some drugs which have relatively low bioavailability are not given orally because of concern of metabolite toxicity -- lidocaine is an example (CNS toxicity, convulsions)

High extraction ratio drugs show interpatient bioavailability variation because all of sensitivity to:

-hepatic function

-blood flow

-hepatic disease (intrahepatic or extrahepatic circulatory shunting)

Drugs poorly extracted by the liver

-phenytoin (Dilantin)
-diazepam (Valium)
-digitoxin (Crystodigin)
-chlorpropamide (Diabinese)
-theophylline
-Tolbutamide (Orinase)
-warfarin (Coumadin)

Avoiding the first-pass effect:

-sublingual (e.g. nitroglycerin)-- direct access to systemic circulation
-transdermal
-use of suppositories in the lower rectum {if suppositories move upward, absorption may occur through the superior hemorrhoidal veins, which lead to the liver}
-inhalation: first-pass pulmonary loss by excretion or metabolism may occur

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