Therapeutic Medicines

Therapeutic Drug Monitoring and penicillin allergy

(Duty of care with toxic drugs)Dr Kieran Hand

Consultant Pharmacist, Anti-infectivesSUHT, November 2007

Why monitor drug levels?

• Optimise dose regimen for individual patient• Explain lack of efficacy• Prevent / confirm toxicity• Evaluate impact of drug interactions• Evaluate impact of low albumin• Evaluate impact of changes in organ function or

fluid status• Check patient compliance

Drugs routinely monitored

• Anti-epileptics– Phenytoin,

Carbamazepine, (Valproate)

• Antibiotics– Gentamicin,

Tobramycin– Vancomycin,

Teicoplanin

• Anti-psychotics– Lithium

• Cardiac glycosides– Digoxin

• Bronchodilators– Aminophylline– Theophylline

• Specialty drugs

eQuest screen - Lithium

eQuest screen - search

eQuest screen - antibiotics

Narrow therapeutic index

When to sample – steady state

The effect of loading dose – immediate efficacy

Blood sampling and the distribution phase

Anti-epileptics

PhenytoinHalf-life 22 hours but caution: saturable metabolism

Time to steady state sampling Varies considerably between patients (1-5 weeks)

Loading dose 18mg/kg slow iv infusion for status epilepticus over 30-60mins (ECG recommended)

Maintenance dose 100mg 6-8 hourly iv (convert to od if stable)200-500mg once daily po

When to take blood Pre-dose

How often to repeat Sample within 2-3 days of initiation then again 3-5 days later. If no change, monitor weekly.

Sampling method Li-heparin/SST

Signs of toxicity Far-lateral nystagmus, diplopia, ataxia, confusion, slurred speech, hyperglycaemia, respiratory/circulatory depression (2-5g lethal)

Target range 10-20mg/L (bound + free drug); Note: high protein binding

Practical issues 100mg iv = 100mg tablet = 90mg liquid

Phenytoin accumulation

Phenytoin – key points

• Saturable metabolism so increase dose carefully• Long half-life (1 day) so pointless to sample blood

before one week if initiating oral therapy• Serum levels must be adjusted for abnormal albumin

concentration – call a pharmacist (low albumin leads to plasma phenytoin level appearing low but tissue levels normal)

• Susceptible to protein binding displacement (plasma level appears low but tissue levels normal)

• Susceptible to liver enzyme inhibition and induction

CarbamazapineHalf-life 30hr then 15hr due to autoinduction

Time to steady state sampling 5-7 days after dose change

Loading dose Slow titration: 100-200mg bd oral > increasing by 100-200mg each week

Maintenance dose 200-800mg bd


How often to repeat After dose changes (5-7 days)


Signs of toxicity Vomiting, CNS disturbances, tachycardia, haemodynamic instability, respiratory depression, coma

Target range 4-12mg/L

Carbamazepine – key points

• Autoinduces it’s own metabolism (one month)

• Wider therapeutic index than phenytoin• Susceptible to liver enzyme induction or

inhibition• Induces increased metabolism of other

drugs

Antibiotics

Gentamicin extended interval dosingC

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Time

Reduced elimination

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Time

MEC

MTC

GentamicinHalf-life 2-3 hours

Time to steady state sampling

6-14 hours post 1st dose sampling window for 5mg/kg regimenBefore and after 3rd dose for 8-hourly dosing

Loading dose Not applicable

Maintenance dose 5mg/kg every 24, 36 or 72 hours or1mg/kg every 8-12 hours

When to take blood 6-14 hours post-dose for 5mg/kg dosing regimenPre-dose for trough1 hour after start of infusion for peak (distribution phase)

How often to repeat Twice weekly if renal function and fluid status stable

Sampling method Plain tube (clotted blood - red top)

Signs of toxicity Nephrotoxicity and renal failure, ototoxicity (vestibular damage or hearing loss)

Target range High-dose regimen – see nomogram8-hourly regimen – peak 5-10mg/L, trough <1.0mg/L for Gram –ve sepsis

Gentamicin – key points

• Gentamicin causes permanent renal failure if levels are kept above 1mg/L for a prolonged period of time

• High-dose regimen (5mg/kg) equally effective as traditional dosing

• High-dose regimen no more toxic than traditional dosing

• See SUHTranet for exclusion criteria

VancomycinHalf-life 6-7 hours

Time to steady state sampling Pre-dose at 3rd or 4th dose

Loading dose 1-1.5 grams

Maintenance dose 1.5 grams bd (see intermittent dosing guideline)


How often to repeat Every 3 days if renal function stable


Signs of toxicity Rapid infusion causes ‘Red Man Syndrome’Nephrotoxicity and renal failure; Ototoxicity with hearling loss, vertigo, dizziness, tinnitus

Target range 10-15mg/L (once daily or twice daily dosing)20-25mg/L continuous infusion

Vancomycin – key points

• Activity related to time levels are above MIC for target pathogen

• Vancomycin is rarely nephrotoxic if monitored carefully

• Nephrotoxicity is usually associated with concurrent prescribing of other nephrotoxic drugs

• ICU uses continuous infusion vancomycin

TeicoplaninHalf-life ONE WEEK

Time to steady state ONE MONTH

Loading dose 400mg 12-hourly for 3 doses is ESSENTIAL

Maintenance dose 400-600mg daily (at least 6mg/kg)


How often to repeat Monthly


Signs of toxicity Renal failure, hearing loss, vestibular disorder, tinnitus

Target range Trough >10mg/L (>20mg/L for IE)Peak 20-50mg/L

Teicoplanin – key points

• Inferior efficacy to vancomycin• Frequently underdosed – associated with treatment

failure• Levels sent off to Bristol - delay• Advantage of once-daily dosing• Reduce dose on 4th day if renal impairment• Less nephrotoxic than vancomycin• Expensive

Cardiac glycosides

DigoxinHalf-life 30-40 hours

Time to steady state sampling >1 week

Loading dose IV 10 microgram/kg in 100mL saline over 2hroral 15 microgram/kg (750-1,500 micrograms in divided doses)

Maintenance dose 62.5micrograms – 250micrograms once daily

When to take blood Pre-dose preferably (at least 6 hours after oral dose to allow distribution)

How often to repeat 1 week after initiation or dose change


Signs of toxicity Anorexia, nausea, vomiting, various arrhythmias, atrial tachycardia, 10-15mg fatal in adults,

Target range 1-2 microgram/L

Practical issues 125mcg tablet 100mcg liquid (2mL) 80mcg iv

Digoxin - key points

• Low potassium potentiates risk of arrhythmias• Maintenance dose usually guesstimated from

weight and renal function• Pharmacist can provide more accurate estimate• Clinically significant interaction with amiodarone• Digibind® reduces mortality in overdose but

phenytoin is a cheaper alternative in mild cases

Antipsychotics

LithiumHalf-life 24 hours

Time to steady state sampling 4-5 days after starting or change in therapy or sodium/fluid intake

Loading dose 400mg-1.2g daily

Maintenance dose 400mg – 1,200mg od po

When to take blood pre-dose

How often to repeat Weekly until dose stable then at least 3-monthly

Sampling method Plain tube

Signs of toxicity Hyperreflexia & hyperextension of limbs, convulsions, psychoses, syncope, renal failure, circulatory failure, coma, death

Target range 0.4 – 1.0 mmol/L

Practical issues Slow release brands not interchangeable

Lithium – key points

• Renal excretion– 100% filtered but 80% reabsorbed– Li+ reabsorption linked to Na+ reabsorption– Influenced by dehydration, sodium depletion,

hypotension– Diuretics (e.g. thiazides) can increase Lithium levels

dramatically• NSAIDs and ACEi’s can increase Li+ levels

toxicity

Bronchodilators

Theophylline /Aminophylline ivHalf-life 8 hours

Time to steady state sampling 2 hours post load, then 12 hours into infusionOral: 5 days after starting

Loading dose 5mg/kg iv if treatment naïve in 100mL over 20 mins

Maintenance dose Infusion 0.5mg/kg/hour (500mg in 500mL)Oral: 200-500mg 12-hourly (slow release)

When to take blood 24 hours into infusionOral – pre-dose (at least 4-6 hours post-dose)

How often to repeat As required


Signs of toxicity Nausea, vomiting and haematemesis, agitation, restlessness, dilated pupils and convulsions, hypotension and life-threatening cardiac arrhythmias

Target range 10-20mg/L

Practical issues Slow release brands not interchangeableTheophylline 790 mg = Aminophylline 1,000mg

Theophylline / aminophylline key points

• Theophylline concentration is increased in– Heart failure– Cirrhosis– Elderly– Liver enzyme inhibitors

• Theophylline concentration is decreased by – Smoking– Social drinking– Liver enzyme inducers

Specialty drugs for monitoring – seek expert advice

• Immunosuppressants– Ciclosporin / Tacrolimus / Sirolimus– Methotrexate

• Anti-epileptics– Valproate– Phenobarbitol– Ethosuximide

• Tricyclic antidepressants– Amitriptyline, nortriptyline, imipramine etc

Important concepts• You prescribe a toxic drug – you monitor it• Seek advice from the ward pharmacist or Medicines Info• Loading dose for drugs with long half-life• Distribution phase (when to sample blood after dose given)• Documenting sampling times• Steady state (when to check levels after start of therapy or

change to therapy)• Actions: reducing dose or extending dosing interval• Slow-release brands are not easily interchangeable• Many TDM drugs are susceptible to serious drug interactions

– caution if starting/stopping other drugs and check with pharmacist or BNF

Penicillin allergy

• Megan, 19-years-old, student• PC ‘Serious infection’• Allergies ‘Penicillin – itchy rash and lips swollen’

• Rate the following antibiotics as:– Safe– Caution – perform risk assessment– Danger

Penicillin allergy

• Clindamycin• Amoxicillin• Moxifloxacin• Daptomycin• Doxycycline• Tazocin• Azithromycin• Gentamicin

• Metronidazole• Ceftriaxone• Vancomycin• Flucloxacillin• Meropenem• Cefuroxime• Augmentin• Rifampicin

Facts about penicillin allergy• 10-20% of patients

reporting a penicillin allergy are truly allergic (Salkind 2001 JAMA)

• Frequency of all ADRs to penicillin in general population is 0.7-10%

• Anaphylaxis occurs in between 1:6,500 and 1:25,000 penicillin courses

• History of atopy is not predictive of penicillin anaphylaxis but may severity

• Patients on beta-blockers may be at increased risk of death if anaphylaxis occurs

• Understanding the classification of penicillin hypersensitivity reactions helps with risk assessment

Gell and Coombs Classification

Time of onset after exposure

Mediator Clinical signs Skin testing useful

Comments

Type I (immediate)

< 1 hour after exposure

Penicillin-specific IgE antibodies

Anaphylaxis and/or laryngeal oedema, wheezing / bronchospasm, angioedema, urticaria/pruritis, diffuse erythema

Yes IV > oralFatal in 1:50,000-100,000 treatment coursesSome IgE reactions occur from 1-72 hours post exposure

Late reactions > 72 hours after exposure

Type II >72 hours IgG, complement

red blood cells, platelets

No clearance by lymphoreticular system

Type III >72 hours IgG, IgM immune complexes

Serum sickness, tissue injury

No Tissue lodging of immune complexes, drug fever

Type IV >72 hours Contact dermatitis No

Other (idiopathic)

Usually >72 hours

Unknown Maculopapular or morbilliform rashes

No 1-4% of all patients receiving penicillin 3.5% on rechallenge

Taking a History of Penicillin Allergy: What to Ask• What was the patient’s age at the time of the reaction? Type I reactions most common in 20-50 year olds

• Does the patient recall the reaction?If not, who informed them of it?

How reliable is the history?

• How long after beginning penicillin did the reaction begin?

If onset >3days after exposure then unlikely to be Type I reaction.

• What were the characteristics of the reaction?

If a detailed history of a patient’s reaction to penicillin indicates that the rash was strictly maculopapular, with no signs of a type I reaction, then it appears to be safe to readminister an antibiotic that contains penicillin.

• What was the route of administration? Type I reactions much more likely with parenteral administration

• Why was the patient taking penicillin?

Drug-independent rashes are common in patients with viral infections and infections with numerous bacteria can also be associated with a rash.

• What other medications was the patient taking? Why and when were they prescribed?

Did the reaction coincide with administration of other medications known to cause allergy?

• What happened when the penicillin was discontinued?

A positive dechallenge increases the likelihood of a true penicillin reaction

• Has the patient taken antibiotics similar to penicillin (for example, amoxicillin, ampicillin, cephalosporins) before or after the reaction? If yes, what was the result?

Cross-reactivity to cephalosporins and carbapenems is up to 10% for patients with Type I reaction to penicillins (avoid)

Questions?

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