Pharmacology describes a drug's journey through the body and its effects. Pharmacokinetics involves absorption, distribution, metabolism and excretion of a drug. Absorption depends on route of entry and bioavailability. Distribution is based on volume of distribution. Metabolism occurs mainly in the liver through phase I and II reactions. Excretion eliminates drugs through kidneys or bile. Pharmacodynamics studies how drugs cause their effects by interacting with receptors.
2. Pharmacokinetics
● The description of a drug’s journey through a
patient’s body. (action of body on the drug)
● Involves four main processes:
● (1) absorption
● (2) distribution
● (3) metabolism
● (4) excretion
3. Absorption
● How the patient’s body takes in (absorbs) the
drug.
– Enteral - meaning absorbed through the intestines
– Parenteral, meaning absorbed without the
intestines
4. ● Bioavailability – how much drug is in the systemic
circulation
● Oral drugs < IV drugs > rectal
● (1) not everything is absorbed (incomplete tablet
breakdown, barriers to absorption across the gut
mucosa, gastric acid or enzymatic destruction),
● (2) after absorption through the intestines into the
portal vein, the drug first passes through the liver -
firstpass metabolism
5. Distribution
● Distribution is where the drug goes after it is
absorbed and is usually discussed as the
volume of distribution (Vd).
– Vd = Amount of drug in body/Plasma drug
concentration
● How much of a drug stays in the patient’s
bloodstream and is unbound to protein.
● High Vd = Protein bound drug, Lipid soluble
●
6. Metabolism
● One of the two ways that the body can
decrease the concentration of active drug in the
bloodstream.
– Liver
● Two phases of biotransformation:
– phase I biotransformation (oxidation)
– phase II biotransformation (conjugation)
7.
8. Phase I biotransformation
● Mediated by the microsomal cytochrome P-450
(CYP) monooxygenase system, with CYP3A4 (most
common subtype).
● Reactions - oxidations, reductions, or hydrolysis
● To make the drug more polar (more water soluble).
● Prodrugs: Levodopa.
● Older adults have decreased phase
biotransformation ability
9. Phase II biotransformation
● A molecule is “strapped on” (conjugated) to the
drug, such as an acetyl group, sulfide, or
glucuronide.
● Always makes the drug inactive.
●
10. Metabolism
● Metabolism
– Opioid analgesic codeine is metabolized into the
more active morphine by CYP2D6—10% of whites
have decreased CYP2D6 activity and will not get
adequate pain relief with codeine administration.
– CYP2C19 activates the antiplatelet agent clopidogrel
into the active form.
– Patients with poor CYP2C19 activity (more common
in Asian populations) will not have therapeutic levels
of the drug in their body.
11. ● Differences in CYP activity vary based on
genetics; race and ethnicity.
– Grapefruit juice, cimetidine, erythromycin are
common CYP3A4 inhibitors.
– St. John’s wort, phenytoin, rifampin are common
CYP3A4 inducers
12. Excretion
● Typically by the kidneys
– Glomerular filtration: The drug must be delivered to the
glomerulus if it is to be filtered.
– Active tubular secretion: Probenecid
– Passive tubular reabsorption: Uncharged, lipid-soluble
molecules can be more readily absorbed through renal
tubular cell membranes.
– If the drug is a weak acid, then alkalization of the urine
will increase excretion by making more of the drug in
the charged A− form.
13. ● Excretion via biliary system
– Through the bile to eventually be excreted in the
stool
– conjugation (recall that this is a phase II
biotransformation) with glucuronate can be excreted
in this fashion.
14. Calculations & Kinetics
● Elimination of drugs in terms of zero-order
kinetics versus first-order kinetics.
● Zero-order kinetics: A constant amount of drug
is eliminated per unit of time, so the rate of
elimination is constant regardless of
concentration of drug.
– Examples: phenytoin, ethanol, and aspirin (PEA)
15. ● First-order kinetics: : A constant fraction of drug
is eliminated per unit time, so the rate of
elimination is proportional to the drug
concentration.
● More common method in which drugs are
metabolized.
● Almost all drugs are eliminated by first-order
kinetics
16. Half-life
● Half-life of a drug, which is the time it takes for
half the drug to be metabolized.
– Half-life of zero-order kinetics will change with the
concentration of the drug.
– In first-order kinetics, a constant proportion is
metabolized, the half-life is constant for a specific
drug.
– First-order kinetics drug, the half-life equation:
● Half-life = 0.7 × Vd/Clearance
17. Steady state
● After a patient has taken a drug for a period of
time (typically 4 to 5 times the half-life of the
drug), it reaches a steady state - where the
amount of drug taken equals the amount of
drug leaving the body.
●
18. ● The concept of steady state also applies to
clinical practice.
● Levothyroxine has a half-life of about 1 week.
● How long before a steady state is achieved?
● When should TSH be assessed in a patient?
19. ● The last calculations that you are expected to
know are the loading dose and maintenance
dose for a medication.
● Loading dose= Cp × Vd/F
– Cp is the target plasma concentration,
– Vd is the volume of distribution
– F is the bioavailability of the drug
20. ● Loading dose is a larger one-time dose to get
the patient up to the desired plasma
concentration without having to wait for 5 half-
lives.
● Maintenance dose = Cp × clearance/F
– Cp is the target plasma concentration and F is the
bioavailability of the drug.
21. ● It represents the dose at which the net
concentration of that drug in the bloodstream is
unchanging.
● Therefore the elimination of the drug equals the
rate of administration of the drug.
22. PHARMACODYNAMICS
● The study of how a given drug causes its effect.
– Action of the drug on the body
● Understanding of receptor activity, signal
transduction pathways, and physiologic effects of
a given drug.
● Agonists: activate receptor
● Antagonists: block receptor
● Partial antagonists: elicit a submaximal response
