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Pharmacology 3 > L5: Introduction to Pharmacokinetics > Flashcards

L5: Introduction to Pharmacokinetics Flashcards

1
Q

What is a therapeutic window?

A

Range of concentration of a drug between maximum safe and minimum effective concentrations.

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2
Q

What are the pillars of pharmacokinetics?

A
  • Absorption - transfer of drug to circulation (how quickly the drug is absorbed to the system)
  • Distribution - where drug reaches (how is it distributed)
  • Metabolism - (how drug is acted upon)
  • Elimination - removal of a drug
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3
Q

What are the main routes of drug administration?

A
  • enteral (involves the gastrointestinal tract)
  • parenteral (independent of the GI tract)
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4
Q

What are the routes of parenteral drug administration?

A
  • injection:
    i) intramuscular (to muscles);
    ii) subcutaneous (to subcutaneous);
    iii) intravascular (to veins);
    iv) epidural (to epidural space)
  • topical administration:
    i) cream,
    ii) drops,
    iii) inhaled
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5
Q

What are the routes of enteral drug administration?

A

Most common, but least predictible
- oral: swallowing, tablet/liquid
- sublingual (under tongue)
- buccal (absorbed through membranes of the mouth)

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6
Q

What are the advantages of oral administration?

A
  • convenient - can be self-administered, pain free, easy to take
  • absorption - takes place along the whole length of the GI tract
  • cheap - compared to most other parenteral routes
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7
Q

What are the disadvantages of oral administration?

A
  • sometimes inefficient - only part of the drug may be absorbed
  • irritation to gastric mucosa - nausea and vomiting
  • destruction of drugs by gastric acid and digestive juices (e.g. erythromycin)
  • interaction with food (e.g. digoxin - fibre binding)
  • unpleasant taste of some drugs
  • onset of effect is slow
  • cannot be used in unconscious patients
  • first-pass effect - drugs absorbed from the gut are initially transported to the liver via the portal vein
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8
Q

What is first pass effect?

A

Hepatic metabolism of a pharmacological agent when it is absorbed form the gut and delivered to the liver via the portal circulation.

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9
Q

What is the correlation between the first-pass effect size and a drug reaching systemic circulation?

A

the greater the first-pass effect, the less a drug will reach the systemic circulation when it is administered orally

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10
Q

How is the route of administration for the drug chosen?

A
  • physical characteristics
  • speed which the drug is absorbed
  • need to bypass hepatic metabolism
  • need to achieve high concentrations at particular sites
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11
Q

What are the factors influencing the rate of absorption?

A
  • routes of administration
  • dosage forms
  • concentration of the drug
  • physiochemical properties of the drug
  • protein binding
  • types of transport
  • circulation at the site of absorption
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12
Q

What are the mechanisms of solute transport across membranes?

A
  • passive diffusion
  • filtration and bulk flow
  • endocytosis
  • ion-pairing
  • active transport
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13
Q

What are the barriers to absorption?

A
  • mucous layers (orally administered)
  • protein binding (drugs bind bulky proteins)
  • fat isolation (sequestered in fat, when dissolves in fat)
  • placenta
  • blood-brain barrier
  • cell membrane most ubiquitous
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14
Q

What does pKa for drug absorption determine?

A

pH at which 50% of a drug is ionised;
ionization usually increases with opposing pH, ie basic drugs ionized in acidic solutions

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15
Q

When do weak acid drugs become highly ionised?

A

as pH increases

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16
Q

When do weak bases become highly ionised?

A

as pH decreases

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17
Q

Where are non-ionised forms soluble? Do they cross the membrane?

A

Non-ionised forms are lipid soluble and cross the cell membrane

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18
Q

Where are ionised forms soluble? Do they cross the membrane?

A

Ionised forms are water soluble and do not cross the cell membrane

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19
Q

When do drugs become most concentrated?

A

When they are most ionised

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20
Q

How are ionisation ratios calculated for acidic and basic drugs?

A

According to Henderson-Hasselbach equation:
for acid drugs: pKa = pH + log10([HA]unionised/[A-]ionised)
for basic drugs: pKa = pH + log10([HB+]ionised/[B]unionised)

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21
Q

What’s the ratio of unionised concentration across a cell membrane?

A

unionised concentration is the same on both sides

22
Q

How and why is the solubility changed of a drug for its metabolism?

A

Lipid soluble drugs are transformed to water soluble drugs to enhance secretion

23
Q

What is the primary site for metabolism of a drug?

A

Often liver, other sites include kidney, intestine, lungs

24
Q

What are the cellular sites for metabolism of a drug?

A

Cytosol, mitochondria, lysosomes, smooth endoplasmic reticulum

25
What are the two types of **biotransformation**?
- **Phase I (catabolic)**: oxidation/reduction/hydrolysis reactions - **Phase II (anabolic)**: conjugation reactions - addition of substituent group
26
What are the **types of Phase I reactions** during **biotransformation**? Where and by what are they carried out?
1) **oxidation reactions** (most common) - carried out by liver cytochrome P450 system, e.g. benzodiazepines 2) **reduction reactions** - carried out by liver cytochrome P450 system, e.g. methadone 3) **hydrolysis reactions** - usually at sites other than liver, e.g. oxytocin
27
What **Cytochrome P450 monooxygenase** is responsible for metabolism of ~60% of all drugs? What kind of drugs?
It is **CYP3A4** - Cyclosporin (immunosuppressant) - Tamoxifen (chemotherapeutic) - Clotrimazole (antifungal) - Citalopram (SSRI antidepressant) - Haloperidol (antipsychotic) - Methadone (opiate) - Flunitrazepam (benzodiazepine)
28
What are the **dangers of CYP3A4** being responsible for metabolism of around 60% of the drugs?
**Competition for the enzyme**, problem if taking multiple drugs
29
What are the **inhibitors of CYP3A4**? What do they do?
e.g. cimetidine (**H2-receptor antagonist**) They **prolong the action of drugs** or **inhibit action of those biotransformed to active agents** (pro-drugs) by CYP3A4
30
What are the **inducers of CYP3A4**? What do they do?
e.g. **barbiturates, carbamazepine (anticonvulsant)** They s**horten the action of drugs** or **increase effects of those biotransformed to active agents** by CYP3A4
31
What are the **clinical implications of metabolism** of **imipramine**?
Imipramine is a typical tricyclic antidepressant. The hydroxylating enzyme, CYP2D6, is subject to **genetic polymorphism**, which may account for **individual variation** in response to tricyclic antidepressants. It naturally has different levels of activity.
32
How does **CYP1A1** cause health implications **during metabolism**?
**CYP1A1** is responsible for converting the **relatively innocuous** compound benzopyrene from cigarette smoke into a **carcinogen**.
33
What is **Phase II metabolism**?
These involve the **conjugation of a drug** with an endogenous chemical to form a **polar (ionised) drug** which can be **more easily excreted**. i.e. a molecule endogenous to the body donates a portion of itself to the foreign molecule (adding extra group to the drug)
34
What are the possible **Phase II reactions** during metabolism?
- glucuronide conjugation - acetylation - methylation
35
What is **glucuronide conjugation** during **Phase II metabolism**?
The microsomal enzyme **glucuronyl transferase** conducts the donation of glucuronic acid from endogenously synthesized UDPGA to various substrates (eg morphine) to form **glucuronide conjugates**.
36
What are the **limits of Phase II** metabolism? Example with Paracetamol
Following ingestion, >90% of acetaminophen (paracetamol) is metabolised by **glucuronidation** and **sulphation**. A fraction (<5-10%) is metabolized by predominately **CYP2E1** to *N-acetyl-p- benzoquinoneimine (NAPQI), a toxic metabolite*. Under normal conditions NAPQI is detoxified through conjugation with glutathione. Overdose (~70,000 in UK last year) treated with **N-acetyl-cysteine**.
37
What are the types of **Phase II metabolism**?
- Microsomal enzymes - Non-microsomal enzymes
38
Describe **microsomal enzymes** in **Phase II metabolism**
- *catalyse glucuronide conjugation and most oxidation reactions* - located in the *liver* - *lack specificity* - requiring only that the drug be *lipid soluble* - *inducible by drugs or other foreign substances*
39
Describe **non-microsomal enzymes** in Phase II metabolism
- catalyse the other types of conjugation reactions and most *hydrolysis reactions* - widely distributed in *plasma and other tissues* - *degrade polar substances* which do not penetrate the microsomes - *not inducible*
40
What is the principle organ of **excretion of drugs**? What does it excrete?
Kidney, via urine. Excretes all *water soluble drugs*; *lipid soluble* drugs are reabsorbed
41
How do changes in urinary pH a**ffect the excretion of drugs**?
- *acidic* drugs are excreted in *alkaline* urine - *basic* drugs are excreted in *acidic* urine
42
What are the applications of **changing urinary pH**?
- **poisoning where elimination** of the drug in the urine i desirable: adjust urine pH or dialyse blood against a solution with appropriate pH - **enhance access of a drug** e.g. UTI: if a sulphonamide is being used it helps the urine be made alkaline
43
What are other **routes of excretion** than urine?
- in *faeces*: purgatives, liquid paraffin - in *exhaled air*: volatile anaesthetics, alcohol - in *saliva and sweat*: rifampin (antibiotic), iodides - in *milk*: metronidazole (antibiotic), phenytoin
44
what are the **possible order of kinetics** of drug elimination?
zero or first order
45
When do **zero order kinetics** take place in elimination? What is the amount of the drug cleared?
When substrate concentration *exceeds the capacity of the enzyme system* the rate of the elimination of drug is constant irrespective of the plasma concentration. *Constant amount* of drug is eliminated in unit time, e.g. ethanol 80 mg -> 70 mg -> 60 mg -> 50 mg
46
When do **first order kinetics** take place in elimination? What is the amount of the drug cleared?
The rate of removal is **proportional to the concentration of substrate (drug)**. For most drugs, rate of elimination is proportional to the plasma concentration, *constant fraction* of the drug is eliminated in unit time 80 mg -> 40 mg -> 20 mg -> 10 mg
47
What is the **half-life of the drug**?
If drug has a half-life it must follow first order kinetics. It is related to the rate constant of elimination
48
What is the **plasma half-life**?
The time required for the drug to reduce to half its original plasma concentration.
49
What is the aim of **drug dosing**?
To reach a **steady state** that lies between the **therapeutic threshold** and the **threshold of toxicity**
50
What does the time to reach the **steady state** depend upon?
Depends upon on the **half-life** of the drug, but it is **independent of the dose rate**.
51
Why is the **loading dose** for a drug needed?
Long intervals may not be acceptable for drugs whose action is required promptly. Using a l**oading dose regime can shorten the time to reach steady state**. Of considerable use in clinical practice when speedy therapeutic intervention is required.

Pharmacology 3 (21 decks)

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