Lecture 4 to 5: PK Flashcards
1
Q
ENTERAL ROUTES
A
- Oral
- Sublingual: bypasses first-pass effect
- Rectal: partial avoidance of first-pass effect
2
Q
PARENTERAL ROUTES
A
- IV
- IM
- Sub-Q
- Intradermal
3
Q
EFFECT OF pH ON DRUG ABSORPTION
A
- The protonated form of a weak acid is the more liposoluble form
- The unprotonated form of a weak base is the more liposoluble form.
4
Q
APPLICATIONS OF THE H-H EQUATION
A
ION TRAPPING
- The most important application of this equation is in the manipulation of drug excretion by the kidney.
- If a drug is in a liposoluble form during its passage down the renal tubule, a significant fraction will be reabsorbed by passive diffusion.
- Weak acids are excreted faster in alkaline urine; weak bases are excreted faster in acidic urine.
5
Q
DETERMINATION OF BIOAVAILABILITY (F)
A
determined comparing the AUC after a particular route of administration with the AUC after IV injection.
6
Q
FACTORS THAT INFLUENCE BIOAVAILABILITY
A
- DRUG FORMULATION
- CHEMICAL INSTABILITY
- FOOD AND DRUG INTERACTIONS
- FIRST-PASS HEPATIC METABOLISM
- DRUG SOLUBILITY
- P-GLYCOPROTEIN
7
Q
DRUG DISTRIBUTION
A
- Initially, liver, kidney, brain, and other well- perfused organs receive most of the drug.
- Delivery to muscle, most viscera, skin, and fat is slower.
8
Q
DRUG BINDING TO PLASMA PROTEINS
A
- Acidic drugs bind to plasma albumin and basic drugs to α1-acid glycoprotein.
- Drugs can compete with each other and with endogenous substances for these binding sites.
- Displacement of unconjugated bilirubin from albumin by sulfonamides increases the risk of bilirubin encephalopathy in the newborn, i.e. Sulfonamide admin in mother or newborn causes kernicterus
- drugs with a narrow TI, a transient change in the unbound concentration due to administration of a competing drug could be of concern.
- Warfarin is highly bound to albumin and only a small fraction is free.
- If a sulfonamide is given, it will displace warfarin causing a significant increase in the plasma level of free warfarin.
9
Q
BLOOD-BRAIN BARRIER
A
- only liposoluble drugs can cross the bbb.
- transcellular route
10
Q
DRUG METABOLISM
A
- Many drugs are lipophilic
- But lipophilic compounds are not easily excreted because they are reabsorbed through the tubular membranes.
- Drug metabolism involves two kinds of biochemical reactions:
- phase I: ER & cytosol
- phase II: cytosol
11
Q
PHASE I REACTIONS
A
- oxidations, reductions, decarboxylations, deaminations and hydrolytic reactions.
- usually convert the parent drug to a more polar metabolite
- In some instances activity is only modified or even enhanced.
12
Q
PRODRUGS
A
One example is the drug cyclophosphamide, which is bioactivated by metabolism to an active anticancer metabolite
13
Q
PHASE II REACTIONS
A
- conjugation reactions form a covalent bond between the drug molecule and glucuronate, acetate, glutathione, amino acids or sulfate.
- Not all drugs undergo these sequential reactions (Phase I → Phase II).
- Ex. isoniazid is acetylated by N-acetyltransferase, in a phase II reaction.
- The acetylated conjugate then undergoes a phase I reaction: hydrolysis to isonicotinic acid.
14
Q
SITES OF DRUG METABOLISM
A
- Liver: most imp
- skin, the lungs, the GI tract, and the kidneys.
15
Q
ENZYME INDUCTION
A
- Certain drugs increase the synthesis of one or more P450 isoforms such as
- **phenobarbital: **benzo
- **rifampin: **antimycobacterial
- carbamazepine: anti-epileptic
- St. John’s wort increases the metabolismof various drugs, by inducing CYP3A4.
- Ex. St. John’s Worts co-admin decreases levels of Indinavir, an anti-HIV drug/protease inhibitor
16
Q
XENOBIOTIC RECEPTORS
A
- Drugs can enter hepatocytes and bind to xenobiotic receptors.
- This activates the receptor, allowing it to translocate to the nucleus and bind to the promoters of various enzymes.
- Aryl hydrocarbon receptor(AhR)
- Pregnane X receptor (PXR)
- Note: Hyperforin in St. John’s Worts in the tabl
- Constitutively active receptor(CAR)
18
Q
DRUG TRANSPORT
A
- P-glycoproteinactively transports drugs back into the intestinal lumen.
- This process limits the oral bioavailability of several drugs, including digoxin and HIV-1 protease inhibitors.
- Drug transporters can be induced or inhibited by other drugs.
- For example, macrolide antibiotics, Ex. Clarithomycin, can inhibit P-glycoprotein.
- This inhibition can lead to increased serum levels of drugs, such as digoxin, that are excreted by P-glycoprotein.
20
Q
METABOLISM OF ACETAMINOPHEN
A
- Acetaminophen metabolises in 3 ways:
- Glucoronate
- Sulfonate
- NAPQI (minor, 5%):
- CYP2E1 catalyzes
- normally have enough GSH to detoxify the NAPQI levels
- antidote is N-acetylcysteine when NAPQI is high
- It supplies cysteine for glutathione production, and also reacts directly with NAPQI.
21
Q
EFFECT OF GRAPEFRUIT ON FELODIPINE METABOLISM
A
- Felodipine: Ca2+ channel blocker
- Grapefruit juice inhibits CYP3A4 -> incr. serum felodipine levels
