Past Q completed study Q

Question 1

Define isomer

Answer 1

molecules with the same atomic formula however they have different structures/chemical bonds

Question 2

Divisions of isomers

Answer 2

They can be broken up into structural isomers where the order of atomic bonds differs or steroisomers with the same chemical constituents and bond structure but different confirguration.

Question 3

Stereoisomer divisions?

Answer 3

• Optical isomers have one or more chiral centre which is a carbon atoms or quaternary nitrogen surrounded by 4 different chemical groups - those with a single chiral centre have 2 confirmations and are referred to as enantiomers. Optical isomers with more than one chiral centre are diastereoisomers
• Geometric isomers are where a molecule has dissimilar groups attached to 2 atoms often carbon linked either by a double bond or ring structure and free rotation is restricted

Question 4

Enantiomer define? Types

Answer 4

Enantiomer - An optical stereoisomer that is a mirror image of another but not superimposable with rotation - has a single chiral centre. Same bond structure, atomic make up and 3D shape. Nomenclature is to use R (rectus) and S(sinister) to describe configuration, or dextrose (+) or Levo (-) where optical activity is known but absolute structure is not

Question 5

Why does being an isomer affect pharmacodynamics? Provide example?

Answer 5

• Pharmacodynamics - Pharmacodynamic profile will be affected according to the mechanism of action of the drug
  ◦ Receptor mediated MOA - potency and affinity for receptors are effected by confirmational change so minor structural modifications including mirror image enantiomers can have significant effects on MOA either increasing or decreasing affinity, as well as potency
  ‣ E.g. The relative potency may be markedly different such as in etomidate R vs S
  ‣ The relative potencies may also be similar e.g. isofluorane
  ‣ The property of biological molecules to show stronding preference for one enantiomer over another is called stereoselectivity
  ◦ Ketamine
  ‣ S Ketamine enantiomer has more potent dissociative effects and anaesthetic potency; however the R isoforms may be a better antidepressant
  ◦ Physicochemical MOA - drug effect is likely to be unaffected

Question 6

How does enantiomers and isomers affect pharmaceutics

Answer 6

◦ Molecular and physical properties are identical e.g. boiling point , pH
◦ However they do rotate polarised light in different directions; may appear distinct under X-ray crystallography and different reaction kinetics with chiral catalysts.
◦ Enantiopure preparations significantly add to the manufacturing cost

Question 7

How does enantiomerism or isomerism affect pharmacokinetics

Answer 7

◦ Dose reduction may be possible
◦ Absorption largely depends on physical properties and will usually be the same unless there is receptor mediated pinocytosis or receptor mediated absorption e.g. L Dopa vs D Dopa; or methotrexate D enantiomer is poorly absorbed as does not receive active transport. Additionally first pass metabolism may differ
◦ Distribution - identical unless receptor uptake or protein binding is affected
◦ Metabolism - may have different metabolism as a result of enzyme affinity for metabolism e.g. Warfarin, as R warfarin is metabolised via 3 different CYP3A4/CYP2C19/CYP1A2; whereas S enantiomers is metabolised by CYP2C9 only
◦ Excretion - excretion of isomers may differ under a number of different conditions
‣ Where metabolism to inactive metabolites occurs differently due to stereoselectivity of enzymes
‣ Differential reuptake in renal tubules
‣ Differential transport in biliary clearance or reuptake in bowel wall (recycling)
‣ Differential protein binding afffecting renal clearance
* Toxicity

Question 8

What factors affect diffusion coefficient

Answer 8

molecular size, lipid solubility, temperature, viscocity, molecular properties of the solution

Question 9

Absorption rate

Answer 9

Ficks law

Question 10

Pharmaceutic factors affecting drug absorption

Answer 10

◦ Drug dose - higher concentrations will have faster rates of absorption due to Fick’s laws of diffusion
◦ Molecular size - reduced molecular size increases drug passive absorption via diffusion
◦ Lipid solubility vs ionic —> pKa
‣ Acidic drugs are unionised in the stomach allowing for rapid absorption
* Acidic drugs generally have higher oral bioavailability, poorer hepatic clearance, higher protein binding and smaller volume of distribution
* Basic drugs - poorer protein bringing, larger volumes of distribution, better CNS penetration, decreased receptor selectivity, sequestered in acidic organelles e.g. mitochondria and absorbed better in the stomach
‣ Salts or permanently ionised drugs remain ionised at all times and are not absorbed
◦ Site of administration
‣ PEG, oral vs rectal
◦ Preparation specific factors
‣ Modified release drugs are released more slowly
‣ High surface area drugs - dissolved more rapidly

Question 11

Luminal factors affecting drug absorption

Answer 11

◦ Co-administered medications interacting intra-luminal
◦ Bile salts - emulsifying effect critical for absorption of some substances inc. fat soluble vitamins
◦ Gut bacteria - deactivate or activate drugs
◦ diet factors e.g. binding to substances in food or co-administration with a drug that it combines with e.g. tetracyclines and milk

Question 12

Gut wall metabolism affecting absorption

Answer 12

◦ Enterohepatic recirculation - some drugs are eliminated in the bile and reabsorbed in the jejunum and this can be modified or altered
◦ Metabolism in the gut wall - preceding first pass metabolism absorption into plasma may be modified prior to transfer by gut enzymes, injured enterocytes may lose this function

Question 13

Absorption vs motility

Answer 13

◦ Gastric motility - gastric emptying is a major determinant of absorption
‣ The rate of gastric emptying affects all drugs even those which are well absorbed in the stomach - drug absorption is generally poor in the stomach due to the thick layer of protective mucous but also small surface area and therefore drug absorption is generally slow even if drugs sit in the stomach for a prolonged period.
‣ Gastric motility is affected by
* Food - especially fat
* Viscosity of stomach contents
* Size of tablet/capsule
* Sedation
* Mobility
* Abdominal compartment pressure
* Gastric perfusion
* Autonomic and hormonal activity
* Baseline stomach emptying is minutes when empty, and many hours when full
‣ SMall intestine has a significantly larger surface area and contributed the most to drug absorption
◦ intestinal motility can increase or decrease absorption - slow transit may increase amount of an ingested substance absorbed

Question 14

Absorption potential of the gut wall is affected by (4)

Answer 14

◦ Surface area - microvilli increase the surface area, if there is mucosal breakdown and lost microvilli or resection of bowel then surface area for absorption is reduced —> reduced absorption
◦ Thickness - Increased bowel wall thickness e.g. oedema will reduce absorption
◦ Active transport
‣ Some drugs may have active absorption via pinocytosis, active transport which result in increased drug absorption compared to passive processes only e.g. amino acid absorption or vitamins e.g. thiamine
‣ Genetic - Congenital malabsorption of specific substances
◦ GI blood supply - shock
‣ Reduced mucosal perfusion but increased mucosal permeability due to loss of barrier function with ischaemia. Delayed gastric emptying due to poor perfusion, intestinal wall oedema and altered gut microbiome may affect the processing of drugs
‣ Gut perfusion is the rate limiting step for rapidly absorbed drugs, as it slows it becomes more important for all drugs

Question 15

Define protein binding

2 baseline characteristics

Answer 15

• Protein binding is a reversible, saturatable interaction between proteins and drug compounds in either the plasma or interstitial or intracellular fluid whose dissociation at baseline varies depending on the drug and protein involved occurring in an equilibrium. Only unbound drug is free to cross to sites of effect or sites of metabolism/excretion. Rate occurs rapidly

Question 16

Examples of proteins that bind

Answer 16

number and characteristics of binding vary with pH
* Albumin - neutral or acidic drugs. 6 total binding sites .e.g barbituates/Benzos/ibuprofen (Sudlow site 2), warfarin (Sudlow site 1)
◦ Binding at one site does affect binding of other sites
* Globulins
◦ alpha 1 acid glycoprotein binds basic drugs e.g. morphine, lignocaine
◦ Alpha 2 globulin copper
‣ ceruloplasmin binds vitamins ADEK
◦ Beta 1 globulin iron
* Other
◦ Haemoglobin - phenytoin
◦ Lipoproteins - cyclosporine

Question 17

Factors determining protein binding (4)

Answer 17

• Concentration of the drug itself
• Environmental modifiers
  ◦ PH
  ◦ Temperature
  ◦ Endogenous ligands for the same binding site
• Binding affinity
  ◦ Affinity of drug for protein /association constant
  ◦ Lipid solubility of drug - increased lipid solubility = increased binding
  ◦ PKa - Ionised drugs do not bind to proteins
• Available binding sites
  ◦ Number of available binding sites e.g. albumin has multiple additional binding sites, high capacity; whereas glycoproteins generally have low capacity and are more specific
  ◦ Competition for the same binding sites with other drugs
  ◦ Concentration of binding proteins - e.g. inflammation or chronic liver disease reducing albumin

Question 18

What influence does protein binding have on pharmacodynamics

Answer 18

generally only of significance if protein binding >90% where small changes in bound fraction produce large changes in unbound drug concentration.
* Pharmacodynamics - only unbound fraction is available free for pharmacological effect
◦ When there are abrupt changes to bound fraction there will be changes in unbound drug concentration which has a subsequent effect on drug availability at receptor sites and action

Question 19

What effect does protein binding have on Vd

Answer 19

highly plasma protein bound drugs have a smaller volume of distribution, whereas drugs with strong tissue binding have a very large volume of distribution e.g. amiodarone

Question 20

Metabolism and how it is affected by protein bidning

Answer 20

◦ Generallly only free fraction is available for clearance and metabolism
‣ Some drugs have a higher affinity for their metabolic mechanisms than proteins and therefore this does not apply
‣ E.g. Furosemide which is bound to albumin is stripped off the albumin on the basal side of the PCT before furosemide is transported into the cell. IN albumin deficiency there is a decreased delivery of the drug to this site
◦ generally with changes in bound fraction and subsequent changes in unbound drug concentration this has an effect on drug metabolism proportionately and a new steady state is found. For drugs such as phenytoin with near saturated metabolic pathways plasma concentration increases if unbound fraction increases

Question 21

Define first and zero order kinetics

Answer 21

• First order kinetics - the rate of drug elimination at any given time is directly proportional to its plasma concentration at that time
• Zero order kinetics - the rate of drug elimination is independent of the concentration of the drug

Question 22

Draw a graph representing first order and zero order kinetics? Describe the mathematical appearance of the graph? State in words what the graph represents
e.g. of a drug subject to this

Answer 22

Question 23

Provide an example of a drug relevant to intensive care practice that is a good demonstration of first and zero order kinetics

Answer 23

◦ Phenytoin metabolism becomes saturated within the upper limit of the normal range
◦ This results in a transformation from 1st order kinetics to zero order kinetics
◦ Therefore small increases in dose around this level can have large effects on plasma levels —> toxicity
‣ This is especially important in critical care where absorption of phenytoin given PO/NG/NJT can be variable and highly influenced by coadministered feeds and medications leading to fluctuations in bioavailability —> which when combined with its metabolism profile can rapidly lead to toxicity
‣ Additionally it is highly protein bound and plasma free component will increase in states of low albumin! Meaning when in the higher range of total drug concentration it has a risk of toxicity
◦ During zero order kinetics there is no steady state - if the drug delivery exceeds the rate of excretion plasma levels will continue to rise infinitely until ingestion stops or toxicity causes death
◦ Additionally to add to the complexity Amiodarone, erythromycin, fluconazole all inhibit the enzyme metabolising phenytoin (CYP2CP and CYP2C19) meaning first order kinetics will change to zero order kinetics at lower levels; while fluoroquinolones and folate supplements do the opposite

Question 24

What is half life

Answer 24

• Hlaf life is the time taken for the amount of drug in the body (or plasma concentration) to fall by half

Question 25

A constant proportion of drug is eliminated per unit of time - what does this represent

Answer 25

FIRST order kinetics
Exponential decline in drug concentraiton over time

Question 26

What do you log in a concentration vs time curve?

Answer 26

Concentration

Question 27

Concentration at any time in relation to a concentration time curve of linear kinetics is?

Answer 27

Concentration at any time is = Intiial concentration x e ^ -kt
Where k is the elimination rate constant = proportion eliminated per units of time (/hr) (= clearance / volume of distribution)
T = time

Question 28

What relationship does half time have to pharmacokinetics

Answer 28

Rearranged: t 1/2 = 0.693 x volume of distribution / clearance
0.693 is the logarithm of 2 (exponential rate of elimination if there is first order kinetics)

Question 29

Volume of distribution =

Answer 29

◦ V = total amount of drug in the body / plasma drug concentration
◦ V = plasma volume + fraction unbound in plasma / fraction unbound in tissue x tissue volume

Question 30

What effect does Vd have on half life

Answer 30

◦ Half life is increased by increasing volume of distribution
◦ The larger the volume of dsibtuion the more drug is concentrated in tissues compared to blood, and therefore not exposed to metabolism or clearance mechanisms based in plasma

Question 31

What are the 4 factors affecting Vd

Answer 31

‣ Properties of the drug - molecular size, charge, pKa, protein binding, tissue bidning,lipid water partition coefficient
‣ Properties of the patient - volume status, protein content, body fluid pH, competitive drug for binding sites
‣ Pathophysiology - age, gender, obesity,pregnancy, oedema
‣ Extracorpereal sites of distribution

Question 32

Clearance is

Answer 32

the volume of blood cleared of drug per unit time (litre/hr)

Question 33

Clearance in relation to half life is

Answer 33

Half life increased by reduced clearance

Question 34

Clearance in relation to blood flow

Answer 34

◦ Clearance in each organ or each site is a reflection of blood flow to the organ and efficiency of irreversible drug extraction.
◦ Clearance can be anywhere between 0 and the total blood flow to the organ

Question 35

Elimination rate has what relationship to clearance

Answer 35

◦ Elimination rate = clearance x plasma drug concentration

Question 36

What factors affect clearance 6

Answer 36

‣ Concentration of the drug
‣ Susceptibility to bio transformation -clearance by metabolism eg. Hepatic
‣ Susceptibility to removal by filtration or diffusion e.g. lungs, renal
‣ Active secretion
‣ Functional status of clearance organs
‣ Blood delivery to organs of clearance

Question 37

Why does half life even matter

Answer 37

• Duration of action after a single dose
• Time required to reach steady state with chronic dosing - 3-5 half lives
• Dosing frequency requirted to avoid large fluctuations in plasma concentration

Question 38

What is the calculation for loading dose

Answer 38

• Loading dose = volume of distribution x desired peak plasma concentration

Question 39

What effect would increasing Vd have on loading dose?

Answer 39

◦ Therefore with increasing volume of distribution increasing loading doses are required to achieve the same plasma concentration. This reflects the lost plasma concentration during initial dosing to redistribution until steady state is achieved
◦ Additionally if increased plasma concentration is desired a loading dose will need to be increased

Question 40

What is the concept of a loading dose

Answer 40

◦ The loading dose is used to fill up the volume of distribution to enable immediate target plasma levels

Question 41

If dosing interval is one half life then loading dose is>

Answer 41

twice maintenance

Question 42

What practically can be a problem with loading doses

Answer 42

◦ Practically can become challenging if high volume of distribution the loading dose may be impractically large and lead to toxicity range concentrations especially if slow redistribution, therefore sometimes loading is divided

Question 43

Maintenance dosing =

Answer 43

• Maintenance dose (mg/hr) = clearance (L/hr) x steady state drug concentration/target concentration (Mg/L)

Question 44

Steady state occurs when

Answer 44

◦ Steady state occurs when: elimination rate = maintenance dose rate
◦ This occurs because in first order kinetics increased drug concentration = increased elimination

Question 45

Time to reach steady state is affected by

Answer 45

Time to reach steady state is determined by half life - 3-5 half lives. Giving a loading dose more immediately reaches the target concentration. In many contexts effect is desired far quicker than 3-5 half lives e.g. analgesia, AF control , antibiotics MIC

Question 46

How is the loading dose affected by critical illness

Answer 46

n the critically ill a higher plasma concentration may be desired which will require an increased loading dose
‣ This higher dose may be desired due to faster onset of effect at remote organs or factoring in microvascular dysfunction and reduced tissue penetration requiring increased doses
◦ The volume of distribution in critically ill patients can be increased or decreased due to
‣ Decreased volume of distribution —> reduced loading and maintenance dose rates
* Variation in lean body mass and total body mass e.g. with sarcopenai in prolonged critical illness will influence compartmental distribution of medications
* Hypovolaemia
‣ Permeability - increased volume of distribution for hydrophilic drugs from increased total body water (fluid overload) and third spacing —>increased loading and maintenance infusion rates; for lipophilic drugs the volume of distribution will remain the same.
* In some instances e.g. volume of distribution changes due to loss of barrier functions e.g. Benzylpenicllin more easily penetrating the CNS in meningitis

Question 47

Maintenance dosing can be affected in critical illness due to

Answer 47

Changes in clearance and steady state drug concentration desired

Question 48

Why might clearance be affected in critical illness 5

Answer 48

◦ Decreased hepatic blood flow in shocked patients will reduce clearance of high extraction ratio drugs e.g. propofol therefore requiring reduced maintenance dose rates
‣ May also require more prolonged dosing intervals if intermittent dosing
‣ Oral loading dose would decrease due to reduced first pass metabolism, but IV loading unchanged
◦ Clearance can be altered by alterations in metabolism induced by hypothermia or hyperthermia influences on body enzymes e.g. decreased hepatic clearance of midazolam and propofol in hypothermia
◦ Interactions with other medications given may result in enzyme inhibitors or inducers altering the metabolism and therefore clearance of drugs
◦ Decreased renal blood flow and function of secretion mechanisms will reduce clearance of unchanged drugs and active metabolites e.g. aminoglycosides. This will require reduced maintenance dose rate and possibly increased dosing interval
◦ In certain instances increased clearance may occur early in hyperdynamic circulatory states resulting in increased clearance —> increased maintenance dose rate + potentially increased frequency of dosing if intermittent
◦ Gut stasis in critical illness can increase Enterohepatic recirculation and reabsorption of drugs cleared via biliary mechanisms, and biliary stasis can enhance the failure of clearance

Question 49

How might monitoring in critical illness be different?

Answer 49

• Protein - reduced protein levels e.g. albumin will increase free drug levels of highly protein bound drugs e.g. phenytoin
  ◦ Decreased protein impacts measurement of drug levels, will result in increased clearance and increased drug effect
  ◦ Competition for protein binding e.g. bilirubin competing for albumin binding sites —-> increased free unbound fraction of the drug

Question 50

Dosing interval affected by

Answer 50

Dosing interval is influenced by:
* Elimination half life - you don;t wait for all of the drug to be eliminated before the next dose
◦ The longer the dosing interval in proportion to half life the greater the fluctuation between doses
* Therapeutic index
* Convenience

Question 51

Describe the 5 domains of drug action

Answer 51

Physicochemical
Receptors
Cell membrane
Enzymatic
Intracellular

Question 52

What is a drug

Answer 52

substances which exert an effect on the body, either by interacting with macromolecule structures or changing the physical or chemical properties of the body

Question 53

How might a drug have a physicochemical effect (3)

Answer 53

• Changing the physical or chemical properties of a medium or solution
  ◦ Sodium bicarbonate - creatinine a more alkaline environment
  ◦ Helium - reduces the viscosity and resistance to flow of air
• Changes in the physical or chemical properties of another exogenous substance
  ◦ Activated charcoal
  ◦ Chelation agents e.g. desferoaximine and iron
• Action by physical properties of drug itself
  ◦ Reflective properties of zinc oxide

Question 54

How might a receptor action of a drug act?

Answer 54

◦ Direct effect by binding with receptor e.g. opioid receptors
◦ Indirect effect by influencing the relative affinity of another endogenous substance for a receptor or displacing it from its usual binding site
◦ Modulation of receptor function e.g. benzodiazepines
◦ Acting as a substrate for a receptor e.g. vitamins

Question 55

Cell membrane receptors may act via 2 primary mechanisms - what are they? Describe subdivisions of each and provdie examples

Answer 55

• Directly - amphotericin
• Voltage gated ion channels - involved in the conduction of action potentials in excitable tissues
  ‣ e.g. lignocaine
• Receptor mediated - proteins often integral to a membrane containing a region to which a ligand binds specifically to elicit a response
  ◦ Altered ion permeability - Ligand gated ion channels - membrane spanning complexes with the potential to form a channel with selective ion conductance
  ‣ Pentameric - 4 membrane spanning units e.g. nicotine ACh receptor at NMJ allowing Na to enter, GABA A receptor, 5HT3
  ‣ Ionotropic glutamate - AMPA, NMDA and Kainate
  ‣ Purinergic - mechanosensation and pain
  ◦ Intermediate messengers
  ‣ GPCR - transducer a signal from one side of the cell to another through 7 transmembrane spanning domains connecting to a G protein which facilitates intracellular signal transduction in either an inhibitor and excitatory manner - beta blockers acting on beta receptors.
  ‣ Tyrosine kinase receptors - insulin
  ‣ Guanylyl cyclase e.g. nitric oxide
  ◦ Transmmembrane transport protein activity e.g. SSRI

Question 56

Enzymatic drug actions can include? How might these act?Provide example

Answer 56

biological catalysts which for the most part drugs inhibit; resulting in reduced concentration of the metabolite, or increased concentration of the substrate usually metabolised.
* Substrate for enzyme activity e.g. vitamins —>reduced concentration of substrates for enzyme creation reduces enzyme action similar to above mechanism
* Regulation of enzyme activity
◦ Intracellular e.g. phosphodiesterase inhibitors such as milronone
◦ Extracellular enzymes e.g. acetycholinesterase e.g. neostigmine

Question 57

Intracellular drug actions could include? Provide examples of mechanism

Answer 57

alter the expression of DNA and RNA indirectly altering the production of intracellular proteins which can include enzymes, receptors, transport proteins or signalling molecule production
* Regulating gene transcription - corticosteroids, thyroid hormones
* Interction with genetic material - cisplatin

Question 58

How is pharmacodynamics influenced in obesity (2)

Answer 58

• Decreased dose response
  ◦ Resistance to haemodynamic effects of verapamil
  ◦ Resistance to OCP
  ◦ Resistance to atracurium
  ◦ Resistance to insulin
• Exaggerated response
  ◦ Increased sensitivity to respiratory depressant effects of opiates in OSA associated with obesity

Question 59

How is absorption affected in obesity

Answer 59

◦ Usually not altered
◦ Increased gastric emptying rate can occur - resulting in higher oral peak dose - variable and drug dependent
◦ Increased incidence of GORD, delayed gastric emptying due to bariatric surgery —> reduced absorption and lower peak dose of thyroxine, phenytoin
◦ Increased gut perfusion can improve absorption
◦ Poor SC faaltion decreasing SC absorption, and difficult IM access

Question 60

How is volume of distirbution affected in obesity

Answer 60

◦ Increased Vd
‣ Increased fat mass - absolute and proportional —> lipophilic drugs (fentanyl)
‣ increased total body water—>increased Vd for hydrophilic drugs (Gentamicin)
‣ Increased blood volume
‣ Increased organ mass
‣ Increased LBM
◦ Increased alpha 1 acid glycoprotein —> increased binding of basic substances, decreased free fraction e,g. Propranolol

Question 61

How is metabolisma ffected in obesity

Answer 61

◦ Increased cardiac output —> Increased hepatic blood flow —> increased metabolism of high extraction ratio drugs eg. Propofol
◦ Intrinsic clearance —> Phase 1 and phase 2 enzymes —> generally unaltered or increased (phase 2 more likely e.g. oxazepam)
‣ Unless severe NASH —> can reduce hepatic metabolism and blood flow
◦ Increased soluble enzyme activity —>suxamethonium

Question 62

How is elimination affected in obesity

Answer 62

◦ Increased renal blood flow and GFR —> increased clearance of hydrophilic drugs
◦ Increased half life due to increased volume of distribution especially for extremely lipophilic drugs e.g. midazolam
◦ Increased tubular secretion e.g. ciprofloxacin
◦ Decreased GFR due to diabetes

Question 63

Provide an example of a drug that may be markedly affected by its use in obesity

Answer 63

Fentanyl
* Absorption not altered unless transdermally administered —> lipophilic with a increased distance to BV and therefore reduced systemic absorption
* DIstribution
◦ Lipophilic and therefore increased fat mass markedly increases Vd
◦ Increased propensity to accumulate
◦ Reduced clinical effect with plasma levels dropping quickly with redistribution
* Metabolism - largely unaltered
* Elimination - renally cleared faster

Question 64

How does critical illness affect absorption - list some factors

Answer 64

Gastric effects - delayed gastric emptying, gastric pH higher, reduced intestinal motility
- Mucosa;l features - GI permeablity increased to smal solutes, intestinal wall eodema, brush border loss, decreased active efflux from transporters, decreased metabolism in gut wall
- Perfusion - reduced
- Erratic post opertive absorption
- Increased pre absorptive interactions via feeds, blood and vitamins

Question 65

How is the stomach affected in critical illness that affects drug absorption

Answer 65

◦ Delayed gastric emptying
‣ Prolonged gastric transit time, increased gastric drug absorption but this is generally an inefficient and site of minimal absorption. Gastric emptying is the rate limiting step generally in drug absorption
‣ decreased drug absorption e.g. paracetamol - in critical illness absorption reduced by half, and time to peak effect 3x longer
◦ Reduced intestinal motility - slowed gut transit, will reduce the rate of gut absorption because delivery of drug to absorptive surfaces is slowed, but overall absorption/bioavialability of a drug may increase due to prolonged exposure to absorptive surfaces if slowly absorbed
◦ Gastric pH is higher as a result of PPIs = decreased drug absorption of weak bases e.g. clopidogrel

Question 66

How is the mucosa of the gut affected in critical illness that affects drug absorption

Answer 66

◦ GI permeability increased to small solutes, but due to reduced perfusion and local hypoxia cellular processes requiring energy e.g. pinocytosis and active transport of larger or more polar molecules is less efficiency.
◦ Intestinal wall oedema, brush border loss —> reduced surface area, increased distance —> poor absorption
◦ Decreased active efflux from transporters e.g..P glycoprotein on apical surface of cells which pump drugs back into the gut = increased drug absorption
◦ Decreased metabolism in intestinal wall - but may also lead to reduced brush border enzymes and other processes that are essential for absorption in the first place, so may increase or decrease absorption

Question 67

How is perfusion a factor in absorption in critical illness

Answer 67

◦ Reduced mesenteric perfusion as a result of illness/shock but also potentially compounded by noradrenaline/vasopressin which are splanchnic vasoconstrictors + decreased venous return by positive pressure ventilation - decreased drug absorption from gut wall to systemic circulation e.g.paracetamol
◦ Decreased skin and muscle perfusion = decreased IM and SC absorption e.g. heparin

Question 68

How do intraluminal changes in critical illness impact absorption

Answer 68

◦ Increased pre-absorptive interactions via NG feeds/blood/vitamins/oral contrast such as in phenytoin absorption being affected by feeds 1-2hrs before and after reducing drug absorption
◦ Bacterial overgrowth - gut bacteria may metabolise more drugs if stasis, or with broad spectrum antibiotics the reverse might be true

Question 69

How is protein binding affected in critical illness?

Answer 69

◦ Decreased protein = increased free drug levels of highly protein bound drugs e.g.phenytoin
‣ Decreased protein impacts the measurement of drug levels, as drug levels measure total drug in plasma which includes that which is bound, if there is less bound there may still be the same free but the level will be low. E.g. phenytoin is 90% protein bound, but in critical illness this may be 80% effectively doubling active drug concentration
◦ Altered protein binding due to changes in pH = altered free drug levels

Question 70

How is Vd effected in critical illlness? (5)

Answer 70

1. Protein binding - decreased protein binding increases free drug levels
2. Acidosis or alkalosis will effect ionisation and ocmpartment shifts
3. Variation in lean body mass and total body mass
4. ECMO and CRRT increase Vd
5. Permeability 0 increased Vd for hydrophilic drugs with third spacing, Vd often the same for lipophilic drugs but clearance slowed

Question 71

How is the metabolism of drugs affecred by critical illness? (4)

Answer 71

1. Hepatic blood flow
2. Temperature
3. Hepatic enzymes
4. Interactions

• Decreased hepatic blood flow in shocked patients, those with decreased cardiac output secondary to PEEP - decreased clearance of high extraction ratio drugs e.g propofol
  ◦ Drugs that have poor intrinsic clearance in the liver are not affected as much by changes in hepatic blood flow
• Hypothermia induced hepatic enzyme dysfunction = decreased hepatic clearance e.g. midazolam and propofol
  ◦ Or hypothermia decreased tissue metabolism due to reduced blood flow
  ◦ Decreased spontaneous degradation
• Hyperthermia induced enzyme function increase in addition to organ damage systemically releasing enzymes =increased clearance due to enzyme activity e.g. suxamethonium
• Downregulation of hepatic enzymes in hypoxia = decreased clearance e.g. theophylline
• Decreased hepatic synthetic function = decreased levels fo soluble enzymes, decreased clearance of drugs in the plasma
• Interactions with other medications given may result in enzyme inhibitors or inducers e.g. phenytoin inducing CYP enzymes

Question 72

How is elimination affectred in critical illness
Renal 3
Other 2

Answer 72

• Decreased renal blood flow and function = decreased clearance of unchanged drugs or metabolites e.g. aminoglycosides
  ◦ Active secretion, passive reabsorption and filtration Allen suffer
• Reduced secretion due to acute tubular necrosis e.g. flucloxacillin
• Increased glomeular filtration in hyperdynamic circulatory states = increased clearance of drugs (Vancomycin)
• Decreased biliary clearance
  ◦ Biliary stasis
  ◦ Decreased gut transit leading to recirculation

Question 73

Define bioavailability

Answer 73

• the fraction fo the dose which reaches systemic circulation intact (as opposed to reaching the portal circulation)
• = concentration following oral dose/ concentration following IV dose
• Measured
  ◦ Area under the concentration time curve (Dost’s law)

Question 74

What is the equation for bioavailability?

Answer 74

• the fraction fo the dose which reaches systemic circulation intact (as opposed to reaching the portal circulation)
• = concentration following oral dose/ concentration following IV dose
• Measured
  ◦ Area under the concentration time curve (Dost’s law)

Question 75

What factors alter the bioavailability of non oral routes? (buccal, rectal, vaginal)

Answer 75

◦ Mucosal blood flow - buccal, rectal and vaginal absorption
◦ Muscle and SC blood flow
‣ Typically reduced in shock,unless anaphylaxis when it is increased
◦ Tachypnoea - increased RR and higher tidal volumes may improve bioavailability of nebulised drugs and gaseous agents or decrease it in hypoponoea d
◦ Drug lipophilicity
◦ Factors affecting membrane penetration - e.g. molecular size, pKA
◦ PH of mucosal fluid

Question 76

What non liver metabolism occurs as a part of bioavailability 4

Answer 76

‣ Drug metabolism in the gut lumen by bacteria
‣ Metabolism in the gut wall -brush border enzymes
‣ Metabolism in the blood stream - plasma esterases
‣ Spontaneous drug degredation over time

Question 77

What are the two main factors in first pass metabolism affecting bioavailability? Explain how each work, factors which may increase or reduce their action, and explain the effect of high first pass clearance

Answer 77

◦ Hepatic blood flow - decreased in shock, and metabolism slowed proportionally particularly where enzymes non saturable and blood flow determines rate of metabolism
‣ Shunts - shock states with poor cardiac output and hepatic congestion portosystemic shunts may open allowing bypassing of first pass metabolism (cardiogenic shock)
◦ Hepatic enzyme activity - influenced by nutritional state, liver health, other medications acting as either inducers or inhibitors, cofactor concentrations, abolished completely in ischaemia
‣ Drugs with high hepatic excretion ratio - small change in liver enzymes have a small change in first pass metabolism but a LARGE clinically significant change in bioavailability
‣ Drug with low hepatic extraction ratio - change in liver enzyme activity leads to a proportional change in first pass metabolism, which may not change bioavailability by a significant degree
‣ Therefore high first pass clearance means
* greatest individual variability in plasma concentration e.g. verapamil, morphine, metoprolol, propranolol, nifedipine, hydralazine
* Greater difference between oral and IV doses
* Oral bioavailability more affected by drug interactions changing enzyme kinetics
* Portosystemic shunts will have a dramatic effect on bioavailability
* If toxic metabolites occur - oral dosing will increase the amount of these compared to IV

Question 78

What is bioequivalence

Answer 78

Bioequivalence - the extent and rates of absorption of drug from them are so similar there is likely to be no clinically important difference between effects (0.8 - 1.25)

Question 79

Define clearance

Answer 79

• The rate of irreversible elimination of a drug from systemic circulation (measured in volume cleared over time)

Question 80

Hepatic extraction ratio is?

Answer 80

• The proportion of drug cleared/irreversibly removed following one pass of blood flow through the liver

Question 81

What determines hepatic extraction ratio?

Answer 81

‣ Free fraction fo the drug
‣ Intrinsic clearance rate - ability of the liver to metabolise a drug in absence of restrictions due to drug delivery,blood flow or protein binding

Question 82

What si the heaptic clearance equation?

Answer 82

Question 83

How does intrinsic hepatic clearance related to actual hepatic clearance?

Answer 83

Question 84

What is the equation for intrinsic clearance hepatically?

Answer 84

Question 85

What si the Michalis menton constant?

Answer 85

Question 86

What is maximum hepatic clearance?

Answer 86

Hepatic blood flow

Question 87

Low intrinsic clearance drugs - e.g.? How would you describe their enzymes? How does flow affect extraction ratio? How does flow affect clearance? If concentrations are increased what occurs?

Answer 87

◦ Low intrinsic clearance drugs /enzymes capacity driven - highly saturatable metabolism e.g. ethanol and phenytoin
‣ Hepatic extraction ratio drops rapidly with increasing blood flow
‣ Hepatic clearance will not increase significantly with increasing blood flow
‣ Become non linear in their metabolism with increasing concentrations - in phenytoin and ethanols case zero order kinetics occur within commonly observed dose ranges
‣ E.g. diazepam, lorazepam, warfarin, phenytoin, carbamazepine, theophylline, methadone, rocuronium

Question 88

Hihg intrinsic clearance drugs e.g.? How does blood flow influence them? How does blood flow influence hepatic extraction ratio? examples

Answer 88

◦ High intrinsic clearance drugs/high extraction ratio
‣ Hepatic clearance will increase fairly linearly in proportion to blood flow
‣ Increasing the intrinsic clearance will have a diminishing effect on total hepatic clearance
‣ E.g. propofol, metoprolol, ketamine, morphine, lignocaine, propranolol,verapamil and GTN

Question 89

What are the 3 fates based on liver metabolisM

Answer 89

• Mechanisms
  ◦ High molecular weight compounds are excreted in bile e.g. steroid based muscle relaxants
  ‣ Hepatocytes secrete against a concentration gradient
  ◦ Metabolism to renally excreted metabolites
  ‣ E.g. Morphine
  ◦ Enterohepatic recirucaltion
  ‣ Drugs excreted in bile can be hydrlysed in the small bowel by bacteria and if lipid soluble then reabsorbed into portal circulation to the liver where a proportion passes to systemic circulation

Question 90

Describe phase 1 reactions - what type of reaction? Examples of the 3 types fo reactions? Synthetic reactions? Specific reactions? Performed by what enzymes? Where in the liver does it occur? What is the fate of these products

Answer 90

• Non synthetic, non specific reactions converting parent drug to a more polar metabolite by introducing or unmasking a functional group. Largely p450 enzyme reactions which are drug metabolising enzymes in the lipophilic endoplasmic reticulum of the liver named after their maximal absorption of light wavelength
  ◦ Oxidation (removal of electrons) -the most common and P450 driven —>hydroxylation of midazolam
  ◦ Reduction P450 driven e.g. GTN
  ◦ Hydrolysis - not P450 driven e.g. plasma cholinesterase metabolism of succinylcholine
• Phase 1 products are often inactive but may be modified or enhanced; if sufficiently polar they will be readily excreted but many require subsequent phase 2 reaction with endogenous substrate e.g. glucoronic acid to from a highly polar conjugate

Question 91

Phase 2 reactions in the liver - structurally what is done? Why? Are the products active or inactive? faster or slower than phase 1?

Answer 91

• Conjugation reactions or coupling synthetic reactions with endogenous substances to yield water soluble conjugates
  ◦ Can occur before phase 1 reactions, or phase 1 reaction may not occur at all
  ◦ In general products are inactive with some exceptions e.g. NSAIDs and morphine 6 glucoronide
  ◦ E.g. glucoronidation of morphine or propofol
  ◦ Generally faster than p450 reactions

Question 92

How does shock influence blood flow

Answer 92

Effect of shock and critical illness on hepatic blood flow
* Early sepsis - increased cardiac output and hepatic blood flow increased dramatically
* Late sepsis - hepatic blood flow decreases significantly
* Haemorrhage shock - hepatic blood flow decreases, half life of midazolam can be 150% of usual
* Cardiogenic shock - decreased CO and vasoconstriction decrease flow
* Medications
◦ Norepinephrine + epinephrine + dopamine high dose decrease hepatic blood flow
◦ Hydralazine, low dose dopamine, colonising, GTN, SNIP all increase hepatic blood flow

Question 93

How does liver function affect drug metabolism? (3)

Answer 93

• Effects of changes in synthetic function
  ◦ Liver synthesis plasma proteins - this influences the volume of distribution
  ‣ LOw plasma protein levels raise free drug levels (free fraction)
  ‣ Synergistic with concurrent decrease in liver blood flow and hepatic extraction ratio
  ◦ Plasma esterases and peptidases which usually metabolise certain drugs are liver produced
  ‣ Prolonged clearance may eventuate e.g. suxamethonium
• Effect of changes in secretory function
  ◦ Drugs and metabolites relying on biliary excretion will be retained and require dose adjustment
  ◦ Enterohepatic recirculation drugs will have decreased half lives due to failure of this process
  ◦ High bilirubin levels may displace drugs from albumin
  ◦ Decreased secretion of bile —> malabsorption
• Effects of portal hypertension
  ◦ Shunting and reduced first pass metabolism