Q1

What do you understand by volume of distribution?

  • Volume of distribution is the measure of the apparent space in the body available to contain the drug
  • It relates the amount of drug in the body to the concentration of the drug in blood or plasma
  • Vd = Amt drug in body/C
    • Drugs with a high volume of distribution are very tightly bound by tissues compared with blood, so have a much higher concentration in extravascular tissue than in the vascular compartment. If the drug is tightly bound to plasma proteins and not tissues it has a small volume of distribution

 

What factors affect Volume of Distribution?

  • Drug properties
  •  lipid solubility, pKa, pH, protein binding, blood flow
  • Patient properties – age, gender, disease, body composition

What is the importance of Vd in the overdose situation?

Drugs with large Vd (TCAs) cannot be dialyzed whereas drugs with a small Vd (ASA, lithium) can
Give example of drugs with high and low Vd.
High Vd: diazepam; beta blockers; tricyclics; digoxin; morphine; clonidine; fluoxetine; chloroquine; cyclosporin

Low Vd: warfarin; lithium; phenytoin; aspirin; frusemide; valproic acid; tolbutamide; cephalexin

Pass: two from each group

 


Q2

What do you understand by the term ‘second messenger’?

  • A second messenger is an intracellular substance which has its concentration altered by a process initiated by an extracellular ligand. The second messenger then acts to initiate or facilitate an intracellular process.
  • 3 basic steps:
  1. Extracellular process [EC]
  2. Transmembrane signalling system [TM]
  3. Intracellular process[IC]

 

Describe the common steps in the activation of second messengers.

  • Extracellular
    • Extracellular ligand
    • Cell surface receptor activated via ligand detection
  • Transmembrane
    • G protein activation
    • Concentration change of an effector element [enzyme or ion channel
  • Intracellular
    • Change in second messenger concentration
    • Second messenger action on a substrate or enzyme
    • Response

 

Can you give examples of second messengers?

  • Cyclic AMP
  • Calcium and phosphoinositides
  • Cyclic GMP

 


Q3

In the elderly, what factors change with age and alter pharmacokinetics?

Absorption: No major change unless additional underlying associated condition with age
Distribution: Dec lean body mass, Dec body water %, Inc fat body %, Dec serum albumin, Dec apparent Vd and sometimes increased Vd

Metabolism: Liver metabolism does not decline for all drugs, Dec liver blood flow. Dec phase 1> phase 2 reactions, Liver slower to recover from injury

Elimination: Dec renal function & Cr clearance, Half life inc of drugs variable, Dec excretion of volatile substances by the lung

Associated age related illness affecting any of the above

Pass: Cover 2 of 4 with description

Give some examples of drugs commonly used in the emergency department that must have their prescribing altered in the elderly?

  • Benzodiazepines — liver metabolism, renal function; PD
  • sensitivity
  • Opiods —PD sensitivity respiratory effects
  • Antipsychotics —PD sensitivity; lean body mass
  • NSAID — GI, renal
  • Colchicine —renal, narrow therapeutic index
  • Other drugs narrow therapeutic index
  • Drugs primarily excreted renally —gentamicin, acyclovir
  • Digoxin loading dose with dec Vd
  • Amiodarone loading — Vd and PD sensitivity
  • Many drugs as polypharmacy and must check for interactions
  • i.e. Warfarin.
  • So could argue extra precautions with all —polypharmacy,
  • increase risk of error, compliance and administration issues
  • Interactions with age related disease — IHD, COPD (B
  • agonists or B Blockers)
  • Sulphurs/Baetrim —adverse reactions
  • Anticoagulants — falls
  • Drugs which switch to zero order kinetics -phenytoin


Pass:
Must get 4 relevant and plausible examples with correct associated mechanism & must include benzos and opiods.

Prompts:

  • What about commonly used intravenous agents in the ED?
  • What about analgesic agents used in the ED?
  • What about sedative agents used in the ED?
  • Are there any drugs to be reduced with impaired renal function?

 


Q4

What is the half-life of a drug?

  • Time required to change the amount of drug in the body by one-half during elimination

 

How may it be expressed in relation to other pharmacokinetic parameters?

  • T1/2 directly proportional to Vd / Cl

 


Q5

Describe the 3 major steps in a second messenger receptor system.

Cell surface receptor for an extracellular ligand

Intracytoplasmic activation of a G-protein

Activation of an effector (eg adenylate cyclase) with production of the 2nd messenger (eg cAMP)


Pass Criteria: 3 to pass

 


Q6

What are 'spare receptors'?

  • Receptors in excess of number required for maximal physiological effect.

 

Describe the 2 main mechanisms that account for 'spare receptor' phenomenon?

  • Temporal – prolonged effect after transient binding
  • Numerical- limited substrate with excess receptors

 

What is the effect on the dose-response curve of an agonist with increasing concentrations of an irreversible antagonist?

Curve is shifted to the right with increasing agonist concentrations until eventually only a submaximal effect is achieved.

 


Q7

Describe Phase 1 and Phase 2 reactions.

                           Phase 1 makes more polar/reactive

                           Phase 2 conjugation with polar molecule

general 8
 

What organs are involved?

  • Liver
  • Lung
  • Skin
  • Intestinal wall


Pass Criteria: At least 2

 


Q8

Define the term 'volume of distribution'.

  • Amount of drug in body /concentration in blood or plasma

 

How is it possible for a drug to have a VD of 1600L/70kg?

  • Higher concentrations in extra vascular tissues than in blood – e.g. lipid soluble


Pass Criteria: discuss pros and cons of at least two

 

Give examples of drugs with high Vd and Low Vd.

  • High VD (>70L/70kg)
    • Morphine, chloroquine, digoxin, clonidine, fluoexitine, tricyclics, beta blockers, diazepam
  • Low VD (<50 L/70kg, approximating TBW or ECF volume)
    • Aspirin, frusemide, antibiotics (gentamicin, amoxicillin, cephalexin), tolbutamide, phenytoin, valproic acid, lithium, warfarin

 

If a drug is distributed in the TBW, what is it’s VD?

  • TBW: 0.6 L/kg or 42 L/70kg

 


Q9

What formula describes Drug Clearance?

Ratio of rate of elimination of a drug to its concentration in blood / plasma

general 7

Pass Criteria: Must get formula to pass

 

What is Flow Dependent Elimination?

For drugs that are readily cleared by their organ of elimination (high extraction ratio), the rate of elimination is dependent on rate of drug delivery to the organ which is determined by blood flow and plasma protein binding.

[Systemic CL = CLrenal + CLliver + CLother]

Pass Criteria: Must mention drug delivery / blood flow to pass

Can you name any drugs that have Flow dependent elimination?

Hepatic –

  • lignocaine
  • propanolol;
  • verapamil
  • morphine
  • pethidine


Pass Criteria
: 1 example

 


Q10

What are the sites of drug biotransformation?

  • Liver
  • GIT
  • Lung
  • Skin
  • Kidneys


Pass Criteria: Must get Liver and two others

What is a Phase 1 biotransformation reaction?

  • Conversion of a parent drug to a more polar / water soluble form by the adding or unmasking of a functional group, most commonly by oxidation but also by reduction or hydrolysis.
  • The hepatic CYP (P450) enzymes are responsible for the majority of these reactions


Pass Criteria: Must mention more polar or water soluble & oxidation

What is meant by enzyme induction, in liver biotransformation?

  • Repeated administration of a substrate brings about either enhanced enzyme synthesis or reduced enzyme degradation causing increased metabolism of the substrate

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