Transcript Chapter 16 Cholinesterase Inhibitors

Chapter 4
Pharmacokinetics
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Pharmacokinetics
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Application of pharmacokinetics in
therapeutics
Passage of drugs across membranes
Three ways to cross a cell membrane
Polar molecules
Ions
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Pharmacokinetics
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Absorption
Distribution
Metabolism
Excretion
Time course of drug responses
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Fig. 4-1. The four basic pharmacokinetic processes.
Dotted lines represent membranes that must be crossed as drugs move throughout the body.
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Application of
Pharmacokinetics in Therapeutics
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By applying knowledge of pharmacokinetics
to drug therapy, we can help maximize
beneficial effects and minimize harm.
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A Note to Chemophobes
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Chemophobes are students who fear
chemistry.
This chapter contains some of the most
difficult material in the book.
This chapter lays an important foundation for
the rest of the chapters.
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Passage of Drugs Across
Membranes
Three ways to
cross a cell
membrane
• Channels and pores
• Transport systems
P-glycoprotein
• Direct penetration
of the membrane
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Membrane Structure
Fig. 4-2. Structure of the cell membrane.
The cell membrane consists primarily of a double layer of phospholipid
molecules. The large globular structures represent protein molecules
imbedded in the lipid bilayer.
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Passage of Drugs Across
Membranes
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Polar molecules
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Uneven distribution of a charge
No net charge
Ions
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Molecules that have a net electrical charge
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Fig. 4-3. Polar molecules.
A, Stippling shows the distribution of electrons within the water molecule. As indicated, water’s
electrons spend more time near the oxygen atom than near the hydrogen atoms, making the area
near the oxygen atom somewhat negative and the area near the hydrogen atoms more positive.
B, Kanamycin is a polar drug. The —OH groups of kanamycin attract electrons, thereby causing
the area around these groups to be more negative than the rest of the molecule.
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Ions
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Quaternary ammonium compounds
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pH-dependent ionization
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Molecules that contain at least one atom of
nitrogen and carry a positive charge at all times
Acid is a proton donor – tends to ionize in basic
(alkaline) media
Base is a proton acceptor – tends to ionize in
acidic media
Ion trapping (pH partitioning)
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Acidic drugs accumulate on the alkaline side.
Basic drugs accumulate on the acidic side.
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Fig. 4-4. Quaternary ammonium compounds.
A, The basic structure of quaternary ammonium compounds. Because the nitrogen atom has
bonds to four organic radicals, quaternary ammonium compounds always carry a positive
charge. Because of this charge, quaternary ammonium compounds are not lipid soluble and
cannot cross most membranes. B, Tubocurarine is a representative quaternary ammonium
compound. Note that tubocurarine contains two “quaternized” nitrogen atoms.
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Fig. 4-5. Ionization of weak acids and weak bases.
The extent of ionization of weak acids (A) and weak bases (B) depends on the pH
of their surroundings. The ionized (charged) forms of acids and bases are not lipid
soluble and hence do not readily cross membranes. Note that acids ionize by
giving up a proton and that bases ionize by taking on a proton.
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Fig. 4-6. Ion trapping of drugs.
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Absorption
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Movement of a drug from its site of
administration into the blood
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Rate of absorption determines how soon effects
will begin.
Amount of absorption helps determine how
intense the effects will be.
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Absorption
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Factors affecting drug absorption
Characteristics of commonly used routes of
administration
Pharmaceutical preparations for oral
administration
Additional routes of administration
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Factors Affecting Drug
Absorption
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Rate of dissolution
Surface area
Blood flow
Lipid solubility
pH partitioning
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Characteristics of Commonly
Used Routes of Administration
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Intravenous
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Barriers to absorption
Absorption pattern
Advantages
Disadvantages
Intramuscular
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Barriers to absorption
Absorption pattern
Advantages
Disadvantages
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Fig. 4-7. Drug movement at typical capillary beds.
In most capillary beds, “large” gaps exist between the cells that compose the capillary wall.
Drugs and other molecules can pass freely into and out of the bloodstream through these
gaps. As illustrated, lipid-soluble compounds can also pass directly through the cells of the
capillary wall.
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Characteristics of Commonly
Used Routes of Administration
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Subcutaneous
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No significant barriers to absorption
Oral
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Barriers to absorption
Absorption pattern
Drug movement following absorption
Advantages
Disadvantages
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Fig. 4-8. Movement of drugs following GI absorption.
All drugs absorbed from sites along the GI tract—stomach, small intestine, and large intestine
(but not the oral mucosa or distal rectum)—must go through the liver, via the portal vein, on their
way toward the heart and the general circulation. For some drugs, passage is uneventful. Others
undergo extensive metabolism. Still others undergo excretion into the bile, after which they reenter the small intestine (via the bile duct), and then either (1) undergo reabsorption into the
portal blood, thereby creating a cycle known as enterohepatic recirculation, or (2) exit the
body in the stool (not shown).
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Pharmaceutical Preparations for
Oral Administration
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Tablets
Enteric-coated preparations
Sustained-release preparations
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Additional Routes of
Administration
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Topical
Transdermal
Inhaled
Rectal
Vaginal
Direct injection to a specific site (eg, heart,
joints, nerves, CNS)
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Distribution
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Movement of drugs throughout the body
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Distribution
Drug distribution
is determined by
these three factors
• Blood flow to
tissues
• Exiting the
vascular system
• Entering cells
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Blood Flow to Tissues
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Drugs are carried by the blood to tissues and
organs of the body.
Blood flow determines the rate of delivery.
Abscesses and tumors
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Low regional blood flow impacts therapy.
Pus-filled pockets, not internal blood vessels
Solid tumors have limited blood supply.
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Exiting the Vascular System
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Typical capillary beds
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Drugs pass between capillary cells rather than
through them.
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Blood-Brain Barrier (BBB)
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Tight junctions between the cells that
compose the walls of most capillaries in the
CNS
Drugs must be able to pass through cells of
the capillary wall.
Only drugs that are lipid soluble or have a
transport system can cross the BBB to a
significant degree.
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Fig. 4-9. Drug movement across the blood-brain barrier.
Tight junctions between cells that compose the walls of capillaries in the CNS prevent drugs
from passing between cells to exit the vascular system. Consequently, to reach sites of action
within the brain, a drug must pass directly through cells of the capillary wall. To do this, the drug
must be lipid soluble or must be able to use an existing transport system.
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Placental Drug Transfer
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Membranes of the placenta do NOT
constitute an absolute barrier to the passage
of drugs.
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Movement determined in the same way as other
membranes
Risks with drug transfer
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Birth defects: mental retardation, gross
malformations, low birth weight
Mother’s use of habitual opioids: birth of drugdependent baby
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Fig. 4-10. Placental drug transfer.
To enter the fetal circulation, drugs must cross membranes of the maternal and fetal vascular
systems. Lipid-soluble drugs can readily cross these membranes and enter the fetal blood,
whereas ions and polar molecules are prevented from reaching the fetal blood.
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Protein Binding
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Drugs can form reversible bonds with various
proteins.
Plasma albumin is the most abundant and
important.
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Large molecule that always remains in the
bloodstream
Impacts drug distribution
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Fig. 4-11. Protein binding of drugs.
A, Albumin is the most prevalent protein in plasma and the most important of the proteins to
which drugs bind. B, Only unbound (free) drug molecules can leave the vascular system. Bound
molecules are too large to fit through the pores in the capillary wall.
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Entering Cells
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Some drugs must enter cells to reach the site
of action.
Most drugs must enter cells to undergo
metabolism and excretion.
Many drugs produce their effects by binding
with receptors on the external surface of the
cell membrane.
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Do not need to cross the cell membrane to act
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Drug Metabolism
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Also known as biotransformation
Defined as the enzymatic alteration of drug
structure
Most often takes place in the liver
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Drug Metabolism
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Hepatic drug-metabolizing enzymes
Therapeutic consequences of drug
metabolism
Special considerations in drug metabolism
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Hepatic Drug-Metabolizing
Enzymes
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Most drug metabolism that takes place in the
liver is performed by the hepatic microsomal
enzyme system, also known as the P450
system.
Metabolism doesn’t always result in a smaller
molecule.
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Therapeutic Consequences of
Drug Metabolism
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Accelerated renal drug excretion
Drug inactivation
Increased therapeutic action
Activation of prodrugs
Increased or decreased toxicity
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Fig. 4-12. Therapeutic consequences of drug metabolism.
(See text for details.)
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Enterohepatic Recirculation
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Repeating cycle in which drug is transported
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From the liver into the duodenum (via bile duct)
Then back to the liver via the portal blood
Limited to drugs that have undergone
glucuronidation
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Special Considerations in
Drug Metabolism
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Age
Induction of drug-metabolizing enzymes
First-pass effect
Nutritional status
Competition between drugs
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Excretion
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Defined as the removal of drugs from the
body
Drugs and their metabolites can exit the body
through
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Urine, sweat, saliva, breast milk, or expired air
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Renal Routes of Drug Excretion
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Steps in renal drug excretion
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Glomerular filtration
Passive tubular reabsorption
Active tubular secretion
Factors that modify renal drug excretion
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pH-dependent ionization
Competition for active tubular transport
Age
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Fig. 4-13. Renal drug excretion.
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Nonrenal Routes of Drug
Excretion
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Breast milk
Other nonrenal routes of excretion
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Bile
• Enterohepatic recirculation
Lungs (especially anesthesia)
Sweat/saliva (small amounts)
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Time Course of Drug Responses
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Plasma drug levels
Single-dose time course
Drug half-life
Drug levels produced with repeated doses
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Fig. 4-14. Single-dose time course.
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Plasma Drug Levels
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Clinical significance of plasma drug levels
Two plasma drug levels defined
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Minimum effective concentration
Toxic concentration
Therapeutic range
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Therapeutic Range
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The objective of drug dosing is to maintain
plasma drug levels within the therapeutic
range.
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Single-Dose Time Course
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The duration of effects is determined largely
by the combination of metabolism and
excretion.
Drug levels above minimum effective dose –
therapeutic response will be maintained
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Half-Life
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Defined as the time required for the amount
of drug in the body to decrease by 50%
Percentage vs. amount
Determines the dosing interval
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Drug Levels Produced with
Repeated Doses
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Process by which plateau drug levels are
achieved
Time to plateau
Techniques for reducing fluctuations in drug
levels
Loading doses vs. maintenance doses
Decline from plateau
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Fig. 4-15. Drug accumulation with repeated administration.
This figure illustrates the accumulation of a hypothetical drug during repeated administration.
The drug has a half-life of 1 day. The dosing schedule is 2 gm given once a day on days 1
through 9. Note that plateau is reached at about the beginning of day 5 (ie, after four half-lives).
Note also that, when administration is discontinued, it takes about 4 days (four half-lives) for
most (94%) of the drug to leave the body.
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