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Introduction to Metabolism and Pharmacology > Basic Principles 2 > Flashcards

Basic Principles 2 Flashcards

1
Q

Define Apparent volume of distribution (Vd) ?

A

This is the apparent volume into which the drug is distributed, usually expressed in litres (L)

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2
Q

Drugs administered orally may undergo ?

A

Extensive first-pass metabolism

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3
Q

Metabolism by enzymes in gut wall and in the liver, before systemic circulation results in ?

A

Low bioavailability

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4
Q

Such drugs therefore require ?

A

Higher oral dose (e.g. propranolol), or administered via routes that can avoid first pass metabolism: IV, IM, sublingual, nasal, rectal, transdermal, etc

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5
Q

Drugs are only effective if ?

A

They reach the target cells, at an appropriate concentration

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6
Q

Distribution of drugs depends on ?

A
  • Permeability across membranes
  • Binding within compartments
  • pH partitioning
  • Fat:water partitioning coefficient
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7
Q

Total body water is about ?

A

60-80% of total body weight, and this is contained in different compartments:

  • Blood plasma
  • Interstitial fluid (between cells)
  • Intracellular fluid (inside cells)
  • Transcellular fluid (e.g. cerebrospinal, intraocular, peritoneal fluid)
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8
Q

Name two beta blockers ?

A

Propranolol and Atenolol

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9
Q

Explain Propranolol ?

A

It can cause sleep disturbances (vivid dreams); atenolol less so

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10
Q

Propranolol vs Atenolol

A

Propranolol is more lipid soluble and can cross BBB. Whereas Atenolol is more water soluble and does not cross BBB

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11
Q

How about Psychoactive drugs ?

A

This is are things such as nicotine, caffeine, LSD and MDMA. They are highly lipid soluble and
therefore able to pass through the blood brain barrier

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12
Q

Drugs are often ?

A

Bound to proteins, but only free, unbound drugs are biologically active and can move between compartments

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13
Q

In some cases, up to ?

A

99% of total drug can be bound to proteins (e.g. warfarin)

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14
Q

What is Albumin and explain the binding ?

A

is the main drug-binding protein. Others include α1-acid glycoprotein and β-globulin. Binding is rapidly reversible and non-specific.

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15
Q

Plasma proteins do not reflect ?

A

The target tissue, binding produces no physiological effect.

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16
Q

What does binding form ? and which drugs exerts its therapeutic effect ?

A

Forms a reservoir of drugs. Only the free, unbound drug is available to the tissue to exert its therapeutic effect.

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17
Q

What is the Apparent volume of distribution ?

A

This is the hypothetical volume into which the drug (Q) would be distributed in order to obtain the measured plasma concentration (Cp) and account for the total amount of drug administered

Q = dose in mg 
Cp = plasma concentration in mg/L
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18
Q

What does Vd tell us about distribution of a drug in humans ?

A
  • Large molecules that are retained in plasma
    e. g. heparin, an anticoagulant - too large to cross capillary wall
  • Small polar molecules that cannot enter the cells
    e. g. antibiotics such as gentamicin
  • Small drugs that easily cross membranes
    e. g. Ethanol, phenytoin
  • Very hydrophobic, lipid-soluble drugs
    e. g. thiopental
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19
Q

Plasma concentration decreases ?

A

Over time as drug is excreted and/or metabolised

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20
Q

How is drug eliminated ?

A

Metabolism and Excretion

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21
Q

Explain how Metabolism does this ?

A
  • Two phases of drug metabolism
  • Cytochrome P450 (CYP) enzymes
  • Enzyme induction and inhibition
  • First-pass metabolism
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22
Q

Explain how Excretion does this ?

A
  • Excretion via the kidney: glomerular filtration, tubular secretion and tubular reabsorption
  • Excretion via the biliary system
  • Enterohepatic circulation
  • Drug elimination and renal clearance
  • Glomerular filtration rate and kidney function
23
Q

Define Metabolism ?

A

Describes the process by which a drug is altered chemically in the body into its ‘metabolite’, which may be more or less active

24
Q

Where does metabolism occur ?

A

It occurs primarily in the liver, but can take place in the plasma, lungs, stomach, small intestines , kidney, skin and other tissues

25
What are the two phases of drug metabolism ?
- Phase 1 (catabolic) | - Phase 2 (anabolic)
26
Explain Phase 1 reaction ?
1. Oxidation, reduction, hydrolysis 2. Products are generally more polar 3. Addition of groups such as 4. OH often makes products more reactive (functionalisation) - Allow Phase 2 reactions to occur - May make the metabolite more toxic/carcinogenic or more pharmacologically active 5. Mediated by cytochrome P450 enzymes
27
Explain Phase 2 reaction ?
1. Add a group on to molecule: conjugation 2. Chemical groups added included glucuronyl, sulfate, methyl, acetyl or glutathione 3. Often added at the site of functionalisation from Phase 1, e.g. -OH group 4. Usually products become pharmacologically inactive and more water soluble than the original drug and easier for excretion
28
Example: metabolism of aspirin
1. Phase 1 - Aspirin (Drug) - Oxidation, Hydroxylation, Dealkylation, Deamination and Hydrolysis 2. Salicylic acid (Derivative) - due to the OH 3. Phase 2 - Glucuronide (Conjugate) - Conjugation
29
Not all metabolites of drugs are ?
Inactive
30
In some cases, both the drugs and the metabolites are ? give example and explain
Active - E.g. Aspirin (acetyl salicylic acid) is hydrolysed to salicylic acid - Both aspirin and salicylic acid have anti-inflammatory activity - Only aspirin has antiplatelet activity
31
In other cases, the drug is more active after ?
Metabolism
32
What are Prodrugs ? give example and explain
These are drugs which are only active after being metabolised in the body - e.g. Heroin (diamorphine or diacteylmorphine) is a prodrug of morphine but crosses the BBB more easily and therefore much more potent - It is then metabolised to morphine
33
In some drugs, the metabolite is ? give examples and explain
Toxic - Paracetamol is metabolised to N-acetyl-p-benzoquinone imine (NAPBQI). NABQI causes liver damage in paracetamol overdose - Alcohol is oxidised to acetaldehyde by alcohol dehydrogenase. Acetaldehyde causes the 'hangover' symptoms
34
What chemicals are poorly excreted by the kidneys into urine ?
Hydrophobic (lipid soluble). The process of drug metabolism simply converts lipid soluble drugs to water soluble metabolites
35
Most of the Phase I reactions are caused by ?
By the cytochrome P450 microsomal oxidase system
36
There are 18 families of cytochrome P450 genes with?
43 subfamilies
37
CYP 1, 2, 3 families are known to ?
Metabolize lipophilic | drugs
38
Often have what kind of activity ?
Monooxygenase activity: oxidise C-H bond into C-OH bond
39
Give examples of cytochrome P450 (CYP) enzymes inducers
``` Carbamazepine Rifampicin Alcohol (chronic) Phenytoin Griseofulvin Phenobarbitone Sulphonylureas ``` CRAPGPS
40
Give examples of cytochrome P450 (CYP) enzymes inhibitor ?
``` Sodium Valproate Isoniazid Cimetidine Ketoconazole Fluconazole Alcohol (acute use) Chloramphenicol Erythromycin Sulfonamides Ciprofloxacin Omeprazole Metronidazole ```
41
When does enzyme induction occur ?
When a drug administered over a period time increases the activity of microsomal enzymes
42
How is Enzyme induction caused ?
It's caused by increased synthesis and/or reduced breakdown of the enzymes
43
What will happen to drugs metabolised by the same enzymes ?
They will be broken down more quickly and circulate in a lower concentration than anticipated
44
When can effects typically be seen ?
After the first 2 days, but max. Effects may take 2-3 weeks - the length of time taken to synthesise the enzymes
45
What happens due to enzyme inhibition ?
Results in reduced drug metabolism and an increase in concentration
46
Unlike enzyme induction, inhibition usually begins ?
With the first dose of the inhibitor, maximal when inhibitor reaches steady state
47
Give an example of a drug that carries out enzyme inhibition ?
Many drug (e.g. erythromycin) can have an inhibitory effect on the enzymes that metabolise warfarin
48
When does drug interactions occur ?
When 2 or more drugs interact in such a way that the effectiveness or toxicity of one or more of the drugs is altered
49
What can the effect either be ?
Harmful or beneficial
50
Enzyme induction or inhibition by one drug can alter?
The concentration of another drug
51
Give an example of drug interaction ?
E.g. Induction of CYP enzymes by alcohol increases metabolism of paracetamol to its toxic metabolite NABQI. Hence, paracetamol overdose is more serious after drinking alcohol
52
Give example of drug interaction with enzyme inhibitor
- Antibiotics such as clarithromycin and erythomycin inhibit the CYP enzymes that metabolise warfarin (anticoagulant) - This can lead to enhanced anticoagulant effect (increased risk of bleeding) - which can be dangerous
53
Give example of drug interaction with enzyme inducer
- St John's wort is a herbal medicine available to treat mild depressant - Induce CYP3A4 - Increases metabolism of many drugs (e.g. warfarin, digoxin) - Should not be taken with oral contraceptive pill as it metabolises and inactivates the drug - Can also affect the metabolism of other antidepressants

Introduction to Metabolism and Pharmacology (16 decks)

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