Pharmacokinetics Flashcards
What is pharmacokinetics?
The body’s effect on drugs
What are the steps involved in pharmacokinetics?
- Absorption
- Distribution
- Metabolism
- Excretion
What is drug absorption?
The transportation of the unmetabolized drug from the site of administration to the body circulation system
State whether hydrophilic or hydrophobic drugs are absorbed better and why?
Hydrophobic (lipid soluble) are absorbed better
…
This is because Hydrophilic drugs:
1. Pass through the liver unchanged (as they can’t pass into hepatocytes)
2. Show little protein binding
3. Are not subject to tubular reabsorption
4. Are excreted rapidly
5. Poorly absorbed because of their inability to cross the lipid-rich cell membranes
What is drug distribution?
The process whereby an absorbed drug moves from the blood (vascular compartment) to other spaces of the body (such as fat, cells, interstitial space)
What is drug metabolism?
How the drug is chemically altered (usually in the liver)
What is drug excretion?
How the drug and its metabolites leave the body (mainly renal)
What effect does IV administration have on kinetics?
___% bioavailability
Rapid/slow onset
100 % bioavailability
Rapid onset
When compared to IV administration, oral has a faster/slower onset and is subject to ______
Faster onset
Subject to first pass metabolism
Rank the different routes of drug administation, from fastest to slowest rate of absoption
- IV (directly into the bloodstream → 100% bioavailability)
- Inhalation (very rapid due to large surface area of alveoli and rich blood supply in lungs)
- IM (depends on blood flow to the muscle)
- SC (absorption rate can vary with blood flow, fat content, and drug formulation)
- Sublingual/ buccal (bypasses first-pass metabolism, quick absorption into circulation)
- Rectal (variable and often slower than oral; partially bypasses first-pass metabolism)
- Oral (most common, but slower due to digestion, GI motility, and first-pass metabolism in the liver)
- Topical
- Transdermal
What plasma proteins do drugs bind to?
- Albumin (acidic drugs)
- Alpha-1-acid glycoprotein (basic drugs)
Bound/unbround drugs are pharmacologicaly active
Unbound
What is the clinical significance of bound vs unbound (free) drug
- Highly protein-bound drugs (e.g. valproate, phenytoin) require careful interpretation of blood levels
- In hypoalbuminaemia (e.g. liver disease), there is more free drug → increased effect/toxicity.
What is half-life?
The time for plasma concentration of a drug to fall by 50%
…
(this determines the dosing interval)
What is Cmax?
Peak plasma concentration
…
(Affects efficacy and side effects)
What is Tmax?
(Time taken to reach Cmax)
…
(Influences onset of action)
What is Volume of Distribution (Vd)?
Indicates extent of drug distribution into tissues
What is Area Under the Curve (AUC)?
Reflects total drug exposure over time
What is the difference between Linear (First-order) and Zero-order kinetics?
Linear (first-order): A constant proportion of drug is eliminated per unit time
Zero-order: A constant amount of drug is eliminated per unit time
What is the clinical significance of a drug that follows Linear (First-order) vs Zero-order kinetics?
- Linear (first-order): The body eliminates a constant fraction of the drug per unit time, therefore the higher concentration → faster elimination rate: allows predictable plasma levels with dose adjustments
- Zero-order: The body eliminates a constant amount of drug per unit time, not a fraction; if your liver can only metabolize 5 mg/hr — it doesn’t matter if there’s 10 mg or 50 mg in your system, it still only clears 5 mg/hr: increased risk of toxicity due to accumulation with small dose changes
Give examples of medications that follow zero-order kinetics.
- Phenytoin
- Ethanol
- High-dose aspirin
…
(note: most psychotrophics follow linear first-order kinetics)
What is the Cytochrome P450 System (CYP450)?
A family of enzymes mainly found in the liver and intestinal wall responsible for phase I metabolism (oxidation, reduction, hydrolysis) of drugs
List the key CYP450 isoenzymes that are most clinically relevant for psychiatry.
CYP1A2
CYP2D6
CYP3A4
CYP2C19
CYP2CP
CYP1A2:
A. Common substrates
B. Inhibitors
C. Inducers
A. Common substrates:
1. Clozapine
2. Olanzapine
3. Asenapine
4. Agomelatine
5. Melatonin
…
B. Inhibitors:
1. Grapefruit juice
…
C. Inducers:
1. Smoking
2. Carbamazepine
…
(note: CYP1A2 is involved in metabolism of clozapine; anything that inhibits CYP1A2 increase clozapine levels; anything that induces CYP1A2 decreased clozapine levels)
CYP2D6:
A. Common substrates
B. Inhibitors
C. Inducers
A. Common substrates:
1. Amphetamines
2. Atomoxetine
3. Aripiprazole
4. Clomipramine
5. Fluoxetine*
6. Olanzapine
7. Risperidone
8. Mianserin
9. Imipramine
10. Venlafaxine
11. Zuclopenthixol
…
B. Inhibitors:
1. Fluoxetine*
2. Paroxetine
3. Bupropion
4. Asenapine
5. Amitriptyline
…
C. Inducers:
NOT KNOWN
CYP3A4:
A. Common substrates
B. Inhibitors
C. Inducers
A. Common substrates:
1. Aripiprazole
2. Clonazepam
3. Donepazil
4. Fentanyl
5. Methadone
6. Mirtazapine
7. Quetiapine
8. Zopiclone
…
B. Inhibitors:
1. Fluoxetine
2. Paroxetine
…
C. Inducers:
1. Carbamazepine
2. Phenobarbital
3. Phenytoin
4. St John’s Wort
What kinetic changes occur in pregnancy?
What kinetic changes occur in the elderly?
What kinetic changes occur in liver/kidney disease?
What kinetic changes occur in children?
With regards to psychotrophics, what is the difference between lipophilicity and hydrophilicity?
Lipophilic drugs cross the BBB more easily and are widely distributed (e.g. diazepam).
Hydrophilic drugs stay in plasma; less CNS penetration
What is the blood brain barrier?
A highly selective semipermeable membrane that regulates the passage of substances between the bloodstream and the brain
In the blood brain barrier, what prevents the passage of hydrophilic substances?
Tight junctions
…
(only small, lipophilic, uncharged drugs can cross)
What is P-glycoprotein and what is its role?
One of the most well-known transporters at the blood brain barrier, this ATP-driven pump actively extrudes certain drugs and toxins, ensuring they don’t gain access to the delicate neural environment
…
(important for CNS effects of psychotropics)
What is pharmacogenetics?
Study of single gene variants affecting drug metabolism
What is pharmacogenomics?
Broader approach, including multiple genes/genomic data
Which psychotrophics require therapeutic drug monitoring (TDM)?
- Lithium
- Clozapine
- Sodium valproate
