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Pharmacokinetics Flashcards

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0
Q

How would you work out Molarity?

A

Molarity = grams per litre/molecular weight

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1
Q

Give some possible targets of drugs

A 
Enzymes
GPCRs
Ion channels
Transporters
Nuclear hormone receptors
Other receptors
Integrins
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2
Q

What is affinity?

A

The likelyhood of a ligand binding to its target

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3
Q

What are Bmax and Kd?

A

Bmax= max binding capacity (gives info of number of receptors)

Kd= the dissociation constant, the concentration of drug needed for 50% receptor occupancy. The lower Kd the higher the affinity

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4
Q

What is efficacy?

A

The likelyhood of activation

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5
Q

What are Emax and EC50?

A 
Emax= the maximum response
EC50= the effective concentration, the concentration that gives 50% of the maximal response, a measure of potency
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6
Q

What type of ligands have affinity and efficacy?

A

Agonists

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7
Q

What type of ligands have affinity only? (No efficacy)

A

Antagonists

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8
Q

How would you obtain binding information for drug-receptor interaction?

A

Use radioligands

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9
Q

What’s the difference between concentration response curves and dose response curves?

A

Concentration response curves are used in measuring a response in cells/tissues.
Dose response curves are used in measuring a response in a whole animal.

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10
Q

What is the potency of a drug determined by?

A

Efficacy, affinity and number of receptors.

EC50 is a measure of potency, the lower EC50, the higher the potency.

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11
Q

How does salbutamol target B2-adrenoceptors to relax the airways in asthma, but avoid the other B-adrenoceptors (such as B1 in the heart that increase the rate and force of contraction)?

A

Salbutamol is a B2-adrenoagonist.
It has a slightly lower Kd for B2 receptors than B1, so has slightly higher affinity for B2.
A high B2 selective efficacy and route of administration (oral spray) limits B1 activation and side effects.

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12
Q

How does salmeterol target B2-adrenoceptors to relax the airways in asthma, but avoid the other B-adrenoceptors (such as B1 in the heart that increase the rate and force of contraction)?

A

Salmeterol is a longer activity B2-adrenoagonist.
It has no selective B2 efficacy but side effects are prevented through a large difference in affinity. Kd is much lower for B2 than B1 so affinity for B2 is much higher.

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13
Q

Why may less than 100% receptor occupancy give 100% response ie. EC50<Kd

A

Some tissues have spare receptors (receptor reserve)

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14
Q

Why do some tissues have spare receptors?

A

It increases sensitivity, which allow for bigger responses at smaller concentrations of agonists.

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15
Q

Explain what is meant by ‘partial agonist’

A

Agonists that cannot produce a maximal response, even with full receptor occupancy.
EC50 is equal to Kd, partial agonists can be more or less potent than full agonists (since potency depends on affinity and efficacy).

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16
Q

Is a particular agonist always a full/partial agonist? Explain

A

No, a partial agonist may not always be a partial agonist, depending on the tissue and the biological response.
Ie. In one tissue the activation of all receptors may not be enough to produce a full response, but another tissue may have more receptors so may produce sufficient signal for a full response.

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17
Q

Discuss the clinical use of partial agonists

A

Morphine is a full agonist of the u-opioid pain relief receptor but can cause respiratory depression.
Buprenorphine is a partial agonist with a higher affinity but lower efficacy than morphine. Can be advantageous as it may give adequate pain relief with less respiratory depression.

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18
Q

When can a partial agonist act as an antagonist of a full agonist?

A

If the partial agonist has higher affinity but lower efficacy than the full agonist it occupies receptors and limits the response.

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19
Q

What are the three different types of antagonist?

A
  1. Reversible competitive
  2. Irreversible competitive
  3. Non-competitive
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20
Q

Explain what IC50 is

A

The concentration of antagonist giving 50% inhibition

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21
Q

Describe the properties of Reversible Competitive antagonists

A

They are surmountable (can be overcome by increased agonist concentrations)
Cause a parallel shift to the right of an agonist concentration response curve.

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22
Q

Give an example of a reversible competitive antagonist

A

NALOXONE
Competitive antagonist at u-opioid receptors to reverse opioid mediated respiratory depression. High affinity means it competes effectively with other opioids eg heroin

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23
Q

Describe the properties of Irreversible Competitve antagonists

A

Occurs when the antagonist dissociates slowly/not at all.
Not surmountable (not overcome by increased agonist concentrations) so at higher concentrations the maximal response is suppressed.
Causes a parallel shift to the right of agonist concentration response curves.

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24
Give an example of a irreversible competitive antagonist
PHENOXYBENZAMINE | Non-selective irreversible competitive antagonist a1-adrenoceptor antagonist used in hypertension in pheochromocytoma.
25
Describe the properties of Non-Competitive antagonists
Bind to allosteric site, not the orthosteric site on the receptor and reduce effects of agonist binding. Has high receptor subtype selectivity. Causes parallel shift to the right and decreased maximum response of agonist in concentration response curves.
26
Define pharmacokinetics
What the body does to the drug
27
List local sites of administration for drugs
Eye Skin Inhalation
28
List the systemic sites of administration for drugs
Enteral: oral, rectal, sublingual Parental: subcutaneous, intramuscular, intravenous, inhalation, transdermal
29
Define oral bioavailability
The proportion of a dose given orally (or by any other route other than intravenous) that reaches the systemic circulation in an unchanged form.
30
How can bioavailability be expressed?
Bioavailability can be expressed as amount or rate. Amount: depends on GI absorption and first pass metabolism, measured by area under curve of a blood drug level against time plot. Rate: depends on pharmaceutical factors, measured by peak height and rate of rise of drug level in blood.
31
Explain the therapeutic ratio
The maximum tolerated dose/the minimum effective dose | = LD50/ED50
32
What is the relevance of the therapeutic window?
Drug levels must be kept within the therapeutic window. | Drugs with larger therapeutic windows (eg penicillin) are safer because they are less likely to reach toxic levels
33
How are drugs with smaller therapeutic windows kept within the window?
Use regular administration to keep drugs between ED50 and LD50, or use drug with slower release
34
Describe the first pass effect
Substances absorbed from the lumen of the ileum enter venous blood, drain into hepatic portal vein, transported directly to the liver which is the main site of drug metabolism. Any drug absorbed from the ileum may be extensively metabolised during the first pass through the liver.
35
How can the way the patient receives the drug differ?
Formulation of the drug: solid/liquid | Site of administration: local/systemic-enteral/parenteral
36
Which methods of drug administration avoid the first pass effect?
All parental routes Sublingual Rectal
37
Define drug distribution and state how it is calculated
The theoretical volume into which a drug has distributed assuming that this occurs instantaneously = amount given/plasma concentration at time 0
38
Do hydrophilic or hydrophobic drugs have smaller volume of distribution and why?
Hydrophilic drugs have a smaller volume of distribution because they remain in plasma and are not absorbed by fat.
39
Do hydrophilic or hydrophobic drugs have larger volume of distribution and why?
Hydrophobic drugs have a larger volume of distribution as they are continuously absorbed by fat, so are removed from the plasma.
40
Define an object (class 1) drug
The object drug is used at a dose much lower than the number of albumin binding sites, as an equilibrium is reached with some free drug
41
Define a precipitant (class 2) drug
The precipitant drug is used at a dose greater than the number of albumin binding sites as all binding sites must be filled before any free drug exists.
42
Explain protein binding interactions
Class 2 drugs (precipitant drug) can displace class 1 drugs (object drug), raising the free levels of the object levels which increases risk of toxicity.
43
When are protein binding interactions important?
When the object drug: Is highly bound to albumin (>90%) Has a low therapeutic index Has a small volume of distribution
44
Why are protein binding interactions transient?
Although free drug levels rise, elimination rates will also rise (in 1st order kinetics) so a steady state can be restored in a few days
45
What precipitant drugs can displace warfarin?
Aspirin Sulphonamides Phenytoin
46
What precipitant drugs can displace tolbutamide?
Sulphonamides | Aspirin
47
What precipitant drugs can displace phenytoin?
Valproate
48
How can you calculate the rate of metabolism of a drug metabolised by enzymes that obey michaelis-menten kinetics?
Vmax [C] / Km+[C]
49
When do first order kinetics occur?
When the drug is used at a lower concentration that Km
50
When do zero order kinetics occur?
When the drug is used at concentrations much larger than Km
51
Define first order kinetics
The rate of decline of plasma drug level is proportional to the drug concentration. Half life can be defined
52
Define zero order kinetics
The rate of decline of plasma drug level is constant regardless of concentration (as the enzyme is saturated)
53
What lines do first order and zero order kinetics give on a plasma concentration is plotted against time?
Zero order - straight line down | First order - decreases quickly then levels out
54
What lines do first order and zero order kinetics give when log plasma concentration is plotted against time?
Zero order - decreases slowly at start then more rapidly | First order - straight line down
55
During drug administration, how many half lives does it take to reach a steady state?
5
56
How can you produce an immediate effect when the drug has a long half life?
Use a loading dose
57
Do first or zero order kinetics give a predictable response? Explain
First order give a predictable therapeutic response as it is proportional to drug concentration. Zero order gives a response that can suddenly escalate as elimination methods saturate.
58
What reactions occur in the 2 phases of liver metabolism?
Phase 1- oxidation/reduction/hydrolysis | Phase 2- conjugation
59
Why is phase 1 drug metabolism necessary?
Most drugs are stable and unreactive so a reactive group must be exposed/added to generate a reactive intermediate that can be conjugated with a water soluble molecule in phase 2.
60
What is required for phase 1 drug metabolism to occur?
Cytochrome P450 enzyme system | NADPH
61
What can effect cytochrome oxidase?
Enzyme inducers and inhibitors
62
Give an example of cytochrome oxidase inhibitor and its effects
Cimetidine | Affects warfarin, can raise free levels above LD50
63
Give an example of cytochrome oxidase inducer and its effects
Rifampicin | Affects oral contraceptive, can lower levels below ED50
64
What is enzyme induction/inhibition of cytochrome P450 more likely to matter clinically?
When the drug: Has a small therapeutic window Is used at minimum ED Metabolism follows zero order kinetics
65
Why can some drugs bypass phase 1? Give an example of a drug that does this
They already have an exposed reactive group. | Morphine
66
What is drug conjugation?
The reactive intermediate from phase 1 is combined with a polar molecule (the conjugate) to form a water soluble complex
67
Give examples of conjugates
Glucoronic acid (most common) Sulphate ions Glutathione
68
What is required for phase 2 drug metabolism?
Specific enzymes | High-energy cofactor: uridine diphosphate Glucoronic acid (UDPGA)
69
For weak acidic drugs, how can you increase excretion? Explain
Make the urine alkaline. Ionises the drug so there will be less tubular absorption because the charged drug stays in the tubule lumen, hence more is excreted
70
For weak basic drugs, how can you increase excretion? Explain
Make the urine acidic. Ionises the drug so there will be less tubular absorption because the charged drug stays in the tubule lumen, hence more is excreted
71
In renal disease what happens to the loading dose and maintenance doses?
Loading dose remains the same as it still requires 5 half lives to reach a steady state. Lower maintenance dose required as the half life of the drug is prolonged.

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