ABCD - Pharmacology (theory)

Question 1

Explain the concept of pharmacokinetic modeling of single and multiple compartment models

Syllabus

Answer 1

A pharmacokinetic compartment is a mathematical concept which describes a space in the body which a drug appears to occupy. It does not necessarily correspond to any specific anatomical space or physiological volume.

The single compartment model:

• The drug administered instantly and completed disperses to every corner of the compartment and is homogenously distributed throughout the volume (of distribution - Vd)
• It is eliminated from this volume at a constant concentration-dependent rate
  
  • The rate of elimination is given by the rate constant for elimination, k (eg. If k = 0.5, then 50% of the drug is eliminated per unit time)
  • The clearance (Cl) of the drug from this single compartment is described by the equation (k x Vd)
• Highly hydrophilic drugs which are confined to body water have single compartment pharmacokinetics (eg. Aminoglycosides)

The two-compartment model:

• The drug administered disperses homogenously into the central compartment
• The drug diffuses in and out of the central and peripheral compartments until an equilibrium is reached (assuming that there is no elimination)
  
  • If the drug is being cleared from the central compartment at a concentration-dependent rate, the concentration/time graph will have two distinct phases of change in drug concentration:
    
    • Distribution phase - initial rapid decline in serum drug concentration
    • Elimination phase - slow decline in drug concentration, sustained by redistribution of drug from tissue stores

The three-compartment model:

• Three compartments (blood, lean tissues, fat)
• For a highly fat-soluble drug, a rapidly given bolus distributes rapidly into all tissues, however lean muscle contains little fat and is therefore a poor storage reservoir for the drug & drug is eliminated from this compartment at the same rate as blood
• The phases in the concentration/time graph are as follows:
  
  • Distribution - initial rapid decline in serum concentration. This phase ends with the concentrations reaching their peaks in the peripheral compartments
  • Elimination - period during which the main effect on drug concentration is elimination. This phase ends when the slow compartment concentration becomes higher than the blood concentration and the total clearance is slowed down by the gradual redistribution of the drug into the blood compartment
  • Terminal phase - elimination is slow as the concentration of drug in the central compartment is minimal. The major defining factor affecting drug concentration during this phase is the redistribution of stored drug out of the slow compartment.
• Mathematically, this model will produce a polyexponential graph, which can be described by equation attached

Representing the three-compartment model in a diagram:

• Ve = effect site
• Kinetics of distribution are usually described as Kxy, where x is the compartment from which the drug is distributing and y is the compartment to which the drug is going (ie - bolus from V1 to V2 is K12)

Question 2

Describe absorption and factors that will influence it

Syllabus

Answer 2

Absorption is the movement of a drug from its site of administration to the central compartment. Absorption may be oral, through the mucosa, transdermal, inhalational, intramuscular or subcutaneous.

• (Note: the characteristic feature of absorption is that the substance is taken up by a volume, in contrast to adsorption where the substance is deposited on a surface - eg. Eating a cake vs smooshing on face)

Bioavailability is the fraction of the dose which reaches the systemic circulation intact (and escapes first past elimination)

• ‘Absolute’ bioavailability compares one non-IV route with IV administration
• ‘Relative’ bioavailability compares one non-IV route or formulation with another
• It is measured using the area under the concentration-time curve (Dost’s Law) - “The ratio of the area beneath the blood level vs time curves after oral administration to that following intravenous administration of the same dose is a measure of the absorption of the drug administered”
  
  • Bioavailability = –> (absolute bioavailability)
  • Bioequivalence (clinical definition) - drugs are considered bioequivalent if the extents and rates of absorption of drug from them are so similar that there is likely no clinically important difference between their effects

FACTORS INFLUENCING ABSORPTION

Drug factors

• Concentration - large drug dose will be absorbed more rapidly because of the high concentration gradient
• Size
  
  • Molecule size - small molecule diffuse more easily
  • Particle size - smaller the particles, the greater the surface area from which the drug will be eluted
• pKa - weak acids and lipophilic drugs are better absorbed
• Tablet disintegration (for PO route) - will determine rate of dispersion

Site properties (route of administration)

• Oral (gastrointestinal)
  
  • Destructive effects of gastric acid
  • Gastric emptying & intestinal transit
    
    • Gastric emptying is the major determinant
    • Slow intestinal motility can ensure complete absorption (while rate of absorption may decrease as delivery of drug to absorptive surfaces is reduced)
  • Splanchnic perfusion
  • Surface area
    
    • Small intestinal SA can be decreased in gastroenteritis (denuded villi) or surgical short gut
  • Characteristics of the gut content (eg. Food - tetracyclines chelate intestinal calcium from milk & forms insoluble complex)
    
    • Emulsifying effect of bile is critical to the absorption of fat-soluble vitamins and minerals
  • Metabolism by gut organisms (they may either deactivate or activate drugs)
• Mucosal
  
  • Irritant effects
• Transdermal
  
  • Integrity of the dermis
  • Characteristics of the subcutaenous tissue
• Inhalational
  
  • Volatility of drug
  • Size of droplets/particles
• Injection (eg. IM)
  
  • Blood flow to site
  • Solubility of the drug in the interstitial fluid

Disease states - Shock

• Globally, cardiogenic/obstructive/haemorrhagic/septic shock will cause decreased perfusion to various administration sites and therefore decreased absorption
• Anaphylactic shock will cause increased perfusion + therefore increased absorption (although there may be decreased penetration of drug to absorption site for the inhalation route due to bronchospasm
• Effect on bioavailability - largely, bioavailability increases
  
  • First pass metabolism
    
    • Hepatic blood flow - decreases, which will decrease metabolism
    • Hepatic enzyme activity - may be downregulated (eg CYP enzymes in septic shock) or abolished completely (ischaemic hepatitis)
    • Shunts - portosystemic shunts may open, which allows drugs to bypass first pass metabolism
  • Already absorbed drugs
    
    • Decreased protein binding - drug binding proteins will have their production downregulated
    • Decrease plasma metabolism - plasma esterase and protease synthesis will be decreased leading to diminished clearance

Question 3

Describe factors influencing the distribution of drugs

Syllabus

Answer 3

Factors affecting Vd:

• Drug factors
  
  • Molecular size (larger molecules = harder to passively diffuse out of central compartment)
  • Molecular charge (High ionised = more likely to be trapped in central compartment)
  • pKa (degree of ionisation & therefore lipid solubility)
  • Lipid solubility
  • Water solubility
• Patient factors
  
  • pH - influences degree of ionisation according to pKa & influences degree of protein binding
  • Body water volume - dehydration will result in concentrated drug levels
  • Protein levels - lower protein = higher unbound drug fraction (may make Vd appear smaller if measuring free drug levels)
  • Displacement - drugs may be displaced by effects of pH or competition from other drugs/substances
  • Age - Body water content decreases & muscle mass decreases - shrinks Vd of water-soluble drugs and decreases tissue binding
  • Gender - Female Vd < male (due to total body water)
  • Oedema/ascites/effusions - increases Vd
• Measurement factors
  
  • Calculation factors
    
    • PK model - Vd can be different if using Vinitial, Vextrap, Varea or Vss
    • Free vs total drug - for highly protein bound drugs, total Vd will correspond to Vd of the binding protein rather than the drug itself
  • Apparatus factors
    
    • ECMO + dialysis tend to adsorb drugs in unpredictable fashion
    • Volume expansion in extracorporeal circuits

Question 4

Define volume of distribution and explain how it is calculated

Own question

Answer 4

Definition:

• An imaginary volume which relates plasma drug concentration to the concentration of drug at site of effect
• The apparent volume into which a drug disperses in order to produce the observed plasma concentration
• V(d) =
  
  • Also, V(d) =
• Volume of distribution calculated by administering dose, measuring plasma concentrations and plotting on logarithmic conc. vs time graph and extrapolating plasma conc. at time 0. V(d) can then be calculated by above equation
• Different V(d) values:
  
  • Vinitial - calculated by extrapolating line from plasma concentration measurements to time 0
    
    • Volume of initial dispersion of the drug (represents behaviour of the drug during the first rapid phase of distribution through the central compartment)
    • Generally determined by the degree of protein binding. Drugs with high protein binding will have larger Vinitial if measuring free drug levels
    • Use - if you know that the drug will have no protein binding, this can be used to calculate total blood volume (eg 53Cr labeled red cells)
  • Vextrap - calculated by extrapolating line from terminal elimination phase to time 0
    
    • Represents behaviour of the drug in tissues
    • Not a lot of clinical utility. Will likely give large overestimate of Vd (low plasma conc at time =0)
  • Varea - non-compartmental calculation of Vd.
    
    • Calculated by Varea = , where β = terminal elimination time constant, X = drug dose and AUC = area under concentration vs time curve
    • Pitfalls - will often underestimate the conc at time zero due to using the terminal elimination constant & therefore overestimate Vd
  • Vss - describes Vd when there is a stable drug concentration
    
    • Vss =
• As drug distributes around the body, (especially with IV administration), higher blood conc.s will reach highly perfused tissues earlier (eg. Brain) and slower perfused tissues later (eg. Skeletal +muscle tissue)
  
  • Eg. Diazepam + digoxin - have similar elimination rates, so plasma conc will be similar at various time points but IV diazepam effect is quicker as effect site is in highly perfused tissue (brain) vs digoxin (cardiac tissue)
  • Therefore if you want quick effect, can calculate a loading dose based on V(d) to achieve desired plasma conc by rearranging above equation:
    
    • dose = V(d) x desired plasma conc

Question 5

Outline the role of the liver in metabolism

Past question

Answer 5

• Liver metabolises drugs by uptake of drugs into hepatocytes from blood.
• Metabolism is dependant on 3 factors: blood flow (QH), strength of binding of drugs to proteins & the efficiency/rate at which hepatic enzymes can break down the drug when that drug is a substrate (Intrinsic clearance - CLint)
• 
  
  • Where CLH = Hepatic clearance; QH = Hepatic blood flow & EH = Hepatic extraction ratio
• But
• CLint can be further defined by:
  
  • the maximal rate at which an enzyme can convert a drug to a metabolite
  • Km - dissociation constant - ie, the lower the constant, the strong the binding of the drug to the enzyme which metabolises it)
• Combining the above 2 equations gives:
• This can be simplified by considering drugs that have a high hepatic extraction ratio (where CLint is high - ie. the efficiency of the hepatic enzymes to metabolise that drug are high).
  
  • In this case, if CLint >>> QH, then approaches and
  • Ie. For drugs that have high liver metabolism, hepatic clearance is determined by hepatic blood flow
  • Examples of these drugs include: GTN, verapamil, propranolol, lignocaine, morphine, ketamine, metoprolol, propofol
• In the case of drugs that have a low hepatic extraction ratio,
  
  • (If QH >>> CLint) then approaches QH and
  • Ie. For drugs that have low liver metabolism, hepatic clearance is determined by drug-protein binding affinity and the rate at which hepatic enzymes can metabolise the drug (intrinsic clearance)
  • Examples of these drugs include: diazepam, lorazepam, warfarin, phenytoin, carbamazepine, theophylline, methadone, rocuronium
• Disease states which alter QH
  
  • Sepsis - early sepsis (hyperdynamic) will increase QH, whereas late sepsis will decrease it
  • Haemorrhage and cardiogenic shock will decrease it
  • Ionotropes - vasoconstrictors like norad and adrenaline will decrease hepatic blood flow, while vasodilators like clonidine will increase it

First pass clearance:

• The extent to which a drug is removed by the liver during its first passage in the portal blood through the liver to the systemic circulation
• This is a combination of :
  
  • Metabolism by gut bacteria
  • Metabolism by intestinal brush border enzymes
  • Metabolism in the portal blood
  • Metabolism by liver enzymes
• Drugs with high first pass clearance will:
  
  • Have a greater difference between oral and IV doses
  • Have more significant changes in oral bioavailability with changes in hepatic enzyme kinetics

How changes in liver function will influence pharmacokinetics:

• Decreased synthetic function - decrease plasma protein synthesis will influence Vd/free drug levels.
  
  • Liver also synthesis plasma esterases and peptidases
• Changes to secretory function - drugs and metabolite which rely on biliary excretion will be retained
  
  • High bilirubin may result in displacement of drugs from albumin as it competes for binding sites
• Portal hypertension - leads to shunting of portal venous blood into systemic circulation (decreases first pass metabolism)

BIOTRANSFORMATION:

The liver plays an important role in the metabolism of most drugs. Most compounds are lipophilic or partially ionised and the liver converts them to hydrophilic substances that may be eliminated by the kidneys or in the bile

Biotransformation

• Phase I- increase hydrophilicity, products may be pharmacologically active
  
  • Oxidation (CYP450, smooth ER)
  • Reduction (reductase enzymes, cytoplasm)
  • Hydrolysis (hydroxylase enzymes, cytoplasm)
• Phase II- conjugation, increase polarity, occurs generally in the cytoplasm, usually inactive
  
  • Glucuronidation (glucuronosyl transferases, most common conjugation reaction)
  • Sulphation
  • Acetylation

Basic chemistry….

• Redox reactions
  
  • Oxidation: loss of electrons (or gain of oxygen) during a reaction by a molecule, atom or ion
  • Reduction: gain of electrons (or loss of oxygen)
• Hydrolysis: a molecule of water breaks one or more chemical bonds
• Conjugation: coupling the drug or its metabolites to another molecule
  
  • Glucuronidation: glucuronic acid, derived from cofactor UDP-glucuronic acid, is covalently linked to a substrate
  • Sulphation: addition of a sulfur (usually SO3) group
  • Acetylation: acetyl group added to an organic chemical compound, usually in place of a hydrogen atom

*Sites on drugs where conjugation reactions occur include carboxy (-COOH), hydroxy (-OH), amino (NH2) and thiol (-SH) groups

Question 6

Define Clearance and its calculation

Own question

Answer 6

• Definition: the volume of blood cleared of drug per unit time
  
  • Refers to the efficiency of irreversible elimination of a drug from the systemic circulation
• Clearance can be calculated wrt total body or a particular organ (eg. Kidney or liver)
  
  • Systemic clearance (Cls) = sum of all clearances
  • Renal clearance (Clr) = fraction of total clearance which is handled by the kidneys
  • Metabolic clearance (Clm) - fraction of total clearance which is the consequence of drug biotransformation, by whatever mechanisms
  • Hepatic clearance (ClH) - fraction of total clearance which is handled by the liver (biliary excretion or metabolism)
  • Intrinsic clearance (Clint) - the hepatic clearance a drug would have if it was not restricted by hepatic blood flow rate
  • Intrinsic unbound clearance (Cl’int) - the intrinsic clearance a drug would have in the absence of plasma protein binding
• Measured in L/hr or mL/min
• Cl (L/hr) =
  
  • In the case of a single dose, it can be measured by:
  • Cl (L/hr) =
    
    • Where AUC = area under curve of concentration vs time graph post single dose of drug
• This equation can be rearranged to determine maintenance dose rate:
  
  • Note: elimination rate can be calculated from the same formula (elimination = CL X plasma drug conc)
• Note: minimum clearance = 0, maximum clearance = blood flow rate to particular organ
• Elimination rate is distinct from clearance and refers to amount of drug removed from body (measured in mg/hour)
  
  • Refers to both removal of unchanged drug in urine/sweat/faeces etc & metabolised drug
  • Does not refer to elimination of metabolites or to drug which binds to tissue and rejoins plasma

Question 7

Describe renal clearance

Answer 7

Renal clearance:

• The magnitude of renal drug clearance is the sum of glomerular filtration and active excretion minus renal drug reabsorption
• Filtration
  
  • Factors affecting filtration:
    
    • Protein binding - glomerulus only filters unbound drug
    • Charge - negatively charged GBM theoretically repels negatively charged drugs
    • Size - molecules <30Angstroms are freely filtered at the glomerulus
    • Non-drug properties - renal disease, renal blood flow
• Secretion
  
  • Active transporters
    
    • Weak acid transporters (substrates eg: β-lactam antibiotics, frusemide, HCT, probenecid)
    • Weak base transporters (substrates: procainamide, ranitidine, trimethoprim, ethambutol)
    • Nucleoside transporters (substrates: ribavarin, gemcitabine)
    • P-glycoprotein transporters (substrates: digoxin, verapamil, cyclosporin)
  • These mechanisms are saturable - when there are multiple suitable substrates, they will compete with each other
  • The rate of clearance by secretion depends on renal blood flow
  • Molecules that are too large to be filtered may still be secreted. Protein bound drugs will not be cleared this way
• Reabsorption
  
  • Passive: if a drug becomes so significantly concentrated in the tubule, it sets up a gradient which favours the diffusion of drug back into tubular cells and back out into the blood
    
    • Therefore factors influencing reabsorption are: drug concentration, urine flow rate, urine pH, drug ionisation
  • Active: mainly happens in PCT.
    
    • Kidneys will attempt to reclaim organic acids, water soluble vitamins, ions and various metabolic substrates like lactate and glucose. Drugs with any molecular resemblance to these will be resorbed in a similar manner
• Metabolism of drugs by the kidneys
  
  • PCT contains enzymes which are capable of digestion (breaking down filtered peptides into proteins + amino acids)
• Adjustment in renal impairment (degree of dysfunction, dose adjustment & monitoring)
  
  • Degree of dysfunction - measure creatinine clearance (renal clearance of drugs is proportional to creatinine clearance, not matter the mechanism of elimination
  • Dose adjustment = non-renal clearance + (fraction of renal clearance x fraction of residual renal function). The loading dose does not need to be adjusted & maintenance dosing can be adjusted by reducing the regular dose, changing the dosing interval, or both
  • Monitoring of drugs levels - essential for drugs with narrow therapeutic index

Question 8

Explain the difference and the clinical relevance, between zero and first order kinetics. (60% marks) Give an example that is relevant to intensive care practice. (40% marks)

Past question

Answer 8

First order elimination kinetics:

• Definition: A constant fraction of drug in the body is eliminated per unit of time
• All enzymes and clearance mechanisms are working at well below their maximum capacity, and the rate of elimination is directly proportional to drug concentration. First order kinetics has a linear upslope on a concentration (x) vs elimination (y) graph.
• Eg. gentamicin

Zero order elimination kinetics:

• Definition: A constant amount of drug in the body is eliminated per unit of time
• Increasing the concentration will have no effect on elimination. This will look like a horizontal line on a conc vs elimination graph
• Eg. Alcohol (Km for alcohol dehydrogenase is very low)

Michaelis-Menten elimination kinetics:

• (Non-linear) kinetics
• At low concentrations, the kinetics are first order. Upon saturating the enzymes, higher concentrations will result in zero-order kinetics
• The maximum rate of reaction = Vmax; The concentration required to achieve 50% of the maximum rate is called Km.
• V = Where V = velocity (rate) of reaction & S = substrate (drug) concentration
• This has relevance to clinical pharmacology. Drugs which have a therapeutic concentration range in the steep part of this curve are said to have a narrow therapeutic range (i.e. the effective dose is not too far off the toxic dose). If relatively large changes in dose produce relatively small changes in the concentration , toxic levels will be difficult to achieve and the drug is said to have a broad therapeutic index.
• As a rough rule, if the drug concentration required to produce a useful effect is above Km, then the drug will have a narrow therapeutic index
• Eg. phenytoin

• Drugs with zero-order elimination have a variable half-life, whereas drugs with first-order elimination will have a fixed predictable half life.
• Zero-order elimination may be very slow in a large overdose
• Drugs with non-linear elimination kinetics and a narrow therapeutic index require frequent plasma concentration monitoring
• First-order elimination kinetics may be seen in normal therapeutic range (i.e the therapeutic range is well below Km ) but in overdose the drug may be cleared with zero-order kinetics.

Question 9

Define half-life, how it is calculated and what it is used for

Own question

Answer 9

HALF-LIFE

• The time taken for half of the drug to be eliminated by the body
• It is an exponential curve
• =
  
  • Ct = concentration of drug at time t; C0 = conc at time 0; k = elimination rate constant
  • At the first half life, Ct = 0.5 x C0 & solving for k gives:
    
    • k =
  • Half life is also a function of clearance (CL) and volume of distribution (V)
    
    • Substituting this into above equation gives:
    • k =
  • So, as volume of distribution increases, half life increases & as clearance increases, half life decreases
• In disease states, CL and V may move in the same direction, so half-life is not useful for determining duration of action of drug
• What half life is useful for:
  
  • Calculating elimination after a single dose of a drug
  • Calculating time to steady state with continuous dosing
    
    • It usually takes ~3-5 half lives to achieve approximate steady state
  • Determining frequency of dosing
    
    • To maintain plasma concentration within therapeutic range. For drugs with short half lives, sustained release preparations may be more useful as very frequent dosing can be impractical. In this setting, plasma concentration is determined by absorption more than elimination

Question 10

Explain the concepts of intravenous bolus and infusion kinetics. To describe the concepts of effect-site and context sensitive half time

Syllabus

Answer 10

Intravenous bolus + infusion:

• In regular doses, drug concentration achieves a steady state in steps, but plasma concentration reaches a point at which dose rate and clearance rates are equal after about 5 half-lives
• In first order kinetics, doubling the administered dose will lead to an increase in duration of action by one half-life
• Loading dose:
  
  • Rapidly achieves the peak concentration necessary to compete with clearance so that the desired effect is achieved and maintained sooner
  • Loading dose is calculated by multiplying the desired peak concentration by the volume of distribution of the drug.
  • If a drug has a high volume of distribution, the loading dose to achieve steady-state concentration may be impractically large
• Dosing interval - generally, for most drugs, the dosing interval is approximately one half-life

Effect site half-time:

• A substance with extensive tissue distribution, will reach peak concentration in different tissues at different times depending on rate of distribution to the tissue. This may result in different clinical effects at different times.

• The phase of distribution into the ‘clinically interesting’ compartment is known as effect site distribution, or distribution into the biophase (biologically active phase of distribution)
• The effect site is a virtual compartment which is in some way linked to the central compartment
  
  • As the movement of drugs between compartments is concentration driven, the rate of drug movement can be described as a first-order constant - ke0
• ke0 is calculated based on plasma concentrations and clinical effect. It reflects those drug properties that affect diffusability
• Equilibrium between the central compartment and effect-site compartment follows first-order kinetics, described by constant ke0. Using this constant, it is possible to generate a value for ke0 half-time or t1/2ke0
  
  • t1/2ke0 = 0.693/ke0
  • This value represents the time required for the effect-site compartment to reach 50% of the plasma concentration as an infusion of the drug is running to maintain a constant plasma concentration

• If a drug redistributes out of plasma to effect site quickly (ie. Lower t1/2ke0), this decreases time to peak effect and increases magnitude of peak effect for a given dose

Context sensitive half times:

• The time required for a 50% decrease in the central compartment drug concentration after drug administration has ceased, where the ‘context’ is the duration of an infusion that has maintained a steady state concentration in the central compartment
• It isnt a number, but a relationship of how long it will take for concentration to decrease by 50% as a function of the duration of infusion
  
  • Propofol approaches a maximum CSHT of ~20minutes but fentanyl can reach an excess of ~300minutes
• Determinants of context sensitive half time:
  
  • Volume of the central compartment
  • The rate of systemic clearance of the drug from the body

Question 11

Explain clinical drug monitoring with regard to peak and trough concentrations, minimum therapeutic concentration and toxicity

Syllabus

Answer 11

Characteristics of drugs which make therapeutic drug monitoring useful:

• Marked pharmacokinetic variability
• Therapeutic and adverse effects related to drug concentration
• Narrow therapeutic index
• Defined therapeutic concentration range
• Desired therapeutic effect difficult to monitor (eg. Lithium) or drug is being used prophylactically (to maintain the absence of a condition - eg. Seizures, manic episodes etc)

Timing of sample for monitoring:

• At the beginning of treatment, after steady state has been achieved
• After a dose adjustment has been made
• When factors affecting clearance have changed: eg. Pt develops renal failure, suspected drug interaction
• When treatment seems to be ineffective

Factors relevant to interpretation of drug levels:

• Pharmacokinetic factors:
  
  • Protein binding - total plasma drug level may not be reflective of drug activity (eg. Phenytoin in hypoalbuminaemia - drug is highly protein bound, so lower plasma levels may produce clinical effect)
  • Relationship of plasma concentration to effect site concentration - if drug penetrates variably and incompletely, it is difficult to relate serum levels to effect site levels (eg. Vancomycin in ventriculitis (CSF penetration low despite high plasma conc))
  • Factors which affect plasma concentration - Vd, tissue binding, sites of metabolism
  • Timing of sample in relation to dose - most drug levels are trough levels as it is the least variable point in the dosing regimen (drug concentration change the least over time)
• Pharmacodynamic factors:
  
  • Relationship of plasma concentration to clinical drug effect - in some cases there is no such relationship (eg. Levetiracetam)
    
    • Active metabolites makes this relationship more difficult
  • Individual variability in drug response - therapeutic effect in some individuals may be different than the reported therapeutic window
• Clinical/practical factors
  
  • Simplicity of assay
  • Convenience of sample collection
  • Cost and benefit of the assay

Other important points to remember wrt therapeutic drug monitoring:

• Therapeutic ranges are classified by monitoring effect and drug concentration in small groups of people - so the minimum therapeutic concentration does not ‘switch on’ the therapeutic effect - this is often a continuous spectrum

Question 12

Describe the pharmacokinetics of drugs in the epidural and subarachnoid space

Syllabus

Answer 12

Pharmacokinetics of epidural drug administration

• Administration - about 40mL of fluid can be injected into the epidural space
• Absorption
  
  • Can occur via 4 different routes:
    
    • Exit the intervertebral foramina to reach the paraspinous muscle space
    • Distribute into epidural fat
    • Diffuse into ligaments
    • Diffuse across the spinal meninges and into the CSF
  • Diffusion is the main influence on drug absorption - this will be dependent on properties in Fick’s law - eg. Concentration, surface area (largely determined by volume of infused drug), lipid solubility, protein binding
  • CSF flow and volume is important as it will affect the concentration gradient
• Distribution - systemic distribution follows a 2 compartment model (note: lung water tends to accumulate local anaesthetics due to its low pH)

Pharmacokinetics of subarachnoid drug administration

• Absorption
  
  • High CSF concentration is achieved rapidly, hence absorption into spinal tissue is very rapid
  • With fewer barriers to diffusion (no meninges), required dose is much smaller & onset is more rapid
  • Bypassing the BBB is much easier
  • Systemic absorption is slower - there is no rapid distribution phase (perfusion of subarachnoid space is less extensive & systemic distribution is slower)
  • Increased half life of particularly hydrophilic drugs
• Distribution
  
  • Baricity refers to the comparative density of spinal anaesthetic solution in comparison to CSF (density of solution divided by density of CSF, which is ~1.003mg/mL)
  • Isobaric solutions stay roughly at the level they are injected, while hyperbaric solutions sink

Metabolism (relevant to both)

• The meninges do not perform any major metabolic function & most of the dose enters the systemic circulation unchanged
• Metabolism is therefore dependent on the same pathways as other sites of administration

Question 13

Define and explain dose-effect relationships of drugs, including dose-response curves with reference to graded and quantal response

Syllabus

Answer 13

Graded and quantal response:

• Graded dose-response relationships demonstrate the response to a drug against its concentration
  
  • 4 main parameters describe a graded dose-response curve
    
    • Potency (EC50 - relates to a drugs’ affinity for its receptor)
    • Slope - shallow slope suggests greater chance of overlap between desired effects and side-effects. A slope which is too steep suggests that it will be difficult to achieve precise control of the effects
    • Maximum (Emax - max effect achievable by that drug)
    • Threshold dose - lowest dose at which a drug effect is seen. May be at the zero point but doesn’t have to be (There may be some baseline pre-drug effect eg. NA and arterial tone)

• Quantal dose-response relationships demonstrate the rate of an outcome occurring in a population against the drug dose. A quantal dose response is a defined drug effect which is either present or absent
  
  • “ordered” dose-response relationships describe a series of quantal relationships which are displayed on the same graph - where the increase in the dose of a drug produces a progression of effects which can each be set as the end-point of a quantal relationship (eg. Stages of anaesthesia)

• This graph describes the cumulative percentage of a population which can be expected to achieve a response at a given dose

Question 14

Define and explain dose-effect relationships of drugs, including dose-response curves with reference to therapeutic index

Syllabus

Answer 14

Therapeutic index:

• The median therapeutic dose (ED50) in quantal dose-response curves is the dose at which 50% of individuals exhibit the specified quantal effect.
  
  • It is entirely dependent on the definition of the quantal response
  • It does not necessarily represent a clinically relevant dose
• The median toxic dose (TD50) - the dose at which some clinically relevant toxic effect is reported in 50% of the tested population. This also depends on definition of toxic. Problems:
  
  • Toxicity may develop after years of post-marketing data (eg. Carcinogenesis)
  • Toxicity may be unrelated to dose
• The median lethal dose (LD50) - the dose required to produce a lethal effect in 50% of the population. Same as TD50, however the toxic effect is death. Note: the pharmacokinetics change the LD50 (eg phenytoin administered rapidly may be fatal, whereas the same dose administered slowly may have no toxic effects
• The therapeutic index is the ratio of the TD50 to the ED50 for some therapeutically relevant effect. It is a numeric measure of the selectivity of the drug for its desired effect - the larger the value, the safer the drug. However, it can misrepresent risk (slope of dose-response curves may be different)
• The therapeutic window (or range) is the dose range over which drug is effective and relatively non-toxic in most of the population

Question 15

Define and explain dose-effect relationships of drugs, including dose-response curves with reference to potency and efficacy, competitive and non-competitive antagonists & partial agonists, mixed agonist-antagonists and inverse agonists

Syllabus

Answer 15

Potency and efficacy:

• Potency is defined as the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect
  
  • Two drugs may have the same efficacy but one may achieve the effect at a lower dose
• Efficacy - the degree to which different agonists produce varying responses, even when occupying the same proportion of receptors
  
  • Efficacy can be expressed numerically - as a ratio of the drug’s maximal efficacy to the maximal efficacy of some known potent agonist (aka intrinsic activity or maximal agonist effect)

Competitive and non-competitive antagonists:

• Competitive antagonists - binding of antagonists precludes binding of the agonist (ie binding of the agonist and antagonist is mutually exclusive)
  
  • In the presence of a competitive antagonist, the Emax of the agonist is unaffected, but the potency is reduced
• Non-competitive antagonists - the antagonist opposes the action of the agonist but does so without competing with it for the binding site
  
  • An insurmountable antagonist reduces the Emax of the agnoist

Partial agonists, mixed agonist-antagonists and inverse agonists

• Agonists - a ligand that binds to a receptor and alters the receptor state resulting in a biological response
• An allosteric modulator is a ligand that increases or decreases the action of a primary or orthosteric agonist or antagonist by combining with a distinct site on the receptor macromolecule
• Full agonist - a drug which is capable of producing a maximum response that the target system is capable of
  
  • Spare receptors - refers to unbound receptors when a full agonist has produced the maximal effect on binding a fraction of the total receptor population. If these receptors were inactivated by an antagonist, the initial drug would still be able to produce the maximal effect, but at reduced potency
• Partial agonists - will never achieve the maximal response that the system is capable of because its efficacy is lower than that of a full agonist
• Inverse agonists - a ligand which, by binding to a receptor, produces the opposite of the effect which would be produced when an agonist binds to the same receptor. When given in the absence of any other drug, it will have the opposite effect to the normal expected effect of receptor activation
  
  • Inverse agonists are described as having negative efficacy. This is distinct to ‘neutral’ antagonists, which bind to the receptor and inactivate them (ie produce 0% response)

Question 16

Explain the concept of drug action with respect to receptor theory

Syllabus

Answer 16

Receptor theory:

• Drugs interact with receptors in a reversible manner to produce a change in the state of a receptor
• This interaction can be modeled mathematically and follows the Law of Mass Action
• The binding of drug and receptor determines the quantitative relationship between dose and effect
• Mutual affinity of drugs and receptors determines the selectivity of drug effects
• Competition of mutually exclusive molecules for the same receptors explains agonist, partial agonist and antagonist drug activity
• Occupancy theory describes the concept that the proportion of occupied receptors is related to the effect of the drug (eg. Full agonists with linear relationship)
• The operational model - extends occupancy theory by introducing a constant () as a measure of agonist efficacy (incoporates both tissue responsiveness and drug efficacy)
• The two state model - permits the possibility of ‘baseline activity’ (receptor activation in the absence of an agonist) & allows the existence of inverse agonists (eg. Activity of gated channels)
• The ternary model - incorporates post-receptor amplification of signal due to intracellular second messenger systems (eg. GPCR)

Question 17

Explain the concept of drug action with respect to enzyme interactions & physico-chemical interactions

Syllabus

Answer 17

Drug action:

• Drugs exert an effect on the body either by interacting with macromolecular structures in the body, or by changing the physical or chemical properties of the body
• Non-receptor mechanisms of drug action:
  
  • Change in the physical or chemical properties of the medium or solution (eg. Sodium bicarbonate or helium)
  • Change in the physical or chemical properties of another exogenous substance (eg. Sugammadex)
  • Action by physical properties of the drug itself
• Receptor mechanisms of drug action:
  
  • Direct effect by binding with a receptor
  • Indirect effect by binding with an acceptor (eg. By preventing the binding of another substance or displacing it from its usual binding site)
  • Modulation of receptor function (changing its function or affinity for its ligand without binding to an active site - eg benzos)
  • Acting as a substrate for a receptor
• Types of molecular receptor targets and signalling pathways
  
  • Interaction with cell membrane
  • Regulation of transmembrane protein activity
    
    • Ligand-gated/voltage-gated ion channel permability
    • Transmembrane transport protein activity
    • Regulation of transmembrane enzymes with intracellular signalling pathways
    • GPCR activity
  • Acting as a substrate for enzyme activity (eg. Oxygen, glucose)
  • Acting as a false substrate for an enzyme (methyldopa)
  • Regulation of enzyme activity
    
    • Intracellular enzymes (eg. Phosphodiesterase - milrinone)
    • Extracellular enzymes (eg. Acetylcholinesterase - neostigmine)
  • Interaction with intracellular nuclear macromolecules
    
    • Regulation of gene transcription (corticosteroids)
    • Interaction with genetic material (cisplatin)

Question 18

Explain receptor activity with regard to ionic fluxes, second messengers and G proteins

Syllabus

Answer 18

Ionic fluxes, second messengers and G proteins:

• Ion channels are pore-like transmembrane proteins which alter the local permeability of cell membrane to ions. They are generally fast acting
  
  • Ligand gated:
    
    • Binding of a ligand opens the pore. Without the presence of a ligand, the channel is closed (usually by some amino acid side-chains)
    • Ligand tends to bind to the extracellular domain of the channel (eg. Acetylcholine)
  • Second messenger regulated ion channels:
    
    • Also ‘ligand-gated’ but the ligand is a second messenger (eg channels that open in response to increase intracellular calcium or inositol triphosphate IP3)
  • Voltage-gated:
    
    • Undergo a conformational change when the transmembrane voltage difference reaches some threshold value
• Second messenger systems:
  
  • A second messenger is an intermediate molecule for an intracellular signal transduction cascade which is used to transmit and amplify the signal between an extracellular stimulus and an intracellular effector
  • Characteristics of these systems:
    
    • The ligand-receptor interaction often does not result in the direct activation of the intracellular effector
    • An intermediate molecule used to signal to the effector is synthesised or released in response to the receptor-ligand interaction and degraded afterwards. The rate of synthesis/degredation is tightly regulated to control the magnitude of response to receptor activation
    • The second messenger can act locally, or diffuse distally
  • Examples
    
    • Hydrophobic molecules (eg. DAG + phosphatidylinositols) - mostly work from intermembrane space
    • Hydrophilic molecules (eg. cAMP, cGMP, IP3) - diffuse freely into cytosol
    • Ions (eg. iCa2+, K+, Na+)
    • Gases (eg. NO, CO) which diffuse easily through lipid and water
    • Soluble proteins (Jak/STAT, NF-B)

• G-protein coupled receptors (GPCR)
  
  • Have 7 transmembrane regions & extracellular domain has the receptor
  • They are heterotrimeric (contain subunits)
  • When bound to GTP, these proteins become activated, (-GTP subunit dissociates) which then allows them to regulate the activity of second messenger systems and amplify the signal of receptor activation. The -GTP subunit can either activate or inhibit an effecctor protein, and thie effect depends on the type of -subunit
    
    • Gs proteins are stimulatory. These increase cAMP
    • Gi proteins are inhibitory. These inhibit adenylyl cyclase, reducing cAMP
    • Gq proteins have a variable effect. These:
      
      • Activate phospholipase C, which affects the production of IP3 (stimulates Ca2+ from the SR, affecting enzymatic function or causing membrane depolarisation) & DAG (activates protein kinase C, which has cell specific effects)

Question 19

Explain receptor activity with regard to nucleic acid synthesis, regulation of receptor number and activity & structural relationships for receptors and ligands

Syllabus

Answer 19

Nucleic acid synthesis

• Generally can be classified into steroids and non-steroid
  
  • Steroid receptors are generally present in the extranuclear cytoplasm where they are complexed with chaperone proteins. When an agonist binds them, they are transported into the nucleus where they exert their action
  • Nonsteroid receptors are generally found inside the nucelus as heterodimers (bound with other intranuclear receptors and transcription factors)
• Intranuclear receptors are activated by lipid soluble molecules to alter DNA and RNA expression
• Slow acting

Regulation of drug number and activity:

• Receptor regulation is a form of homeostatic control. Drugs or endogenous ligands binding to receptors produce a downstream effect. In most circumstances, this downstream effect triggers regulatory mechanisms which are designed to homeostatically respond to receptor activation (ie to dampen the response where it is exaggerated or amplify it where it is deficient)
• The mechanisms of regulation can be:
  
  • To increase/decrease the number of receptors
  • To increase/decrease the concentration of downstream secondary messenger molecules (eg. cAMP)

Structural relationships for receptors and ligands:

• Ligands and receptors are described as being ‘complimentary’ if their apposing surfaces interact in a ‘lock and key’ fashion.
• Types of bonding between receptors and ligands:
  
  • Van der Waals forces - weak attraction between polar molecules - become stronger as the molecules get closer, and weaker with increasing distance. Are most important for complimentary molecules (eg. Monoclonal antibodies)
  • Hydrophobic bonding - hydrophobic substances tend to clump together in hydrophilic solutions. This is because the hydrophilic forces are so strong that the hydrophobic molecule is pushed away & tends to clump to other hydrophobic molecules. There is no chemical bond that holds these molecules together (eg. Oil in water)
  • Hydrogen bonds - dipole-dipole interactions. This is how water molecules bond together - the hydrogen atom from one molecule is attracted to the negative end of the other (eg. H2O)
  • Electrostatic interactions - interactions between opposing charges
  • • interactions - aromatic ring ‘stacking’ - when one ring is relatively electron rich and one electron poor (eg DNA double helix)
  • Covalent bonding - electron sharing (eg.phenozybenzamine - potent alpha-1 antagonist)

Question 20

Classify and describe adverse drug reactions

Syllabus

Answer 20

An adverse drug reaction is a harmful or unintended response to a drug

Classification:

• Dose-related reactions
  
  • Adverse effects at either normal dose or overdose and may include extensions of the therapeutic effect (eg. Bleeding in heparin)
  • Includes toxic effects (eg. Serotonin syndrome)
  • Side effects (eg. Anticholinergic effects of tricyclics)
• Non-dose related reactions
  
  • Totally unrelated to dose (any exposure is enough to trigger a reaction) - eg. Allergic, anaphylactic, idiosyncratic (purpura/drug-induced SLE)
• Dose and time-related reactions
  
  • Related to dose accumulation or prolonged use (eg. Adrenal suppression with corticosteroids)
• Time related reactions
  
  • Occur due to prolonged use in a drug that doesn’t accumulate (eg.tardive dyskinesia after decades of typical antipsychotic use)
• Withdrawal reactions
  
  • Undesired effects of ceasing the drug (eg. Opiates, clonidine)
• Unexpected failure of therapy
  
  • Undesirable reduction in drug efficacy (eg. Clearance by dialysis/phasmapheresis, drug interactions, effect of critical illness)

Question 21

Classify and describe mechanisms of drug interaction

Syllabus

Answer 21

Pharmacokinetic interactions

• Absorption
  
  • Formation of insoluble complexes (eg.coadministration of bisphosphonates with calcium reduces bioavailability)
  • Inhibition of active transporters (eg. Inhibition of metformin uptake by repaglinide interference with organic cation transporter (OCT1)
  • Inhibition of efflux transporters (eg. Effect of verapamil on the P-glycoprotein efflux pump reduces the efflux of digoxin - ie. Concentration of digoxin increases)
• Distribution interactions
  
  • Competition for transport protein binding sites (eg. Phenytoin and valproate compete for the same protein binding sites, which tends to displace phenytoin)
• Metabolism interactions
  
  • Competition for the same CYP450 enzymes (eg. Ritonavir)
  • Inhibition or induction of metabolic enzymes
• Elimination
  
  • Competition for active transport (eg. Probenecid decreases active secretion of B-lactams and cephalosporins
  • Interference with solubility (eg. Increased ion trapping of salicylate in alkaline urine due to use of acetazolamide)

Pharmacodynamic interactions

• Receptor function
  
  • Homodynamic - binding to same receptor site (opioids and naloxone; ibuprofen and aspirin)
  • Allosteric modulation - binding to the same receptor but at different sites
  • Heterodynamic - binding to different receptors, but affecting the same second messenger system (antagonist effect of glucagon on cAMP effects of B-blockers
  • Second messenger effects - binding to different receptor/messenger systems but having effect on the same physiological process (eg. Synergistic effects of sedative agents on conscious state)
• Physiological control mechanism (eg. NSAIDs on local PGE2 synthesis in renal circ decreases glomerular perfusion and therefore increases renin secretion (antagonises antihypertensive effects of ACE-inhibitors
• Physiological effects - different receptor systems and physiological mechanisms, all acting on the same clinical effect (eg. GTN and norad)

Question 22

Describe alterations to drug response due to physiological change, with particular reference to neonates/infants

Syllabus

Answer 22

Neonates/infants:

Pharmacokinetics

• Absorption
  
  • Gastric pH is elevated in infants (pH ~4) (alters bioavailability of drugs) & delayed gastric emptying
  • Active and passive intestinal molecule transport is slow in the first four months of life
  • Cutaneous absorption and absorption by inhalation is more rapid
  • IM depot absorption is less rapid
• Distribution. Neonate bodies contain more water + less fat
  
  • Vd for water soluble drugs is greater & smaller for fat soluble drugs
  • Albumin and α1 glycoprotein levels are lower
  • BBB is immature and larger pore sizes (enhanced CNS penetration)
• Metabolism
  
  • Decreased expression of phase I metabolic enzymes
  • Variable expression of phase II enzymes
• Elimination
  
  • GFR is reduced in pre-term neonates
  • Active tubular secretion is immature at birth

Pharmacodynamics - specific points

• Decreased response to bronchodilators (?decrease in expression of beta-2receptors on bronchial mucosa)
• Hypoglycaemia occurs more readily
• CVS collapse occurs more precipitously
• QT prolongation occurs more readily

Question 23

Describe alterations to drug response due to physiological change, with particular reference to the elderly

Syllabus

Answer 23

Pharmacokinetics

• Absorption
  
  • Decreased gastric emptying
  • Diminished gastric acid secretion (also often on PPI) - most pronounced effect for drugs with enteric coating
  • Decreased active transport (due to loss of absorptive surface area & splanchnic blood flow
  • Variable transdermal and subcutaneous absorption (poor circulation, stratum corneum becomes more drug-impermeable)
• Distribution
  
  • Increased ratio of body fat to body water
  • Albumin decreases slightly but α1 glycoprotein levels are either maintained or increased
  • Decreased function of P-glycoprotein efflux pump leads to increased CNS penetration
• Metabolism
  
  • Diminished liver mass and metabolic capacity & decrease hepatic blood flow
  • Increased susceptibility to metabolic substrate depletion
• Elimination
  
  • Decreased renal function

Pharmacodynamics

• Increased sensitivity to toxic effects (impaired defences against side effects)
• Decreased homeostatic mechanisms (eg. Postural hypotension with vasodilators)
• Altered receptor sensitivity

Question 24

Describe alterations to drug response due to physiological change, with particular reference to pregnancy

Syllabus

Answer 24

Pharmacokinetics

• Absorption
  
  • Delayed gastric emptying, decreased gastric acid production, delayed intestinal motility
  • The above factors may be offset somewhat by increase CO and intestinal blood flow
• Distribution
  
  • Increased total body water and body fat with decreased serum protein
  • Increased Vd, increased tissue deposition + increase free fraction due to decreased protein binding (largely theoretical)
  • Engorgement of peridural venous structures results in displacement of CSF out of the spinal canal - decreased spinal doses needed
• Metabolism
  
  • Variable and unpredictable
  • Hepatic blood flow decreases (as proportion of CO), synthesis of enzymes decreases, induction of some hepatic enzymes can increase the rate of metabolism for certain drugs, also some metabolic activity in placenta
• Elimination
  
  • Renal clearance increases mainly due to increased GFR but reabsorption also increases so net effect is unpredictable

Pharmacodynamics

Pregnant women are more sensitive to:

• Volatile and IV anaesthetics (thiopentone >propofol)
• Local anaesthetics

Question 25

Describe alterations to drug response due to physiological change, with particular reference to obesity

Syllabus

Answer 25

Pharmacokinetics

• Absorption
  
  • Tend to have increased gastric emptying.
  • Variable effects of bariatric surgery
  • Transdermal and subcutaneous absorption will be decreased (subcutaneous fat expands in volume without significantly increased vascularity
• Distribution
  
  • Increased Vd for lipid soluble drugs
  • Increased fluid volume due to chronic RAAS activation - increase Vd for water soluble drugs
• Metabolism
  
  • Impaired intrinsic clearance due to fatty liver disease
  • Can get enhanced hepatic metabolism due to increased enzyme activity and increased clearance due to increased hepatic blood flow
  • Increased extrahepatic metabolism (increased doses of suxamethonium needed in obese individuals - in proportion to total body weight instead of predicted lean body weight)
• Elimination
  
  • Increased half-life of lipid soluble drugs
  • Increased clearance rate due to increased GFR + enhanced tubular secretion. But, may have decreased clearnace due to coexisting nephropathy

Pharmacodynamics

• May have increased or decreased dose response
  
  • Relative resistance to effects of insulin, oral contraceptives, verapamil, atracurium
  • Relative sensitivity to opiates (in morbid obesity with sleep apnoea)

Question 26

Describe alterations to drug response due to pathological disturbance with particular reference to cardiac and respiratory disease

Syllabus

Answer 26

Cardiac disease:

Effect on pharmacokinetics:

• Absorption - Decrease CO decreases oral, GI, IM and SC absorption and affects intravenous availability (prolongs arm–>brain circulation time)
• Distribution - Vd may increase (eg - fluid overload) or decrease (haemorrhagic shock)
• Metabolism - low CO reduces blood flow to clearance organs - most affected are drugs with a high extraction ratio
• Elimination - decrease flow to organs of elimination will decrease elimination

Pharmacodynamics:

• CV disease increases susceptibility to adverse effects (eg. QT prolongation, or hypotension from induction agents)
• Chronic HTN dampens clinical response to routine doses of antihypertensives
• Worsening CCF narrows the therapeutic windows for B-blockers and Ca-channels blockers
• Maximal effect of diuretics is blunted by poor renal blood flow due to poor CO

Respiratory disease:

Effect on PK:

• Absorption - inhaled route ineffective if patient apnoeic & poor respiratory function (eg. COPD) will result in decreased delivery of aerosolised particles
• Metabolism - respiratory metabolism of many drugs (LAs, opioids, propranolol) decreased when lung is diseased
• Elimination - eg. Of volatile anaesthetics impossible if patients apnoeic

Effect on PD:

• Increased propensity to hypoxia
• Hypercapnia produces narcosis - additive with other sedative agents
• Chronic exposure to B-agonists (eg. In chronic asthma, may give rise to tolerance)

Question 27

Describe alterations to drug response due to pathological disturbance with particular reference to renal and hepatic disease

Syllabus

Answer 27

Renal disease:

Effect on PK:

• Absorption - decreases bioavailability by decreasing intestinal motility and by decreasing the activity of active transport proteins such as Pgp
• Distribution - Fluid overload may increase the volume of distribution of drugs. Competition for protein binding sites with uraemic toxins and the effect of those toxins on protein structure leads to increase in the free fraction
• Metabolism - Renal failure affect CYP-mediated metabolism of drugs - production of CYP 450 enzymes is decreased (thought to be PTH + cytokine mediated). Renal metabolism of drugs sometimes contributes significantly (eg. Kidneys responsible for degradation of 70% of insulin)
• Elimination - renal clearance of drugs will be affected

Effect on PD:

• Chronic adaptation to renal failure may dampen the response to drugs via indirect mechanisms (eg. Making the pt more resistant to effect of antihypertensives by activating the renin-angiotensin-aldosterone axis
• Tubular pathology can lead to a decreased sensitivity of tubular cells to drugs which target them (ie larger doses of diuretics may be needed)
• Decreased elimination of drugs may give rise to increased pharmacodynamic effect (eg. Vancomycin)

Hepatic disease:

Effect on PK:

• Absorption - High portal venous pressures may impair gastrointestinal blood flow and decrease absorption
• Distribution - decreased protein production will lead to decreased protein binding and increased free fraction of drug. Fluid overload alter the volume of distribution
• Metabolism - decrease in rate metabolism due to loss of hepatic enzymes & circulating enzymes (eg. Plasma esterases) which are synthesised in the liver. Presence of portosystemic shunts results in some fraction of drug bypassing the hepatic clearance systems
• Elimination - biliary excretion of drugs will be impaired if CBD blocked; hepatic parenchymal and canalicular disease will decrease active transport of drugs into bile

Effect on PD:

• Decreased synthetic function can decrease the synthesis of drug targets (eg clotting factors)
• Decreased need for anaesthetic agents in hepatic encephalopathy
• Chronic sympathetic activation tends to dampen the response to B-antagonists (decrease receptor sensitivity)

Question 28

Define tolerance and outline mechanisms of tolerance

Syllabus

Answer 28

Tolerance is the requirement of higher doses of a drug to produce a given response

Mechanisms of tolerance:

• Pharmacokinetic tolerance - persistent exposure makes drug clearance mechanisms more active; classically by induction of metabolic enzymes (eg. Effect of ethanol on CYP450 enzymes)
• Pharmacodynamic tolerance - persistent exposure to the drug produces and adaptive homeostatic response that results in a decreased pharmacological effect
  
  • Receptor downregulation - receptors are inactivated or endocytosed in response to sustained stimulation
  • Receptor deactivation - receptor protein is phosphorylated in response to excess stimulus (eg. Nicotine and nicotinic receptor)
  • Receptor subunit modification - modified receptor complex is selectively expressed, with diminished selectivity for the drug but maintained sensitivity for the endogenous ligand (eg. GABA-A receptor and benzodiazepines)
  • Second messenger systems - deactivation of post receptor second messenger systems (eg. B-agonists)
  • Drug target depletion - some key molecule is used up in the drug action. Subsequent drug dosing will have diminished effect until the key molecule is regenerated (eg noradrenaline depletion due to ephedrine therapy)
• Physiological tolerance - tolerance to the effects of the drug rather than to the drug itself at the receptor level. Physiological adaptive mechanisms may maintain homeostasis. Eg. Vasodilator antihypertensives may be offset by increased heart rate and CO, which maintains BP
• Learned/behavioural tolerance - the development of learned behavioural adjustments that compensate for the drug’s effects
• Others:
  
  • Sensitisation - “reverse tolerance” - subsequent dosing increases the drug effect (eg. Amphetamines)
  • Cross-tolerance - development of tolerance to multiple drugs belonging to the same class, after exposure to only one of them (eg. Nitrates)

Question 29

Define tachyphylaxis, addiction and dependence

Syllabus

Answer 29

Tachyphylaxis

• Rapid decrease in response to repeated doses over a short time period. It features:
  
  • Repeat administration with diminished physiological effect
  • Develops over a short period of time
  • Not dose-dependent - giving larger doses may not restore the maximum effect
  • Rate sensitive (requires frequent dosing)

Addiction:

• A maladaptive pattern of substance use leading to clinically significant impairment or distress. Some features of addiction:
  
  • Involves a behavioural change
  • Preoccupation with using the drug
  • Engaging in behaviour results in satiation or relief
  • Loss of control (impulsiveness, compulsion)
  • Perseverance of behaviour despite negative consequences

Dependence:

• Progressive pharmacological adaptation to a drug. It is:
  
  • Distinct from addiction
  • Requires tolerance to develop
  • Results in a withdrawal syndrome

Question 30

Syllabus

Define drug idiosynacrasy

Answer 30

Drug idiosyncrasy

• An abnormal reactivity to a chemical that is peculiar to a given individual. It could be:
  
  • Abnormally exaggerated response or abnormal lack of response
  • An extension of the normal physiological drug effect
  • A reaction which is unrelated to the expected physiological effect
• Reaction does not seem to be related to dose
• Syndromes of idiosyncrasy:
  
  • Stevens-Johnsons syndrome (SJS) & toxic epidermal necrolysis (TEN)
    
    • Drugs associated: phenytoin, sulfonamides, allopurinol, NSAIDs, B-lactams
    • Features: target lesions, epidermal necrosis and detachment, mucous membrane erosions
  • Serum sickness-like reaction
    
    • Drugs associated: cefaclor, cefprozil
    • Features: fevers, rash, arthralgia, eosinophilia
  • Drug induced lupus
  • Drug induced hepatitis
  • Aplastic anaemia, agranulocytosis
    
    • Drugs: chloramphenicol, dapsone, clozapine, carbimazole
    • Features: can be selective (eg. Neutropenia) or affecting multiple cell lineages

Question 31

Explain the concept of Pharmacogenetics

(Own question)

Answer 31

Pharmacogenetics is the study of variability in drug response due to heredity. It exerts its influence on drug response by influencing:
* Absorption eg. mutations of intestinal trasnport porteins
* Distribution eg. mutatiosn of carrier proteins such as α1-acid glycoprotei
* Metabolism eg. mutations of CYP enzymes
* Elimination eg. mutations of tubular transport proteins
* Pharmacodynamics eg. polymorphisms in the drug target or in downstrream regulator mechansisms

Variability in drug response is in part due to the genetic polymorphism of the human species, which is common, and important in determining an individuals’ susceptibility to adverse drug reactions

Question 32

Explain the mechanisms and significance of pharmacogenetic disorders (e.g. malignant hyperthermia, porphyria, atypical cholinesterase and disturbance of cytochrome function

syllabus

Answer 32

Specific pharmacogenetic disorders:
* Malignant hyperthermia - mutation of the ryanodine calcium channel receptor which causes a hypermetabolic crisis in response to volatile anaesthetics
○ incidence 1:5,000 - 1:50,000
○ Initial - tachycardia, masseter spasm, hypercapnoea, arrhythmia
○ Intermediate - hyperthermia, sweating, combined metabolic and respiratory acidosis, hyperkalaemia, muscle rigidity
○ Late - rhabdomyolosis, coagulopathy, cardiac arrest
○ Mx: Cease volatile, start TIVA, give dantrolene 2.5mg/kg increments to 10mg/kg, Rx of complications
* Porphyria, a mutation of haem synthesis enzymes which causes a build-up of neurotoxic intermediate metabolites (porphyrin precursors) in response to various drugs (anticonvulsants, antibiotics, thiopentone)
○ Autosomal dominant
* Atypical plasma cholinesterase, which fails to metabolise suxamethonium and causes “sux apnoea”
○ Congenital - autosomal recessive
○ Acquired - due to loss of plasma cholinesterase. Can occur in pregnancy, organ failure (hepatic, renal, cardiac), malnutrition, hyperthyroidism, burns, malignancy, drugs (OCP, ketamine, lignocaine and ester Las, metoclopramide, lithium)
○ Measured by dibucaine number. Dibucaine is an amide LA, which inhibits plasma cholinesterase. Greater inhibition indicates a less severe mutation - so normal:normal dibucaine no = 80 (80% inhibited). Dibucaine resistant:resistant has a no of 20 (20% inhibited)
○ Note: acquired disease will have normal dibucaine no but just decreased quantity of enzyme
* G6PD deficiency, a mutation of glucose 6-phosphate dehydrogenase which produces acute haemolysis in response to oxidative stress due to dapsone, methylene blue, fluoroquinolones, antimalarialas and rasburicase

Question 33

Describe and give examples of the clinical importance of isomerism

(Syllabus)

Answer 33

Isomer molecules have the same formula but different molecular structure

Clinical relevance of enantiomerism:
- Pharmaceutics
○ The manufacture of enantiopure drugs is more expensive. Approximately 1 in every 4 drugs currently on the market is a racemic mixture, often because of this factor.
- Pharmacokinetics:
○ Dose decrease is possible by creating enantiopure drugs
○ Absorption - passive remains unchanged, but active transport may favour one drug over another. (L-dopa absorbed more rapidly than D-dopa)
○ Stereoselectivity of first pass enzymes (eg. More active L-verapamil is cleared 2-3x more than D-verapamil), clearance mechanisms and protein binding
- Pharmacodynamics:
○ Enantiomer-receptor interactions - active/partially active/inactive/antagonistic drugs
○ Enantiomer-enantiomer interactions - they will often compete for the same protein binding sites (ie inactive enantiomer will displace the active drug, making it more available

Enantiomer pair members which have a significantly different clinical effect:
- Thalidomide (only one of the enantiomers is teratogenic, but the non-teratogenic one ends up being converted into the other enantiomer in-vivo, making the overall drug effect racemic)
- Ethambutal, of which only the S,S-enantiomer is effective against tuberculosis (whereas the R,R-enantiomer is effective against your eyesight)
- Propanolol, both enantiomers of which have some local anaesthetic effect but only one (L-propanolol) is an effective β-blocker
- Carvedilol, of which only the S-enantiomer is highly effective as a β-blocker (but both enantiomers block α-receptors)
- Labetalol, which has two chiral carbons and therefore four stereoisomers (Riva et al, 1991), of which one is a potent non-selective β-blocker and another is a potent alpha-antagonist.
- Methamphetamine, of which the dextroenantiomer has CNS activity whereas the levoenantiomer is a totally benign peripherally active vasoconstricttor, used as a nasal decongestant
- Ketamine, of which the S-ketamine enantiomer has a more potent dissociative activity