Pomb Pharmacology

Clearance

• Pharmacology: the study of how dosage of a drug links to its effect. This can be divided into two categories:
- Pharmacokinetics: study of dose to concentration, which involves properties such as clearance and volume of distribution
- Pharmacodynamics: study of concentration to effect with two important parameters E¬max and EC50
• Clearance: clearance is a measure of the relationship between concentration and rate of elimination of the drug, i.e. the tendency/ability of a drug to be expelled from the body.

Rate Out = CL × Conc where Rate Out (mg/h), CL (L/h), Conc (mg/L)

- Driving force of elimination is concentration of the drug
- Maintenance dose: the dose that is required to maintain the drug concentration in the body at the target level. This will occur when the rate of drug intake equilibrate with the rate of drug clearance. Thus maintenance dose is simply elimination rate.
• Physiological factors of clearance:
- Blood flow: increased blood delivered to an organ will increase clearance however clearance will never exceed the rate of blood.
- Number of clearing organs: elimination of kidney/liver
- Extraction from blood: fraction of drug concentration removed to be processed by an organ
- Metabolic rate: speed at which the drug is broken down
- Pathologies: thrombosis etc
• Blood flow factor:
- Liver: the largest single organs responsible with an upper limit of blood flow around 90L/h/70kg. Mechanism of clearance is enzyme degradation and bile secretion. The latter is inefficient as drug bile maybe absorbed in gut.
- Kidney: upper limit blood flow of 70L/h/70kg. Only few drug clearances are at this rate. Mechanisms are glomerulus filtration and tubular secretion. Filtration limit is that of the GFR which is 6L/h/70kg but most drugs are reabsorbed by either passive diffusion of active uptake (polar molecules less likely). Tubular secretion is variable, examples include weak acid penicillin.
• Metabolic rate factor: drugs such as glyceryl trinitrate (treat angina) is very unstable and breaks down rapidly in many tissues of the body (clearance also not limited by blood flow), yielding a clearance of 150L/h. Morphine is metabolized extensively through the liver at a slower rate limited by blood flow so 60L/h
• Number of clearing organ factor: gentamicin is eliminated mainly by kidney so have clearance of 6L/h while digoxin is cleared by both kidney and liver so have a higher clearance of 9L/h.
• Extraction fraction factor:
- Small fraction: theophylline extraction in liver is minute while renal elimination is negligible giving clearance of 3L/h
- Very small fraction: warfarin is even slower with only 3L/day
• Clearance classification: drugs can have more than one classification
- Constant: first order whereby clearance is independent of any factors such as organ blood flow and dose.
- Concentration dependent: mixed order where clearance is dependent on concentration of drug in blood
- Flow dependent: organ specific clearance relies on the blood flow
• Concentration dependent clearance:

- At low concentrations, CL = Vmax/Km and elimination will be dependent on concentration (more useful for dosing approximations)
- At high concentrations, rate of elimination will be equal to Vmax as the enzyme saturates and is no longer dependent on concentration
- Concentration in between high and low values will have mixed properties
- In reality all drugs are mixed ordered and true zero order does not occur (only approximated at high doses)
• Glomerular filtration: first-order process
• Concentration dependent: have features of non-linear and michaelis-menten. Renal tubular secretion of penicillin is saturable and is mixed order. Phenytoin is saturable at doses close to those used clinically.
• Flow dependent: flow dependent clearances are usually associated with elimination by the liver. Morphine is an example as when it is given to patients with heart failure, the reduced blood flow means relatively low clearance so maintenance dose is reduced.
• Applications:
- Calculation of maintenance dose rate
- Calculate half-life
- Understanding artificial elimination processes
• Artificial elimination processes:
- Haemodialysis: relatively low so similar to that of real kidney (4L/h for theophylline), used for renal failure
- Haemoperfusion: passing blood from the artery through cartridge designed to adsorb the drug and is double that of haemodialysis (9L/h for theophylline)
- Gut adsorption: swallowing charcoal which binds to drug in the gut to prevent primary adsorption and further causing drugs to diffuse out. This can double clearance for theophylline

Volume of Distribution

• Volume of distribution: relationship between concentration and the amount of drugs in the body, i.e. the apparent volume of the body that have the drug.

Amount = Vd × Conc where Vd (L) and Conc (mg/L)

• Loading dose: the initial dose given to the patient to achieve a target concentration. This requires the knowledge of volume of distribution
- Example: theophylline requires a 10mg/L effective concentration. If the volume distribution is 35L then, the loading dose will be 35×10 = 350mg
• Physical compartments: 3 commonly recognized volumes
- Vascular: volume for large molecules and blood components which split into total blood volume (5L) and plasma volume (2.5L)
- Extracellular: volume for molecules that can leave vascular space but do not cross cell membranes, e.g. highly ionized molecules (18L)
- Total body water: volume for molecules that can cross cell membrane and share the same apparent volume as water distribution (35L)
• Effect of binding: volume of distribution is not restricted to these three compartments but can bind to tissues, proteins or partition into fat and bones. This can either increase or decrease the apparent volume
• Sponge model: drugs such as digoxin binds extensively to Na+/K+ ATPase, an enzyme present in all cells especially in muscles, nerves, and kidneys. As a result when plasma concentration of digoxin is measured, it would be much lower than if it is uniformly distribution
- Example: binding of drugs by receptors means digoxin concentration is plasma is only around 1mg/L so with same dose of 350mg will produce a volume of distribution of 350L.
• Red herring model: drugs can also bind to plasma proteins such as albumin (by warfarin) or alpha1-acid-glycoprotein (by lignocaine). As a result, distribution of drug in plasma would be much higher giving an falsely low volume of distribution when examined.
- Example: the concentration of the drug is 100mg/L so same dose of 350mg would only produce a volume of distribution of 3.5L
• Warfarin: 99% of warfarin is bounded to plasma proteins with only 1% unbound. Thus as a result, depending on which drug state is measured, apparent volume for unbounded warfarin would be 100 times that of the total warfarin.
- Ideally unbounded form is preferable
- However if the binding fraction remains constant, either way would not matter
• Indications: overall small volumes are indicative of drug binding while bigger volumes are due to unbound.
• Effect of plasma proteins: plasma proteins is only a small part of tissues that bind drug in the body, the effect on unbound drug concentration is negligible even if displacement occurs.
- For warfarin, plasma is around 25% of distribution volume. Only 10% of the protein can be displaced giving an increase in 2.5% in unbounded amount, which is very minute
• Partition: distribution into spaces
- Fat: lipophilic drugs such as thiopentone partition into fat which increase the volume of distribution in obese people. While hydrophilic drugs will have no effect
- Bone: drugs adsorb to bone such as tetracycline and bisphophonates will also have relatively large volumes of distribution
• Range of volume of distributions:
- Tiny: warfarin, binds to plasma proteins
- Small: gentamicin, does not bind but highly ionized so distributed in the ECF fluid. The apparent volume is very close to that of the ECF
- Medium: theophylline, not polar so can cross cell membranes so have apparent volume of distribution very close to total body water
- Large: digoxin, binds to receptors
• Pharmakinetic compartment: volume of distribution for drugs at a particular point in time
- Apparent central compartment volume: the initial distribution space after drug intake (approximated by the ECF volume as drugs diffuse rapidly into this compartment)
- Apparent tissue compartment volume: the later distribution space after sufficient time has passed. This is called the steady state volume and is usually greater than the initial volume
• Distribution rates: time course of distribution varies with each drugs
- Minutes: thiopentone, an intravenous rapid anaesthetic, distribute rapidly to the brain then to the rest of the tissue in the body which losses the effect
- Hours: digoxin binding is slow and takes hours to ready steady state value
- Days: lithium poison is very slow, similar to sodium exchange.

Absorption and Half-life

• Absorption: uptake of drugs into the body
- Extent: total amount of drugs entering the body not dependent on time
- Rate: speed of entrance (changes with time)
• Fraction absorption: fraction of drug absorbed across the gut wall and passes into the portal venous system.
- Small unionized molecule such as theophylline are absorbed almost 100% while large ionized molecules like gentamicin cross membranes with difficulty (<5% is absorbed)
- Drugs that cross the luminal cells can be metabolized in the gut wall (simvastatin), typically by CYP3A4 or transported back into the lumen (digoxin), e.g. P-glyco-protein removes 30%.
• First pass extraction: fraction of drug extracted from the blood into the liver.
- Higher metabolizing capacity of the hepatic enzymes would be able to metabolize almost all drugs that pass through, giving a higher hepatic extraction ratio.
- Morphine has high intrinsic hepatic clearance with around 60% removed after an oral dose.
- Ethanol conversely have variable extraction rate ranging from 10% to 70%. This is because extraction is sensitive to rate of delivery and absorptions, i.e. ethanol absorption will be slowed by food
• Hepatic extraction: this is affected by
- Blood flow: low blood flow gives plenty of time for drugs to be extracted
- Intrinsic clearance: low clearance will mean less drug is metabolized per unit of time
• Bioavailability: the overall extent of absorption measured by combining both gut absorption and hepatic extraction. It represents the availability of the drug in the body.

F = f × (1-ER)

• Input methods: three types of drug absorption method
- Bolus: instantaneous delivery approximated by rapid intra-venous injection. Used in cardiovascular collapse and adrenaline is sent to heart
- Zero-order: absorption rate is constant for a defined period of time through constant rate of intra0-venous infusion.
- First order: absorption rate is proportional to amount of drug at the absorption site, i.e. rate would be higher at initial dose.
• Zero-order properties: key parameter is the duration
- Physiology control: absorption through the small intestine is very rapid hence the rate limiting step is the gastric emptying of the drugs dissolved in the stomach. Gastric emptying usually occurs at a constant rate so behaves like a constant rate infusion.
- Pharmaceutical control: drugs can also be formulated to dissolve and be released very slowly as a rate limiting step.
• First order properties: direct absorption through the gut wall
- Intestinal absorption: proportionality constant (KA) relating drug amount at the site of absorption to rate of absorption. The constant also corresponds exactly to the half-life of the absorption process (ln2×KA).
- Absorption after 4 half lives is above 90% and considered to be complete
• Applications:
- IV/Oral dose conversion: intravenous dose is divided by F to get the equivalent oral dose.
- Time to peak concentration/effect: rate of drugs absorption in conjunction with elimination can be used to predict the time (Tmax) of peak concentration (Cmax)/effect for a drug.
- Substitution of generic medicines: using rate (Cmax and Tmax) and extent of absorption (area under curve) to judge whether a generic drug is bioequivalent to the originator product
• Half-life: used to describe the time course of first order exponential functions.
- Accumulation half lives: identical to elimination half lives which is used to describe how fast a drug accumulates.
- Half-life is calculated from
• Accumulation: when a drug is administered by constant rate infusion, it will accumulate 50% after 1 half life as the other 50% is eliminated. After 2 half lives, 75% of max will be reached while 75% is eliminated. Eventually a point is reached where constant infusion is equal to constant elimination producing the steady state.
• Accumulation factor: ratio of the concentration at steady state to concentration after the first dose at the same time after the dose:

- Accumulation factor of 1 would mean infinite dosing interval, i.e. infinite time after initial dose would mean all drug will be eliminated. So another dose would give the same concentration as the first dose producing an accumulation factor of 1 (no change)
• Applications:
- Absorption: absorption half-life can be used to predict time of peak concentration as it occurs when drug absorption is equal to drug elimination. Approximately 3 half-lives.
- Elimination: helps predict time to steady state and elimination. Drug elimination is similar in time course to drug accumulation with approximately 4 half-lives.

Drug Metabolism

• Biotransformation: metabolic steps that converts drug from one form to another
- Act as major route of drug elimination
- Activate and deactivate drugs
- Can produce toxic products
- Sources of patient variability
- Reasons for certain drug-drug interaction
• Two phases:
- Phase I: the drug is oxidised into an inactive intermediate. The major enzyme responsible is cytochrome P450.
- Phase II: the inactive intermediate is solubilised by adding a polar functional group. The step is termed conjugation and performed by transferase enzymes such as glucuronyl, suphate, acetate.
• Cytochrome P450: over 70% of drugs are metabolized by this enzymes. Located in liver and gut wall.
- CYP1,2,3: drugs
- CYP4,5,8: fatty acids, prostaglandins
- CYP7,11,17,21,24,27: steroids
• Mechanism of cytochrome P450 action: the enzyme is membrane protein situated in the inner membrane of mitochondria or in the endoplasmic reticulum. Its active site contains a haeme bounded via a cysteine ligand.
- Type I: electrons from Mitochondrial NADA is passed to FAD/FMN and delivered to P450 via ferredoxin. The reduce iron can then oxidize substrates
- Type II: for ER enzymes, electron is donated from NADPH through FAD and FMN to P450. Metabolism of most drugs through this pathway requires O2 and NADPH
• CYP1A2:
- Marker drug: theophylline
- Clinical drug: theophylline
- Drug interaction: tobacco, green veges (inducers)
• CYP1E2:
- Marker drug: ethanol
- Clinical drug: paracetamol
- Drug interaction: ethanol (inducer)
• CYP2C9:
- Marker drug: warfarin
- Clinical drug: warfarin
- Adverse event: increased bleeding risk
- Ethnicity: Caucasian 25% and Asian 1%
• CYP2C19:
- Marker drug: S-mephenytoin
- Clinical drug: acid pump inhibitors such as omeprazole
- Therapeutic benefit: cure gastric-oesophageal reflux mainly in poor metabolizers
- Ethnicity: Caucasian 4% and asian 20%
• CYP2D6:
- Marker drug: desbrisoquine
- Clinical drug: tricyclic-antidepressants and beta blockers
- Drug interaction: fluoxetine, quinidine (inhibitor)
- Ethnicity: Caucasian 7% and asian 1%
• CYP3A44:
- Marker drug: simvastatin
- Clinical drugs: HMG-CoA reductase inhibitor, protease inhibitor, immunosuppressant
- Drug interaction: inhibit by ketoconazole, grapefruit juice and induced with St John’s Wort

Pharmacogenetics and interactions

• Pharmacogenomics: the investigation of variations of DNA and RNA characteristics as related to drug response. It involves DNA mapping, list bases.
- Pharmacogenetics: a subset of pharmacogenomics that involve the influence of variation of DNA sequence on drug response.
- Applications: drug discovery, development and clinical practices
- Epigenetics: study of drugs targeting methyl groups of DNA that prevent drug function
• Variability of drug effects:
- only 50% of drug effects can be predicted from factors such as genetics (fast acetylators) or environmental (renal function)
- the remaining 50% is unpredictable
• Pharmacokinetics: drug disposition, most important component is clearance and the effects of its variability.
- Drug metabolism pathways: variability in cytochrome P450 including CYP1A1, CYP2D6, CYP3A4. These are phase I reactions to inactivate the drug
- Non-cytochrome metabolism: acetylation, glucuronidation, purine breakdown, alcohol/acetaldehyde dehydrogenase. These are phase II conjugation reactions to solubilise the drug and genetic variability change clearance
- Transporter: P-glyco-protein
• Glucuronidation: glucuronic donated from UDP glucuronic acid. Marker drug bilirubin is used to indicate functionality, i.e. hyperbilirubianaemia in Gilbert syndrome (glucuronidation impaired)
- Clinically relevant drugs include anti-cancer drug Irinotecan. The drug is hydrolysis to SN-38, the active metabolite. SN-38 is eliminated by glucuronidation mediated by the enzyme UGT1A1
- Side effects of SN-38 due to UGT1A1 deficiency include severe diarrhoea and neutropenia
- In 10% Caucasians, variation of UGT1A1 cause patients to be susceptible to toxicity
• Acetylation: transfer of acetyl group from acetyl-CoA. Marker drug is procainamide.
- Clinical drugs include anti-arrhythmic (procainamide) and anti-tubcerculous (isoniazid)
- 50% of Caucasian of low clearance while only 10% with lecture.
• Sulphation: purine metabolism. No marker drug available
- clinical relevant drugs are 6-mercaptopurine used for childhood acute lymphocytic leukaemia azathioprine for Crohn’s disease and rheumatoid arthritis
- Metabolism of 6-mercaptopurine is by TPMT (thio-purine-methyl-transferase). Deficiency of this enzyme cause side effects such as severe diarrhoea and neutropenia
- TPMT homozygote deficiency occurs 1/300 requiring 10 fold dose reduction
• Alcohol/Acetaldehyde dehydrogenase: marker drug is ethanol
- Clinical relevant drug include ethanol which is metabolised by alcohol dehydrogenase to acetaldehyde and then metabolized further by aldehyde dehydrogenase.
- Hence increased activity of Alcohol DH and decreased activity of acetaldehyde will increase acetaldehyde levels causing major flushing.
- 50-80% Asian have excessive flushing with ethanol while other tolerate larger quantities
• P-Glyco-Protein transporter: exports drugs out of the cells causing multi-drug resistance.
- Present in cancer, rheumatoid arthritis, IBD, epilepsy
- Increased activity of PGP transporter cause decrease drug absorption and increase transport out of the brain and tumours.
- Activity also associated with ABCB1 poiymorphism.
• Pharmacodynamics: drug effects
• Warfarin resistance: variation in the Vitamin K epoxide reductase C1 will produce differences in warfarin resistance (35% have decreased activity)
- Not due to increased CYP2C9, i.e. no clearance effect.
• Malignant hyperthermia: extreme temperature (1/20000)
- Ryanodine receptor defect leading to increased Ca2+ release in muscles. Excess twitches produce heat.
- Treated with halothane and succinylcholine which are muscle relaxing agents
• Beta-adrenoceptor potency: excessive beta-adrenaline effect.
- Propranolol used to slow down B-receptor activity
- IC50 is 2x lower in Chinese as they are more sensitive to propranolol effect (e.g. heart rate slowing)

Immediate Drug Effects

• Mechanism:
- Drug effects are immediately related to observed drug concentration
- Drug effects are delayed in relation to observed drug concentration
- Drug effects are determined by the cumulative action of the drug
• Ec50: a concentration for 50% of drug effects. Similarly Ec80 is for 80% of drug effect.
• Emax: maximum effect of a drug, only achieved at infinite dose. As result it is only an estimated value
• Concentration and effect: if assumed that receptor binding is proportional to the effect, then binding of the drug (concentration) will form a hyperbolic curve relationship with the effect
- Log-dose response curve: if concentration is logged, the curve becomes sigmoidal and allows a greater range of value to be plotted. Main feature to note is that between 20% and 80% of Emax is almost linear.
- Limitation of this model is that at 0 concentration, effect is undefined and also a maximum effect is not recognized at infinite dose.
• Emax model: fundamental description of the concentration effect relationship. It has strong theoretical support from the physicochemical principles governing binding of drug to a receptor.

where E is drug effect
- When concentrations are low in relation to EC50, effect is more or less proportional to concentration by the constant (Emax/EC50)
• Hill co-efficient: used to describe the steepness of the gradient for the sigmoid curve. It was noticed that O2 saturation curve was steeper than what the simple Emax model predicted. By adding the hill co-efficent as an exponential parameter to concentration, gradient was increased.

- Large hill co-efficient: effects increases very rapidly with concentration forming almost an on-off model with threshold concentration around EC50. Examples are local anaethetics on nerves
- Small hill co-efficient: effect increase is slow with dosage change,
• Time course of effect:
- Features include length of effect, half life (only occur for specific concentrations) and relationship with EC50
- Concentration of 100x EC50: response almost at Emax and at such high point, dose-effect relationship is flattened meaning a huge drop in concentration (after 4 hl) will only decrease effect slightly (100% to 70%), i.e. shallow depreciation. This shows that drugs with short half-lives will have big effects. Common examples are beta blockers, ACE inhibitors
- Concentration of 10x EC50: with lower doses, the dose-effect gradient becomes steeper. After 4 half lives the drop in effect is around 70% from 90% initially
- Concentration of EC50: when a dose of EC50 is given, the effect is only 50% but as shown before, the dose-effect relationship is approximately linear so after 4 half lives, effect also decreases by the same proportion (93.75%)
• Disappearance of response:
- Flat: almost independent when Conc > EC80
- Linear: proportional to time when EC80 > Conc > EC20
- Exponential: proportional to concentration when EC20 > Conc (at this point, the effect can be plausibly described as having a half life)
• Duration of response: defined as the time the drug response if above EC50
- Doubling the initial dose will increase duration of response by 1 half life.
• Applications:
- Doubling dose does not lead to doubling of effect
- Dosing interval depends on half life and EC50 (to chose an optimum dosing interval to maintain drugs effect above that of produce by EC¬¬¬50)

Poison and poisoning

• Types of poisoning
- Acute overdose: excess drug concentration (easier to monitor)
- Chronic exposure: exposing children to pollution
• Diagnosis:
- History: often unreliable as patient does not convey all information
- Pupils
- Skin
- Odour
- Blood
- Urine
• Pupil:
- Constricted: due to increased parasympathetic and decreased sympathetic, e.g. opiates (morphine), clonidine, anti-cholinesterases.
- Dilated: due to decreased parasympathetic and increase sympathetic, e.g. atropine, tricyclic antidepressants, amphetamine
• Skin:
- Sweating: increased sweating from amphetamine and decrease sweating from atropine
- Bullae: blisters on the skin indicative of carbon monoxide and barbiturates (central nervous depressant)
• Odour:
- Ethanol: smell of alcohol
- Garlic: arsenic and organophosphates (anti-cholinesterase)
- Almonds: cyanide poisonning
• Blood content
- Salicylate: aspirin overdose
- Paracetamol
- Ethanol
- Carbon monoxide
- Tricyclics
- Digoxin
- theophylline
• Urine content:
- Salicylate
- Opioids
- Tricyclics
• Treatment:
- Absorption
- Elimination
- Specific antidote
• Absorption:
- Emesis: forceful expulsion of the content of the patient’s stomach. Syrup of ipecac is administrated orally or intravenously
- Gastric lavage: using a tube inserted into the stomach via the mouth to remove gastric fluid and content. Vomitting can be induced and hence not suitable for corrosives and hydrocarbon as these can enter the trachea
- Activated charcoal: the most effective means of drug removal. The sticky charcoal is ingested and it binds to drugs in the stomach. Usually dose is 50g every 4 hours.
- Fuller’s earth: an effective treatment of paraquat poisoning. Ingested and have similar effect to charcoal
• Elimination:
- Enteral dialysis: activated charcoal when bound to drug can reverse concentration gradient causing drugs in the blood to diffuse out into the gut
- Haemoperfusion: blood pass out of the artery into a test tube which contains charcoal and exchange resin which binds and remove the drug. Blood is directed back into the vein. Excess bleeding may occurs
- Haemodialysis: venopuncture and blood passes through an apparatus. Drug diffuse through into water and removed. Can be used for methanol and ethylene glycol
- Diuresis: not used anymore due to electrolyte imbalance and limit ability to eliminate
• Specific antidotes: naloxone and flumazenil is no longer used as treatment but diagnostics, e.g. injection of antidotes causes patients to wake up then shows overdose
- N-acetyl-cystenine: paracetamol
- Naloxone: morphine (competitive)
- Flumazenil: benzodiazepines (competitive)
- Ethanol: methanol (competitive which block metabolism of methanol to formic acid)
- Chelation: organic compound ligands that detoxify poisonous metals, e.g. deferrioxamine (iron), succimer (lead), D-Penicillamine (copper), hydroxycobalamin (cyanide)
- Atropine and pralidoxime: anti-cholinesterase
- Fab fragment: digoxin (bind to the drug and eliminated through urine)
• Paracetamol hepatotoxicity: paracetamol is metabolized to NAPQ1 (N-acetyl-p-benzoquinoneimine) by CYP2E1
- CYP2E1 is induced by ethanol
- NAPQ1 is inactivated by glucothione (reserves are used up by large amount of paracetamol). Build up of NAPQ1 will cause liver damage.
• Succimer incompetence: trial showed that after a long period of time, both placebo and succimer group have the same level of lead in their blood
• Clinical applications:
- Specific antidotes are uncommon
- Physiology and pharmacology are important in diagnosis
- Factors affecting drug clearance should be considered if using elimination procedures

Target concentration intervention

• Steps of drug therapy:
- Diagnose
- Determine objective of treatment
- Select appropriate drug and dose and method of administration
- Determine whether effect is met
- Re-evaluate for changes
• Evaluation of effects:
- Aspirin taken for headache can be reported from patient
- Metoprolol taken for hypertension and heart failure can have blood pressure monitored and decreased BNP
- Warfarin taken for stroke prevention in atrial fibrillation is seen with decreasing clotting and increase INR
- Nortryptilline taken for depression. Effective if patient reports improvement to symptoms
• Purpose of measuring drug concentration:
- Surrogate measure of effect: concentration is related to effect
- Marked PK variability: the dose-concentration is unpredictable as it varies with each person. Personalized treatment is necessary
- Monitor toxicity: ensure safe dosage for drugs with narrow therapeutic index (anti-convulsants), check for drug interaction and changes in clearance (kidney failure may decrease clearance and cause toxicity)
- Drug development
- Overdose and abuse
• Target concentration intervention: aims to optimise and individualize the dose of a drug based on measurement of plasma concentrations. This will reduce PK variation.
• Factors of TCI:
- Bioavailability
- Volume of distribution: depends on whether drug is bounded to proteins
- Clearance: varies more with size instead of age
- Half life
- Loading dose and maintenance dose
- Timing of samples: trough and steady state
• Variation in bioavailability:
- Absorption of drug through gut is predictable with ample amount of transporters and does not vary to a significant degree
- Metabolism has the most important influence as it varies greatly between patients, e.g. morphine is absorbed but 60% is removed by liver. In liver failure, bioavailability increase
- Avoid opiates in hepatic failure as they precipitate encephalopathy
• Variation in volume of distribution: relationship between concentration and amount of drug in the body
- Depends on size and so dosed according to kg (usually remains constantly within a person but clearance varies
- Muscle mass decrease with age so drugs such as digoxin which binds Na/K ATPase will reduce with aging
- Obesity: dose should be given based on lean/ideal body weight as majority of drugs does no distribute into fat. Overdose will occur if total body weight is used.
• Variations in clearance: controlled by liver and kidney
- The irreversible removal of drug from blood over time composed by renal and hepatic clearance
- Renal failure: decrease in proportion of clearance to the decrease in GFR
- Hepatic failure: doesn’t always change the clearance and less predictable than changes in GFR
• Diazepam: metabolized by the liver to desmethyldiazepam and then to oxazepam. The half life increase from 20 hours to 80 hours in elderly people and this means greater concentration of drug accumulated at stead state (toxicity). Hence very sensitive
• Loading dose and maintenance dose: LD = Vd × target concentration while MD = clearance × target concentration.
• Requirements for TCI
- Knowledge of target concentration to relate to drug effects (assuming similar pattern between patients)
- Knowledge of dosing amount and time
- Knowledge of when to measure the sample. Peak is unreliable so trough most commonly used (measured just before next dose). Exceptions are digoxin, due to large volume of distribution, requires time to distribute into tissues and thus measure 6 hours after dose.
• Case example: patient admitted with atrial fibrillation and HR of 150/min. Digoxin is administrated.
- Target concentration is 0.5ng/mL (toxicity at 2.0ng/mL). Vd for digoxin is 500L/70kg so 60kg is
, accounting for 0.7 bioavailability is
- Digoxin clearance is 7/hr/70kg so , accounting for bioavailability is (62.5 µg tablets is given)
- After 4 half-lives, serum level is 0.3ng/mL. Testing for real clearance :
- New dose is 411 µg/day. 375 µg digoxin is given daily to match needs.
- New dose caused excess toxicity due to reduction in renal clearance. New trough level is 3.6mg/mL and corresponds to 3L/hr clearance.
• Digoxin toxicity: treatments
- Keep K+ in high normal range and Ca2+/Mg2+ stabilize heart
- Atropine/pacing for bradycardia
- Digoxin specific antibody fragments for overdose/severe toxicity
• Examples of drug concentration measurement:
- Methotrexate chemotherapy: monitor levels after dosing and give folinic acid to minize toiciy
- Gentamicin: monitor levels to avoid accumulation and toxicity
- Vancomycin: monitor trough levels to ensure adequacy of treatment and to reduce risk of toxicity (dose needs to be 4-5 times the level sufficient to kill)
- Anti-convulsants: monitored to ensure optimal dosing and check adherence to treatment.
- Phenytoin: phenytoin clearance can be saturated so increase in dose can lead to a much greater concentration after a particular level. Drug concentration needs to be monitored and slow infusion ensured no accumulation.
- Paracetamol overdose: plot elimination against time and compare to normal to assess risk of liver failure and death

Adverse Drug Effect and Medication Errors

• Adverse effects: harmful or significantly unpleasant effect of medicine within doses intended for therapeutic effect
- Carotene can increase risk of lung cancer, old drugs such as methyldopa is outdated because it causes sedation and depression.
- Thus drug choice must involve weighing up risk and benefits, e.g. cancer drugs cures cancer but cause short term vomiting and hair loss
- Prescribing drugs that is unuseful is major cause of adverse effects. E.g, amoxicillin (an antibiotics) is used to treat viral infection but the clavulanic acid can cause skin rashes, diarrhoea and thrush
• Side effects: any effects of a drug that are not part of its therapeutic effects, e.g. can be beneficial.
- Example: sildenafil was originally used as a treatment for angina but unanticipated effect of curing erectile dysfunction.
• Choice of drugs:
- Prescribe only if it is needed
- Always use a better tolerated drug by the patient
• Adverse effect with overdose: high cause of morbidity (3-5% of hospital admission)
- Digoxin, a drug cleared renally, when dosage is not adjusted for a patient with renal failure, toxicity can occur.
- Diclofenac Sodium causes peptic ulceration
• Classification of adverse event:
- Type A: augmented, i.e. exaggeration of the original effect. E.g. high BP is treated with antihypertensive but result is hypotension and falling over.
- Type B: bizarre/idiosyncratic, i.e. adverse effect that is not predictable (most are immunological mediated and not dose dependent unlike type A). For example, penicillin cause anaphylaxis by binding to IgE of mast cells leading to decrease in blood pressure, rash, swelling of throat
• Vulnerability:
- increased risk of adverse effect due to renal or hepatic impairement (reduced clearance so increase in concentration of drugs)
- slow metabolizers, e.g. perhexilene used for angina cause hepatoxicity
- variability: chloramphenicol eye drops used for infection can cause bone marrow failure, 1:25 – 1:50000
• NZ Pharmacovigilance Center: receives submission of adverse effects. Once or twice is tolerated but repeated reports will mean the drug is prohibited
• Causality of drugs: it is uncertain for cases whether an adverse effect is linked to drug intake, e.g. Ace inhibitors with coughing. Confirmation is acquired through
- Timing: adverse effect occur after drug intake
- Cessation: adverse effect stop when drug intake stops
- Rechallenge: retake of the drug will cause adverse effect to reoccur
• Medical errors: doctors are prescribers, nurses are administrators and pharmacist are dispensers. Human error can occur at any of this stage.
- Wrong medicine: gentamicin is given for pneumonia instead of amoxicillin and the patient will not improve.
- Wrong dose: pyelonephritis of the kidney is caused by E.coli from irinary infection. E.coli is sensitive to gentamicin. But renal failure with no adjustment can cause damage to kidney and ear.
- Wrong route: IV and oral. IV to muscle can cause muscle damage and pain.
- Wrong frequency: diltiazem is a Ca2+ blocker to relieve atria fibrillation and tachycardia. It is short acting so 4 times a day with 60mg each time. But 240mg a time is given and the patient suffers heart block and death.
- Wrong patient: morphine error, 7000 deaths per year
• Reducing medical errors:
- Electronic prescription for increase legibility of writing
- Barcoding to overcome wrong patient
- Packaging medicine, e.g. KCl and NaCl should be separated as if KCl is used instead of NaCl for flushing, ventricular tachycardia can occur
- Admission/discharge, ensure medicine is not incorrectly reported, e.g. hypothyroidism as 150 microgram should be prescribed but only 50 microgram is given.

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