Case 1 Pharmacology Flashcards by Joe Edwards

What does “volume of distribution” mean (in words)?

The volume of fluid a drug would need to be dissolved in to account for the mass of drug administered, and the plasma concentration after the drug is administered.

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What does Vd stand for?

Volume of distribution

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How is volume of distribution calculated?

Volume of distribution = known mass of drug given (D) / plasma concentration of drug given (C0)

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Complete the sentence. A high volume of distribution indicates that a X proportion of the drug moves out of the plasma.

X = high

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What does “clearance” mean (in words)?

The rate at which blood plasma is cleared of a drug.

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Complete the sentence. Clearance is the volume of X cleared of a drug per unit Y.

X = plasma
Y = time

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What does t1/2 stand for, and what does this mean?

Half-life, the length of time is takes for the plasma concentration of a drug to halve.

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How can C0 (initial concentration) be calculated from a plasma concentration-time graph?

Extrapolating the graph back to t=0, and reading the expected plasma concentration at this time.

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What does the 0 mean in C0?

Time = 0 seconds (immediately at time of drug administration)

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How can half-life be calculated from a plasma concentration-time graph?

The difference in time between a plasma concentration “C”, and C/2, can be found from a plasma concentration-time graph (to determine the time it takes for the concentration to halve)

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How can the reliability of the half-life value calculated from a plasma concentration-time graph be improved? (2 steps)

Read off the concentration at more than one pair of concentration (e.g. c=6M and 3M, then c=8M and 4M)
Calculate a mean.

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How can half-life be calculated using the elimination rate constant?

t1/2 = ln(2) / Kel

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What does Kel describe?

The elimination rate constant (the fraction of a substance that is removed per unit time).

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Complete the sentence. Kel is a constant for X order kinetics.

X = first

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How is clearance calculated?

Cl = Kel x VD

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Drugs with longer half-lives have to be administered more frequently. True or false? Explain why.

False. These drugs persist in the body for longer as they are eliminated less rapidly, so often have to be administered less frequently.

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Drugs with shorter half-lives have shorter-lasting effects. True or false? Explain why.

True. These drugs persist in the body for a shorter time as they are eliminated more rapidly.

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What does a plasma concentration-time graph look like for a drug with first order kinetics?

Smooth decreasing curve - gradient decreases over time

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What does a plasma concentration-time graph look like for a drug with zero order kinetics?

Straight, decreasing line

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Complete the sentence. The plasma levels of drugs with first order kinetics decrease proportional to X.

X = = the plasma concentration of that drug (at any particular moment)

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There is a relationship between the decrease in plasma concentration of a drug with zero-order kinetics and its plasma concentration at any particular moment. True or false? Explain why.

False. The rate of elimination of these drugs is independent of their plasma levels.

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Why might a particular drug have zero order kinetics?

All of the metabolising enzymes are saturated due to a large excess of the drug, so the rate of elimination remains constant.

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Why are drugs with zero order kinetics more likely to produce toxic plasma concentrations in some individuals? (2 points)

Their concentration stays higher for longer

* Plasma concentration is variable between individuals (e.g. depending on the availability of elimination enzymes)

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What is an example of a drug with zero-order kinetics?

Ethanol (+ many others)

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What does ‘steady-state’ mean in terms of the balance between drug administration and excretion?

The amount of drug administered exactly replaces the amount of drug excreted in each administration cycle.

What types of drug administration timing favour reaching steady-state? (2 types)

* Continuous (e.g. intravenous infusion) | * “Little and often” (e.g. a drug taken multiple times a day).

What negative outcomes can happen if the desired steady state is not reached for a drug? (2 outcomes)

* Toxic dosing (overshooting desired plasma concentration) | * Subtherapeutic dosing (undershooting desired plasma concentration)

After how many half-lives is steady state achieved?

5 half-lives (for 97% desired plasma concentration)

How is steady state concentration calculated?

Steady state concentration (CSS) = (Bioavailability x Dose) / (Dosing interval x Clearance)

What is a loading dose?

A larger initial dose of a drug given to obtain desired steady state more quickly

What is a maintenance dose?

The dose given in each administration following the loading dose to maintain the desired steady state

How is maintenance dose calculated?

Maintenance dose = Clearance × Desired Steady State concentration

Why is the maintenance dose lower than the loading dose?

The maintenance dose only needs to replace the drug lost (through metabolism/elimination) since the last administration, whereas the loading dose is starting from a plasma concentration of 0.

If no loading dose is given, it will take longer for steady state to be reached. True or false? Explain your answer.

True. If no loading dose is given, then the first few maintenance doses will fail to reach the desired steady state, and will be partially eliminated by the time the next dose is given, leading to a much longer time for steady state to be achieved.

What does ‘steady-state’ mean in terms of plasma drug concentration?

Plasma drug concentration is in a constant range.

How can genetic variation influence how drugs are eliminated by enzymes by the body?

Some people have defective elimination enzymes (e.g. CYP450) that have reduced function than the normal “wild-type” enzymes, hence some drugs are excreted more slowly and remain in the plasma for longer.

How could the prescribing of a drug differ for those with defective CYP450 enzymes? (2 ways)

* Lower dose | * Longer time between doses

How could the prescribing of an orally administered drug differ for those that have reduced GI absorption?

Different route of administration, e.g. IV.

What type of variation can lead to two or more different phenotypes for a particular characteristic, e.g. the way a CYP450 enzyme works in drug elimination?

Polymorphic variation

``` How might disease of the: a) Gut b) Kidney c) Liver affect the pharmacokinetics of drugs? ```

a) Gut: may affect absorption if enterally adminstered b) Kidney: may affect elimination (excretion) c) Liver: may affect elimination (excretion) and metabolism (e.g. activating drugs)

What affect might liver cirrhosis have on drug elimination and drug half life?

* Elimination might be slower for some drugs as the liver is damaged. * Drugs may therefore persist in the body for longer, increasing their half-life

What are the important factors affecting pharmacokinetics of drugs in neonates? (2 factors)

* Higher total % body water (for distribution) | * Underactive conjugation enzyme systems (for phase 2 drug metabolism)

What are the important factors affecting pharmacokinetics of drugs in the elderly? (2 factors)

* Lower % total body water (for distribution) | * Higher % total body fat (for distribution)

What are the major pharmacodynamic factors that affect drug response? (3 factors)

* Receptor sensitivity * Tolerance * Organ disease

By what mechanisms does receptor sensitivity affect an individual’s sensitivity to different drugs? (3 factors)

* Number of receptors expressed on the cell surface of the target cells may affect drug sensitivity. * Variation in shape of the target receptors (due to genetic variation) may affect drug sensitivity. * Variation in the concentration of completing substrates (competitive and non-competitive inhibitors) may affect drug sensitivity.

How does organ disease affect an individual’s sensitivity to different drugs?

Abnormalities in a particular diseased organ may change how the drug affects that organ, reducing a drug’s efficacy.

What is the first-line treatment for uncomplicated Stage 1 hypertension?

Lifestyle advice (e.g. stopping smoking, reducing salt intake, increasing exercise, reducing stress)

When is antihypertensive drug treatment considered in management of hypertension? (3 scenarios)

* Persistent stage 3 hypertension * Persistent stage 2 hypertension * Persistent stage 1 hypertension with an additional indication (e.g. QRISK3 >10%, renal disease, diabetes)

What is meant by the ‘step-wise’ approach to pharmacologically managing hypertension?

One drug (e.g. an ACEI, then CCB) is introduced at a time and the effects observed before additional drugs are added.

Which first-line antihypertensive drug class might be first prescribed to a 49-year old patient with Indian family origin and no other health conditions?

ACE inhibitor

A patient was prescribed an enalapril for hypertension but has stopped taking it due to adverse side-effects. They are prescribed an alternative drug. What is the most likely side effect they experienced, and which alternative drug class is most likely to have been prescribed?

Dry cough | Angiotensin II receptor blocker (ARB)

A 54-year old white male diagnosed with hypertension has shown insufficient improvement after taking valsartan and amlodipine. Which class of drug may be prescribed next?

Thiazide-like diuretic

Which first-line antihypertensive drug might be first prescribed to a 64-year old patient with African family origin and no other health conditions?

Calcium channel blocker

A 56-year old white female diagnosed with hypertension has shown insufficient improvement after taking indapamide and lisinopril. Which class of drug may be prescribed next?

Calcium channel blocker

A 50-year old female with African family origin takes trandolapril, lacidipine and indapamide for hypertension but at a recent check-up she was told her hypertension was not sufficiently managed. Which class of drug might be prescribed next? (3 suggestions)

* Alpha blockers * Beta blockers * Potassium-sparing diuretics / aldosterone antagonists

Which first-line antihypertensive drug class might be first prescribed to a 48-year old diabetic patient with African family origin and no other health conditions?

ACE inhibitor

What is a contraindication/caution for ACE inhibitors?

First dose hypotension/some diuretics/renal failure

What is a contraindication/caution for ARBs?

Left ventricular hypertrophy/Afro-Caribbean family origin/older age

What is a contraindication/caution for calcium channel blockers?

Cardiogenic shock/aortic valve stenosis/unstable angina/hepatic impairment

What is a contraindication/caution for thiazide-like diuretics?

Addison’s disease/electrolyte imbalance/diabetes/severe liver disease

What is one similarity and one difference between the mechanism of action of ACEIs and ARBs?

* Similarity: both inhibit RAAS pathway * Difference: ACEIs blocks formation of Angiotensin II in the first place, whereas ARBs stop it from binding to its receptors

How do calcium channel blockers improve hypertension? (2 mechanisms)

* Inhibit calcium influx in heart, inhibiting depolarisation therefore reducing contractility, reducing pre-load * Inhibits smooth muscle contraction, reducing vasoconstriction

Which chemical transporter is blocked by thiazide-like diuretics?

Na/Cl symporter in distal convoluted tubule

How do thiazide-like diuretics improve hypertension? (2 mechanisms)

* Vasodilator effect in vascular smooth muscle | * Increase diuresis, lowering ECV

What is a side effect for ACE inhibitors?

Dry cough/alopecia/angina/angioedema

What is a side effect for ARBs?

Abdominal pain/diarrhoea/dizziness/hyperkalaemia/renal impairment

What is a side effect for calcium channel blockers?

Dizziness/flushing/headache/nausea/palpitations/peripheral oedema/rash/vomiting/tachycardia

What is a side effect for thiazide-like diuretics?

Constipation/electrolyte imbalance/headache/postural hypotension

Which antihypertensive drug class is most plasma protein bound?

ARBs

From most to least, rank the four major antihypertensive drug classes on their bioavailabilities.

Thiazide-like diuretics (~100%), CCBs (60%), ARBs (32%), ACEIs (25%)

Which antihypertensive drug class undergoes 1st pass metabolism to the active metabolite?

ARBs

Which antihypertensive drug classes are metabolised by CYP450 enzymes?

ARBs, CCBs

Which antihypertensive drug class has the longest half-life?

CCBs (30-50 hours)

What method of administration is used most commonly for the 4 major antihypertensive drug classes?

Oral (P.O.)

Which antihypertensive drug classes are excreted in urine?

ACEIs, ARBs, CCBs

Which antihypertensive drug class is partially excreted in faeces (bile)?

ARBs