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Medicinal Chemistry > Lecture 2 - Pharmacokinetics > Flashcards

Lecture 2 - Pharmacokinetics Flashcards

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1
Q

How might the pharmacokinetics of a drug prevent it from being effective?

A

Poor absorption/distribution = not reach site of action
Rapid metabolism
Not metabolised enough (pro drugs)

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2
Q

What are the essential pharmacokinetic features of an orally administered drug?

A

Hydrophilicity - to dissolve and be transported in blood
Lipophilicity - to cross lipid membranes, be absorbed in the GI tract, enter cells and pass BBB
Must be able to survive stomach acidity and enzyme activity

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3
Q

What are some potential problems with an orally administered drug?

A

Too hydrophilic = too easily excreted by kidneys
Too lipophilic = accumulates in fat tissue
Not lipophilic enough = cannot pass BBB
Too anionic = binds albumin and globulins in plasma
Too cationic = binds nucleic acids

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4
Q

Why are fungal infections so dangerous if they get inside the body?

A

Most antifungal medications are very lipophilic - they are not hydrophilic enough to be transported in the bloodstream

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5
Q

What are the 3 measurable pharmacokinetic parameters?

A

Plasma concentration
Biological half life
Rate constants e.g. elimination rate constant

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6
Q

What occurs during the ‘pharmacokinetics’ phase of drug development?

A

Test the measurable pharmacokinetic parameters
If not optimal, determine the structural cause
Create analogues with slight variation in structure
Test again until it is improved

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7
Q

What is the overall aim of drug metabolism?

A

To make a drug more hydrophilic so it can be more easily filtered and excreted by the kidneys
And to pharmacologically inactivate the drug

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8
Q

What occurs during Phase I metabolism?

A

Unmasking or addition of a polar group

Small increase in hydrophilicity

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9
Q

What occurs during Phase II metabolism?

A

Conjugation of a group onto the exposed polar group
Takes place in the liver and gut wall
Large increase in hydrophilicity
Products are usually pharmacologically inactive

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10
Q

Name 6 methods by which metabolism can be studied

A

Radiolabelled drugs e.g. 3H (measure conc in plasma/urine)
Chromatography e.g. HPLC or MS (Mass Spectrometry) to analyse blood/urine samples
NMR
In vitro liver preparations
Transgenic mice (e.g. that lack certain enzymes)

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11
Q

Name 8 biological factors that can affect drug metabolism and explain how

A 
Dose (enzyme saturation)
Route of administration (first pass effect)
Species differences
Sex (body mass)
Age (liver function, immune system)
Presence of disease (e.g. liver disease)
Interactions with other drugs (synergism, grapefruit)
Genetics (enzyme activity)
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12
Q

Which enzymes carry out oxidation of hydrocarbons to alcohols?

A

Carried out by monooxygenases, such as cytochrome p450 enzymes, or the flavin monooxygenase system

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13
Q

Which functional groups are readily hydrolysed?

A

Ester > Carboxylic Acid + Alcohol (rapid hydrolysis by acetylcholinesterases)
Amide > Carboxylic Acid + Amine (slow hydrolysis by non specific amidases)

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14
Q

What are the most common phase II reactions?

A 
Glucuronide formation 
Sulphate formation
Glutathione conjugation
Acetylation
Methylation
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15
Q

Name 7 functional groups that can be easily metabolised, and therefore should be avoided in drug structures. Say what the reaction is and name the products

A

Ester hydrolysed to carboxylic acid + alcohol
Amide hydrolysed to carboxylic acid + amine
Methyl oxidised to alcohol, aldehyde, carboxylic acid
Sulfide oxidised to sulfoxide or sulfone
Thiol oxidised to disulfide
Benzene hydroxylated to phenol
Nitro reduced to amine

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16
Q

Name 4 ways by which resistance to metabolism can be increased

A

Steric shields
Bioisosteres (electronic effects)
Combined steric/electronic effects
Metabolic blockers

17
Q

Describe how a steric shield can increases resistance to metabolism

A

Tertiary butyl groups/methyl groups/aromatic rings can block access to a readily hydrolysed group e.g. an amide

18
Q

What is a bioisostere?

A

A different chemical substituent with similar biological properties

19
Q

Give 2 examples of how a bioisostere can increase resistance to metabolism

A

Replacing the group attached to an ester or amide to form carbamate, which is much more resistant to hydrolysis
Converting part of the structure into an aromatic ring - very difficult to hydrolyse

20
Q

Give 2 examples of how metabolic blockers can increase resistance to metabolism

A

Addition of a methyl group at a commonly oxidised site prevents oxidation
Replace a methyl group with a chlorine (much less susceptible to oxidation)

21
Q

How can resistance to metabolism be decreased?

A

Addition of metabolically labile groups that enhance metabolism, such as a methyl group

22
Q

Give 5 uses of prodrugs

A 
Improve absorption
Protect from stomach acid
Prolong drug activity
Mask toxicity
Improve taste (for oral drugs)
Improve hydrophilicty
Target tumours
23
Q

Describe how a prodrug can be used to improve membrane permeability

A

Drugs containing a carboxylic acid or alcohol group may be too polar to be absorbed in the gut. Instead they are administered as esters which is then hydrolysed in the blood to release the free acid or alcohol. For example the ACE inhibitor Enalapril contains a carboxylic acid group

24
Q

Describe how a prodrug can be used to prolong drug activity

A

Azathioprine (immunosuppressant) contains an aromatic ring, which has to be removed via a non-enzymatic reaction which takes a very long time
Or addition of a fatty side chain ensures absorption into fat and slow release into the bloodstream

25
Q

Describe how a prodrug can be used to mask toxicity

A

LDZ is a prodrug for diazepam
Insertion of an extra lysine residue, which has to be hydrolysed, prevents very high initial plasma concentrations which can cause drowsiness
Administering an acid as an ester (salicylic acid) also protects the stomach

26
Q

Describe how a prodrug can be used to increase hydrophilicity

A

The antibiotic Chloramphenicol is administered as chloramphenicol succinate when administered by injection, as it has much better hydrophilicity

27
Q

Describe how a prodrug can be used to target tumours

A

Cyclophosphamide is an anti-cancer drug/DNA alkylating agent. Metabolised into active form by phosphoamidase, which is found in high levels in tumours

28
Q

Where does drug metabolism take place?

A

In all tissues, although mostly the liver, kidneys, lungs, brain and placenta

29
Q

What are the most common reactions that may occur during phase I metabolism?

A

Can be done by oxidation (most common), hydrolysis, reduction, hydroxylation, deacetylation/demethylation, isomerisation

30
Q

Which functional groups are readily oxidised? Draw these out

A 
Methyl group > Alcohol
Primary alcohol > Aldehyde > Carboxylic Acid
Secondary alcohol > Ketone
Amine > Nitro
Sulfide > Sulfoxide > Sulfone
Thiol > Disulfide
31
Q

Which functional groups are readily hydrated?

A

Benzene > Phenol

Epoxide > Diol

32
Q

What are the structures of

  • an acetyl group
  • a carbamate group
  • a sulphate group
A

Draw these out

33
Q

Which enzyme carries out oxidation of alcohols to aldehydes and carboxylic acids?

A

Dehydrogenase

34
Q

Which enzyme carries out hydroxylation reactions?

A

Cytochrome p450

35
Q

Which enzymes carry out phase II reactions?

A

Transferase enzymes

36
Q

Which substrates are needed for

  • methylation
  • acetylation
A

S-adenosyl methionine

Acetyl CoA

37
Q

Describe how a prodrug can be used to protect the drug from stomach acid

A

Also addition of a long molecule onto the antibiotic Piyamampicillin gives something for the stomach enzymes to attack, protecting the rest of the molecule

Medicinal Chemistry (12 decks)

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