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Year 1 Pharmacology > Lecture 6: Pharmacokinetics 2 > Flashcards

Lecture 6: Pharmacokinetics 2 Flashcards

1
Q

ADME

What is absorption?

A

The movement of a drug from outside the body into the blood (systemic circulation)

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2
Q

ADME

What is distribution?

A

The movement of drug out of the blood (systemic circulation) into extravascular fluids and tissues

Normally occurs by diffusion across capillary walls

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3
Q

What is drug distribution?

A

The post-absorbative reversible transfer of a drug from the systemic circulation to other compartments of the body e.g. fat, muscle, brain

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4
Q

How much blood does the heart pump every minute and what is the total blood volume of the body?

A

5L per minute
Typical blood volume is 5L

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5
Q
  1. What is the bulk flow of drugs in the bloodstream?
  2. What does it depend on?
A
  • Bulk flow directs drugs passively within blood vessels passing through major organs
  • Bulk flow depends initially on the blood flow to each organ (perfusion)

*but the drug is still in circulation until it distributes into extravascular fluids and tissues by diffusion *

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6
Q

What does bulk flow between compartments determine?

A

How long a drug will be present in the body after administration

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7
Q

Define:
1. Plasma water
2. Interstitial water
3. Intracellular water
AND
* Are they extracellular or extravascular?

A
  1. Blood volume (extracellular fluid volume)
  2. Fluid between tissue cells (extracellular+extravascular)
  3. Fluid inside tissue cells (extravascular)
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8
Q

What are 5 of the highly perfused organs?

A
  • Lungs
  • Kidneys
  • Liver
  • Brain
  • Heart
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9
Q

What decreases total drug levels in plasma?

A

Excretion/elimination

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10
Q

What does IV drug administration distribution depend on?

A
  • Tissue perfusion
  • Plasma protein binding
  • Drug permeability
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11
Q

Describe how drugs bind reversibly to plasma proteins

A
  • The drug/plasma protein complex is a temporary storage compartment
  • The drug bound to plasma protein is pharmacologically inactive
  • As the free plasma levels of drug falls (due to distribution or elimination) more of the bound drug is released from the complex to become free drug

Drugs may displace eachother from plasma proteins if they bind to the same plasma protein

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12
Q

How is the extent of drug distribution defined?

A

By its apparent volume of distribution estimated by the dilution principle

small volume + drug = more conc
large volume + drug = less conc

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13
Q

What do volume of distribution (Vd) values mean?

A
  • Vd is the volume of body fluids in which a drug appears to have been distributed
  • It can tell us which compartment it has been distributed in
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14
Q

What does it mean if the volume of distribution is equivalent to or more than bodyweight?

A

This means it must be congregating somewhere in the body, giving a false reading.

e.g. thiopentone sequesters into the fat

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15
Q

What is the volume of distribution?

A
  • Vd is a fixed characteristic of each drug and is independent of drug dose
  • Units of Vd are L but is often expressed per body weight to compare individuals (L/Kg)
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16
Q

What can effect the volume of distribution to make it deceptive?

A
  • If the drug is not evenly distributed in the body compartments it can access
  • If the drug is strongly absorbed or congregated in any compartment (bone, adipose) it may dilute plasma levels so much that it gives appearance of large Vd
17
Q

What does the blood brain barrier (BBB) allow/exclude?

A

Excludes
* Large drug molecules
* Water soluble drugs
Allows
* small lipid-soluble drugs e.g. ethanol, morphine

18
Q

When is the blood brain barrier deficient?

A
  • In fetus/newborn as its not fully developed yet
  • In infections e.g. meningitis, makes the BBB weaker which can have a positive impact of allowing antibiotics through to target infection
19
Q

What drug and physiological factors can effect the distribution of an oral drug?

A

Drug factors
* Lipid solubility
* Molecular weight
* Ionisation
* Tissue/cellular binding
* Duration of action
* Therapeutic effects
* Toxic effects

Physiological factors
* Vascularity (e.g. tumours nonvascular)
* BBB
* Plasma protein binding
* Drug interactions
* Therapeutic index
* Disease
* Genetics
* Age

20
Q
  1. Why did metabolism evolve?
  2. What is the main organ of metabolism and how does it work?
A
  1. To detoxify foreign chemicals (carcinogens, toxins in plants and environment)
  2. Liver: catabolises lipophilic drugs to inactive and water-soluble metabolites which are:
    - returned to circulation for kidney excretion (renal excretion)
    - excreted to bile and gut (faecal excretion)
21
Q

Why are environmental substances potentially harmful?

A
  • They are lipophilic
  • Can enter cells and cross the BBB
  • Aren’t efficiently excreted by the kindeys
22
Q

What % of drugs are hydrophilic enough to bypass metabolism (directly by renal excretion)

A

20-25%

23
Q

What is the overall rate of elimination important for?

A

Determining the rate of drug administration needed to maintain adequate concentrations in the body

24
Q

What is first pass metabolism?

A

Where the drug is

25
Q

What are the basics of phase 1 and phase 2 of metabolism?

A

Phase 1:
* Inactivation of drug
* Involves cytochrome P450 enzymes
* Addition of hydroxyl, suphydryl or amine groups

Phase 2:
* Conjugation of drugs
* Involves transferase enzymes
* Makes dugs more hydrophilic (polar) and water soluble for excretion

26
Q

What are cytochrome P450 enzymes?

A
  • Family of isoenzymes found in hepatocyte smooth endoplasmic reticulum (SER)
  • Membrane-bound haemoproteins (containing Fe), bind a substance and directly catalyse inactivation reactions (phase 1 metabolism)
  • Co-operate with other enzymes for conjugation that water-solubilise the initial metabolite (phase 2)
27
Q

What cytochrome P450 enzymes mediate phase 1 metabolism?

A

CYP1-3 mediate 70-80% phase 1 metabolism

28
Q

What are:
1. Good metabolisers
2. Poor metabolisers

A
  1. Good metabolisers:
    * mutations making drug more active
    * metabolising drug quickly
    * plasma drug conc goes down quickly
    * requires more drug to maintain expected drug conc
  2. Poor metabolisers:
    * mutations which mean the enzyme doesnt work well
    * drugs arent metabolised quickly
    * drug cant get broken down
    * plasma conc remains high
    * less drug given to give expected plasma concentration
29
Q

What are the 6 members of phase 2 enzymes? what do they do?

A
  1. GST: glutathione congugation
  2. AAT: amino acid conjugation
  3. UGT: glucuronidation
  4. NAT: acetylation
  5. SULT: sulphation
  6. MT: methylation
29
Q

What are the sites of phase 1 and 2 metabolism?

A

Phase 1: smooth ER of hepatocytes
Phase 2: secondary enzymes in the cytoplasm

30
Q

What are the consequences of factors affecting metabolism?

A
  • Can generate active or longer-lived metabolites from some drugs
  • May convert inactive drug to active
  • May generate toxic metabolites
31
Q

What 5 factors affect metabolism?

A
  1. CYP450 induction
  2. CYP450 inhibition
  3. Genetic polymorphisms
  4. Age
  5. Disease

Year 1 Pharmacology (6 decks)

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