Q21

What factors determine the difference in drug metabolism between individuals?

Genetic – enzyme level differences

Diet – induce / inhibit enzymes

Environmental – exposure to enzyme inducers

Age – extremes have decreased enzyme activity or decreased levels of cofactors

Sex – increased metabolic rate in males

Drug-drug interactions – enzyme induction or inhibition, substrate competition

Disease states – hepatic, pulmonary, cardiac, thyroid, inflammatory

Liver size & function

Circadian rhythm

Body temperature

3 of 4 bold to pass

What is meant by 'enzyme induction'?
Prompt: What effect does it have on metabolism?
Prompt: What effect does this have on the pharmacological action of the drug?

Drug causes an increased rate of synthesis or decreased rate of degradation of enzyme causing:

accelerated substrate metabolism

decreased pharmacological action of the inducer or a co-administered drug.

Bold to pass

 


Q22

List the various molecular mechanisms of transmembrane signalling.

1.            Lipid soluble ligand crosses membrane and binds to intracellular receptor.

2.            Transmembrane receptor protein with ligand binding to extracellular domain regulating intracellular enzymatic activity

3.            Transmembrane receptor protein that binds and stimulates protein tyrosine kinase

4.            Ligand-gated transmembrane ion channels

5.            Transmembrane receptor protein, G protein, intracellular second messenger

Describe 3 mechanisms to pass

Describe the function of the system involving G proteins.

Transmembrane signally system with 3 separate components. Extracellular ligand binds to specific cell surface receptor. This receptor then activates G protein located on cytoplasmic surface of membrane. Activated G protein changes activity of effector element (enzyme or ion channel) leading to a change in concentration of second messenger.

Bold concepts to pass

 


Q23

What is first pass metabolism?

After absorption of an orally ingested drug, portal blood delivers drug to liver

  • Metabolised in gut wall
  • Metabolised in portal blood
  • Metabolised by liver
  • Excreted into bile

before reaching systemic circulation ie Reduces bio-availability of a drug

Pass: Basic definition. Has to include some changes of drug

How can you increase bioavailability? Give an example.
Prompt: Apart from ....what can also increase its bioavailability.

1 Different route of administration

IV

IM / SC

SL

PR — low

Still may have some first pass

metabolism — only 50% bypasses

liver

lnhalational

Transdermal

2 Depending on properties of drug

Increase absorption

  • Hydrophilic
  • Lipophilic
  • Actively pumped into gut

Pass: Must talk about alternative routes

 


Q24

Define drug clearance.
Prompt: Units of measurement of clearance.

1.            Volume of plasma/blood cleared per unit time, or
Rate of elimination

2.            CL =        concentration
CL systemic = CL renal + CL liver + CL other

Pass: Need to know either of the two

What is the relationship between clearance and the dosing frequency of a drug?

  1. Knowing the clearance of a drug will allow the dosage to be worked out to achieve the target concentration. To maintain steady state, the dosing rate Crate in’) must equal the rate of elimination Crate out’)
  2. Maintenance dose needs to be adjusted for disease state which affect clearance eg renal failure.
  3. Dosing rates (mg/h)

= Rate of elimination (steady state) = CL x target conc.

Pass: Need to know 2 out of 3

Please give an example of dosage adjustment for impaired clearance.

Gentamicin, digoxin in renal failure.
Loading dose not affected, maintenance dose reduced or dosage interval increased.

Pass: Need to give one example

 


Q25

With respect to the biotransformation of drugs, please distinguish between Phase I and Phase II reactions.

  1. Phase I convert the parent drug to a more polar metabolite by introducing or unmasking functional groups such as —OH, -NH2, -SH.
  2. Phase I examples: Oxidations including cytochrome p450 dependent and independent, deaminations, desulfurations, dealkylations, dehydrogenations, Reductions, Hydrolysis.
  3. Phase 11 involves conjugation in an endogenous substrate to form a highly polar conjugate.
  4. Phase II reactions include glucuronidation, acetylation, sulfation, methylation, glutathione conjugation.
  5. Both types of reactions result in more polar compounds that are more amenable to urinary excretion.


Pass if definitions correct

Does Biotransformation generally result in more or less active metabolites?

Prompt: Please give some examples

Usually less active (detoxification) may frequently result in metabolites with residual pharmacological activity or even enhanced activity (activation).

Pass: Must know this and give at least one example

 


Q26

What variables influence the extent & rate which a drug is absorbed?

1. Route of administration- PO; SC; SL; PR

2. Nature of the absorbing surface

(a)          Cell membrane – single layer of intestinal epi cells compare to several layers of skin cells.

(b)          Surface area – lung, small intestine, stomach

3. Blood Flow –blood flow enhances absorption SL v SC

4. Drug Solubility – lipid soluble drugs –

5. Drug Formulation – i.e. enteric coatings


Pass: Need 3 of main concepts

Explain why aspirin absorption is enhanced by the low pH in the stomach?

Aspirin is an acidic drug (pKa 2.98) relatively un-ionised in the stomach & more ionised in the small intestine (i.e. absorbed more readily from stomach)

Pass: Aspirin is more lipid soluble in stomach & absorption is greater here

Prompt: How does ionisation of a drug affect it’s solubility?

Drugs exist as weak acids or weak bases & in the body they are either ionised or un-ionised; Ionised(charged polar) water soluble; Un-ionised (non-polar) lipid soluble

Pass: Need to correctly state un-ionised drugs lipid soluble

 


Q27

Describe Phase 1 and Phase 2 reactions in drug metabolism.
Prompt 1: What are some of the biochemical reactions that characterize phase 1 reactions? (Oxidation, reduction, hydrolysis)
Prompt 2: How does phase 2 reactions enhance the excretion of a drug?

Process of chemical modification of a drug leading to more hydrophilic, more polar, readily excreted compound.

Phase 1 (Functionalization) reactions: converts parent drug to more polar often inactive metabolite – process of oxidation, reduction, hydrolysis where polar functional group (OH, N H2,SH) is introduced- majority reaction via cytochrome P450 enzymes.

Phase 2 (Conjugation) reactions: metabolites combine with endogenous glucuronic a, sulphate, acetylcoenzyme A or glutathione to form more polar metabolite– reactions catalysed by different transferase enzymes.

Note: Phase 1&2 can occur alone, sequentially or simultaneously. Metabolites can be more active or toxic than the parent drugs.


Pass: Need basic understanding of ingeneral “metabolise to more polar and excretable compounds”

Phase 1

1 example: (oxidation, reduction, hydrolysis) CYP450

Phase 2

1 example: Conjugation to form more polar compound+ one example of the

endogenous substances

 


Q28

Define bioavailability.

Fraction of unchanged drug reaching systemic circulation following administration by any route. AUC (conc-time) is a common measure of the extent of bioavailability.

Pass: Bold

What factors affect bioavailability?

3 Factors

a)            Extent of Absorption

i)             Too Hydrophilic or too lipophilic

ii)            Reverse transporter associated with P-glycoprotein – pumps drug back to gut lumen

iii)           Gut wall metabolism

b)            First Pass Elimination

i)             Metabolism by liver before it reaches systemic circulation

ii)            Small additional affect if drug has biliary excretion

c)            Rate of Absorption

i)             Determined by site of administration and drug formulation

Pass: Bold

How can you overcome the effects of high first pass metabolism?

Change route of admin to: Sublingual, transdermal, rectal, inhalation, IV, IM ; increase dose

Pass: need two routes of admin

 


Q29

How does Hartmann's differ from normal saline?

  • Addition of Sodium Lactate, Potassium Chloride, Calcium Chloride (+pH adjustment)
  • Na 131, K 5, Cl 112, Ca 2, Lactate/Bicarb 28 mmoL
  • Compare normal saline – Na 150, Cl 150

Pass Criteria:

  • Bold to pass

What are the potential advantages of Hartmann's solution in resuscitation?

  • Closer to physiologic – potassium, calcium
  • Less hyperchloraemia
  • Effective bicarbonate – some (slow) good effect on acidosis (proof of superiority lacking)

Pass Criteria:

  • Bold to pass

What are the potential complications of IV fluid therapy?

  • Overload/under resuscitation
  • Hypothermia
  • Extravasation
  • Acidosis
  • Electrolyte abnormalities
  • Osmo changes
  • Air embolism
  • Infection
  • Cerebral oedema
  • Haemodilution

 


Q30

What is drug clearance?

  • Measure of the ability of the body to eliminate a drug
  • Rate of elimination in relation to drug concentration
  • CL = rate of elimination/concentration

Pass Criteria:

  • Reasonable definition to pass

What factors affect drug clearance?

  • Concentration – Dose & Bioavailability
  • Elimination – specific organ function / blood flow & protein binding
  • Major sites of elimination are kidneys and liver – therefore factors that affect these organs’ function and blood flow will have most effect

Pass Criteria:

  • One for each element

What is the difference between capacity-limited and flow-dependent drug elimination?

  • Capacity-limited is saturable (zero order)
    • Examples: aspirin, phenytoin, ethanol
  • Flow-dependent is non-saturable (1st order)
    • (organ blood flow, protein binding)
    • Examples: alprenolol, amitriptyline, imipramine, isoniazid, labetalol, lignocaine, morphine, propoxyphene, propanolol , verapamil

Pass Criteria:

  • Bold to pass

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