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pharmacology > Drug elimination I (distribution, metabolism, elimination) L5 > Flashcards

Drug elimination I (distribution, metabolism, elimination) L5 Flashcards

1
Q

What happens to drug once it has been absorbed into plasma

A

it gets distributed to other body compartments
this distribution is not equal

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2
Q

what factors affect distribution

A
  1. blood perfusion of the tissue or organ
  2. ability to cross the membrane
  3. plasma protein binding ability
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3
Q

give percentage of free drug in different compartments

A

intracellular water: 35%
fat: 20%
interstitial water: 16%
plasma water: 5%
transcellular water: 2%
-( CSF digestive secretions peritoneal fluid )

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4
Q

what are 3 different ways drug can cross membrane

A
  1. lipophilic, unionised: lipid bilayer
  2. small, water soluble: aqueous pores
  3. hydrophilic, ionised: carrier proteins
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5
Q

what are two important membranes

A
  1. GI tract
  2. blood brain barrier
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6
Q

what is the blood brain barrier

A

Continuous layer of epithelial cells around brain and spinal cord
means brain inaccessible to many drugs
Can become leaky with inflammation
Benefits of BBB preventing CNS effects of certain drugs e.g. antihistamines and sedation
Psychoactive drugs need to be able to penetrate BBB

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7
Q

what did the mice experiment show about blood brain barrier

A

mouse injected with histamine labelled with C13
- shows up black
parts of the mouse was black/grey
brain was completely white
- shows impermeable nature

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8
Q

what are the two main plasma proteins and what do they bind to

A
  1. albumin
    - Binds mostly acidic drugs (e.g. warfarin, NSAIDs) and a small number of basic drugs (e.g. TCA’s)
  2. α1 acid glycoprotein (AAG)
    - Binds mostly basic and neutral drugs
    ↑ inflammatory disease
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9
Q

what factors does the amount of drug bound to plasma proteins depend on

A
  1. Concentration of free drug in plasma
  2. Affinity for the binding site on proteins (2 sites per albumin molecule)
  3. Concentration of protein
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10
Q

what is the purpose of plasma proteins

A

bound drugs can not cross membranes
Small differences in binding e.g. 99.5 vs 99% can have large effects on free drug concentration and therefore drug effect

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11
Q

how do we quantify distribution

A

using Apparent volume of distribution (Vd)

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12
Q

what is volume of distribution (Vd)

A

volume of fluid that would be required to contain the total amount of drug in the body (Q) at the same concentration as that present in the plasma Cp

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13
Q

what is the equation for volume of distribution (Vd)

A

total amount of drug administered (Q)/ plasma concentration (Cp) at time 0
units of volume i.e. l or ml

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14
Q

what does volume distribution not tell us

A

what compartment the drug is in

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15
Q

if a drug has a high volume distribution, what does it mean interms of composition in plasma

A

higher the Vd, less bound to plasma proteins so leaves blood quicker into tissue

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16
Q

how are drugs eliminated from the body

A

via metabolism and excretion

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17
Q

what is the main route of excretion
and what are the two other routes

A

in urine via kidneys
intestine, skin, lungs

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18
Q

what happens to lipophilic drugs before they are excreted

A

need to be metabolised to more polar products making them water soluble
Polar = positive charge on one area of molecule and negative charge on other e.g. water

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19
Q

describe the two pahses of metabolsim

A

phase 1:
- catabolic mostly mediated by cytochrome P450
phase 2:
- Anabolic conjugation reactions

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20
Q

what is the aim of phase 1 reactions

A

Enzymatic reactions which often expose or introduce a hydroxyl (-OH), amino (-NH2), sulfhydryl (-SH), or carboxyl (-COOH) polar functional group to the lipophilic drug

21
Q

what is oxidation
where does it mainly take place

A

addition of oxygen and/or the removal of hydrogen (really loss of electrons)
in the liver

22
Q

what is hydroxylation

A

Conversion of a hydrogen to a hydroxyl group by adding oxygen
R-H ⇒ R-OH

23
Q

what is deamination

A

Conversion of an amino group to a carbonyl group via addition of oxygen and removal of hydrogen
R-C-NH2⇒R-C=O

24
Q

what is dehydrogenation

A

Conversion of a hydroxyl group to a carbonyl group via removal of hydrogen
R-C-OH ⇒ R-C=O

25
Q

what is Functionalisation

A

Introduction of a reactive group
Products more reactive, and sometimes more toxic.

26
Q

what are cytochrome P450

A

Large family of related but distinct enzymes
- may act on same substrate but at different rates
- Embedded in smooth endoplasmic reticulum
- Require oxygen, NAPDH (nicotinamide adenine dinucleotide phosphate) and NAPDH-P450 reductase
different types of P450 metabolise different drugs

27
Q

give variations in P450

A
  1. between species
  2. genetic polymorphisms
    - CYP2C9 genetic variants are common = Low metabolic activity
  3. environment factors
    - consume, things you are exposed to, other drugs- could induce or reduce metabolism of drug- affects plasma concentrations of drug it is metabolising
28
Q

give 3 examples of other phase 1 enzymes

A
  1. Butrylcholinesterase
    - structurally similar to acetylcholine – overactivates cholinergic receptors on muscles to cause paralysis = neuromuscular blocker
    - hydrolyses suxamethonium
  2. Aspirin esterase
    - In plasma
    - Hydrolyses aspirin to salicylate
  3. Alcohol dehydrogenase
    - In liver cell (hepatocyte) cytoplasm
    - Oxidises ethanol to acetaldehyde
    - Requires NAD+
29
Q

what is the aim of phase 1 and 2 reactions

A

decrease lipid solubility and thus increase renal excretion

30
Q

what do phase 2 reactions need to occur

A

donors
- compounds which donate their group

31
Q

what is conjugation
where does it occur

A

attachment of a substituent group
liver

32
Q

what happens during phase 2 reactions and what are their products normally like

A

Another chemical or group is added to exposed group making them more water souble so more likely to be excreted
If not enough donor, cause more reactive group= toxic
products are norammly inactive

33
Q

what are the chemicals that can be conjugated and what are their donors

A

Glucuronyl - UDP-α-glucuronide
Sulfate - Glutathione
Methyl - S-adenosyl methionine
Acetyl - acetyl CoA

34
Q

what enzyme is used in phase 2 reactions

A

UDP – glucuronyl transferase

35
Q

what are pro-drugs

A

a drug that is inactive and becomes active once it is metabolised

36
Q

how are drugs eliminated

A

Depends on physicochemical properties of drug & metabolites

37
Q

how can drugs be eliminated

A
  1. faeces
    - mass transport in gut
  2. urine
    - water soluble, filtered out by kidneys- penicillin
  3. exhaled
    - volatile gases
  4. breast milk
    - secreted into glands
  5. sweat
    - secreted into glands
38
Q

how do we quantify elimination

A

total clearance (ClTot)

39
Q

what is total clearance (ClTot)

A

Volume of plasma (or blood) cleared of the drug per unit of time (usually l/hr) to achieve overall elimination of drug from the body

40
Q

what is the equation of total clearance (CLTot)

A

Total body CL = sum of all organ CL processes
- CLTot = CLmet + CLren + Clall the other ones

41
Q

what equation is used to estimate clearance from graph

A

Divide the dose given (Q) by
the total systemic exposure to the drug (Area under curve)

42
Q

what is the equation for clearance (L) of a drug administered by IV or orally

A

IV dose (mg/L) / IV area under the curve (mg/L/hr)
oral dose X bioavailability (F) / oral area under the curve

43
Q

what is first order kinetics

A

rate of elimination directly proportional to drug concentration
= Exponential decay
- 25%↓ in concentration dependent of concentration

44
Q

what is zero order kinetics

A

25%↓ in concentration independent of concentration
= linear decay

45
Q

what is elimination rate constant (Kel)

A

fraction of drug eliminated per unit time at any time point

Expressed as (time)-1 so if 0.1 hr-1 = 10% of drug at that point is eliminated per hour

46
Q

what is the equation for elimination rate constant

A

total clearance/ volume of distribution

47
Q

what is the equation for elimination rate constant slope when using plasma concentration

A

Slope = a/b h-1
Example
Kel = ln (10/2)
5.8-3.4 hours

Kel = 1.61 = 0.67 hr-1
2.4 hrs

~ 67% of drug remaining eliminated / hr
at that time point
- use PP

48
Q

what is elimination half life (t ½)

A

Time taken for plasma drug concentration to reduce by 1/2

49
Q

what is the equation for half life

A

ln2/Kel
after about 6 halfs life, very little drug left in body

pharmacology (13 decks)

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