Pharmacology, Statistics Flashcards
Pharmacokinetics - definition
Movement of a drug throughout the body (what the body does to the drug)
Pharmacodynamics - definition
Relationship between drug dosage/ concentration and response (what the drug does to the body)
Idiosyncrasy - definition
The principle by which people react differently to different drugs
Concentration-time curve
- This graph represents drugs that exhibit first order kinetics
- Ascending curve represents liberation of drug/ dissolution and absorption
- After Tmax (= time that the maximum concentration of drug occurs), metabolism and elimination become rate limiting
• AUC = area under the concentration-time curve
o Reflects degree of systemic exposure from a given drug dosage
o Can be worked out by integrating plasma concentration
o Concentration and time dependent
o Unit g/l/hour
- IV bolus – plasma concentration maximum at T = 0 then rapid fall due to redistribution, then falls slowly due to elimination – E.g. IV diazepam distributes to maximum concentration in brain same as plasma
- Oral medications / some IV – delayed action due to slow distribution to site of action – E.g. IV digoxin distribution to cardiac muscle, no advantage on IV over oral due to delayed effect/distribution
- Once redistribution complete, effects/concentrations related to plasma concentration
Absorption - definition
- Definition = extent to which intact drug is absorbed from the gut lumen into the portal circulation
- Expressed as fraction of the dose which is absorbed from the gut
First pass metabolism
• Definition = extent to which drug is removed on initial passage through the liver during the first passage of portal blood through the liver into the systemic circulation
• Avoiding 1st pass metabolism
o IM = often faster and more complete than oral
o SC = slower absorption than IM
o Buccal/sublingual = direct absorption into systemic circulation (bypass hepatic portal circuit)
o Rectal = 1/3 systemic (partial avoidance of 1st pass effect)
o Inhalation
o Topical = local effect only
o Transdermal = systemic effect, but slow absorption
Bioavailability and bioequivalence
Bioavailability
• Definition = fraction of a drug dose administered by an extravascular route (eg oral/ IM/ SC) that is absorbed into the systemic circulation
o Defined by comparison of AUC following oral dose compared to IV dose
o High bioavailability = 1, low bioavailability = 0
• Affected by
o Absorption
o First pass metabolism
Example
• 100mg dose
• 80mg absorbed intact into portal circulation (fraction 0.8)
• 60mg extracted first pass metabolism (hepatic extraction ratio 0.75), 20mg escapes
• Therefore bioavailability = fraction absorbed x fraction escaping first pass metabolism
o 0.8 x 0.25 = 0.2 = 20%
Bioequivalence
• Definition = clinical definition referring to two formulations of a drug
o Considered to be bioequivalent if the bioavailability means likely to be no clinical difference between effects
o Extent and rate of absorption are not significantly different from that of a standard reference drug administered at the same dose
o Indicates that two drug products, when given to the same patient in the same dosing regimen, results in equivalent concentrations of drug in plasma and tissues.
• Utility
o Compare bioavailability of one drug vs another (eg for generic brands)
• NOTE
o Does NOT work for prodrugs
o Deviation allowed is +/- 20% (for both AUC + Cmax) - log transformed therefore 80%-125% for AUC + Cmax
This 20% difference may be clinically significant for those with a narrow therapeutic range
Volume of distribution
• Definition = the hypothetical volume that would be required to dissolve the total amount of drug at the same concentration as found in the blood
o Relates plasma drug concentration to total amount of drug in the body
o E.g. if drug has plasma concentration 10mg/L when there is 1000mg drug in the body, Vd is 100L
• Factors affecting volume of distribution
o Relative strength of binding of the drug to tissue components compared with plasma proteins
o Molecule size – E.g. monoclonal antibodies and IVIG unable to enter cells due to large molecular size
• Low vs high Vd
o Low
Suggests drug is confined to intravascular space (high blood concentration)
Occurs if poorly lipophilic and highly plasma bound
E.g. heparin, warfarin, aspirin, gentamicin
o High
Suggests that drug is distributed to tissue/fat widely
Occurs if bound to tissues and not blood, most of drug in tissues and little in plasma
Usually highly lipophilic
E.g. nortriptyline, imipramine, chlorpromazine
• Utility
o Calculating loading dose to get to therapeutic range quicker (i.e. same as steady state concentration)
o Clearance determines steady state concentration
o If there is higher VD then will require higher loading dose to reach steady state and fill up the volume of distribution
Example
• A bolus dose 200mg given
• At Time 0s concentration was 10mg/L
• Therefore VD = 200mg / 10mg/L = 20L
Compartment models
• Compartments are hypothetical space that quantitates the relationship between drug dosage and the amount of drug in the body at a given time
• 1 compartment model = treats all body fluids and tissues as one space with definable rates of in and out
• 2+3 compartment models = separate fluid/ organ/ tissue spaces
o Recognizes that some drugs get taken up into certain organs first, then eliminated into a second compartment
o Gradients will change as drug passes into another compartment
Protein binding drugs
• When a drug combines with plasma/ extracellular / tissue proteins to form a reversible drug-protein complex
• These complexes are inactive, cannot be readily metabolized/ excreted
• If a drug is highly protein bound:
o Vd will be large
o Elimination half-lives will be long
o Susceptible to increased Vd in conditions with extravascular protein leak (eg nephrotic syndrome)
Hepatic extraction ratio
• Hepatic extraction ratio = amount of drug cleared by liver metabolism on first passage through
Example
• Propranolol 80% blood entering liver is extracted (extraction ratio 0.8)
• Liver blood flow is 90L/hour
• Therefore 0.8 x 90L = hepatic clearance of 72L/hour
Determinants of the hepatic extraction ratio
- Liver blood flow
- Unbound fraction – ability of liver to remove drug depends on protein binding as it is only the free (unbound) drug that is available for diffusion from blood into liver where metabolism occurs
- Intrinsic clearance – ability of liver to remove (metabolise) drug (it is what hepatic clearance would be without restrictions of blood flow and protein binding)
a. Cannot exceed hepatic blood flow
When very low enzyme activity – SYSTEMIC CIRCULATION affecting clearance
• I.e. LOW hepatic ability to remove drug = low hepatic ER
• DEPEDENT on unbound fraction or intrinsic clearance
• Not much influence on blood flow and extraction low anyways
• Example – diazepam, warfarin, theophylline, phenytoin, carbamazepine
When very high enzyme activity
• I.e. HIGH hepatic ability to remove drug = HIGH hepatic ER
• DEPENDENT on blood flow
• Not much influence on unbound fraction or intrinsic clearance as already high
• Example – GTN, propranolol, verapamil, lignocaine, morphine
Phase 1 metabolism
- Goal = designed to make drug more water soluble + less toxic
- Introduce/ reveal a functional group within the substrate drug molecule that serves as a site for a phase II reaction
- Non-synthetic, simple changes are made to the molecule
• Reactions
o Oxidation = CYP450
o Reduction = flavin
o Hydroylses = esterase
Cytochrome P450 enzymes
- Group of related isoenzymes involved in phase I drug metabolism reactions
- Present in large quantities in ER of liver, but also lung, kidney and intestinal wall
- Involved in the hydroxylation +/- oxidation of drugs and lipophilic endogenous substances
- Cytochrome activity varies with age, race, genetic factors
- The most important CYPs in humans are the groups 1, 2 and 3
Inducers • Anti-epileptics o Phenobarbitone o Carbamazepine o Oxcarbazepine o Phenytoin • Rifampicin • Ethosuxamide • Steroids • Topiramate • St John’s wort
Inhibitors
• Azole antifungals = voriconazole, posaconazole
• Macrolide antibiotics = clarithromycin, erythromycin
• Cimetidine
• Valproate
• CCBs = verapamil, diltaizem
• Grapefruit juice
Phase 2 metabolism
- Goal = add onto drug molecule for elimination
- Conjugation with acetate, glucuronic acid, glycine and sulfate
- These processes increase the polarity of an intermediate metabolite more water solubility
- Enzymes involved: NAT1/NAT2 arylamine N-acetylransferases, glucoronosyl transferases (UGTs), epoxide hydrolase, glutathione S-transferases (GSTs), sulfotransferases (SULTS) and methyltransferases
• Examples
o Gluocronosyl transferases
Catalyze conjugation of glucuronic acid with several drugs: morphine, paracetamol, NSAIDS, benzodiazepines
Immature processes in neonates -> hyperbilirubinemia, grey baby syndrome, INCREASED clearance of morphine
UGT1A1: the major ugt gene product responsible for bilirubin glucoronidation. Mutations (usually involving a TA repeat in the atypical TATA box of the UGT1A1 promoter) cause Crigler-Najjar syndrome and Gilbert syndrome
o NAT-2 polymoprhisms (arylamine N-acetyl transferases)
High level of slow metabolisers
Involved in metabolism of sulfasalazines, procainamide + isoniazide induced lupus + SJS/ TENS
o TPMT
Catalyses S-methylation of sulfur containing compounds – 6-MP, azathioprine and 6-thioguanine
1/300 people have TPMT deficiency (AR trait)
Risk of increased myelosuppression with above drugs
Phase 3 metabolism
• Transport of conjugated drug into bile – transporters are part of ATP binding cassette (ABC) superfamily
Clearance and elimination
o Clearance
Definition
• Irreversible elimination of drug from the systemic circulation – either by excretion of the unchanged drug (into urine, gut, expiration) or the metabolic conversion of the drug into a different chemical compound
• Volume of blood from which a certain amount of unmetabolized drug is removed per unit time
Usually constant over the therapeutic range (except drugs with zero order kinetics such as phenytoin and ethanol)
Clearance is the parameter which relates elimination to concentration
o Elimination
Definition = irreversible removal of the drug from the body
Divided into two components
• Excretion = removal of the intact drug
o Kidneys = renal (correlates to renal function)
o Liver = biliary excretion (parent compounds or metabolites)
o Lungs = pulmonary (MINOR)
• Biotransformation = chemically converted into a metabolite
o Enzymatic process
o Mostly occurs in the liver, but does NOT correlate with LFT
o Other site = intestine, lung, kidney
• Clearance + Elimination
o Therefore, clearance will remain constant as it is a characteristic of particular drug and patient, so that the elimination varies directly with plasma drug concentration
o At steady state elimination dictates maintenance dose in order to keep drug plasma concentrations same
o Another definition for clearance is the constant relating rate of elimination of a drug to plasma drug concentration
Clearance is defined as ‘the volume of blood cleared of drug per unit time’. … Drug elimination rate is defined as ‘the amount of drug cleared from the blood per unit time’ In first order kinetics, elimination rate is proportional to dose, while clearance rate remains independent of the dose.
Renal elimination
• Principles of renal clearance
o Equivalent to filtration + secretion – reabsorption
o Can only be quantified by measuring urine
o Classic drugs excreted renally = vancomycin, beta-lactams
o For most drugs GFR is most important – secretion/ reabsorption not relevant
o Usually correlates with renal function
Eg. halving of renal function half clearance of drug
• Dependent on three processes
o Filtration – determined by:
GFR – determined by renal function
Fraction unbound (bound drug unable to be filtered)
o Secretion – active, determined by:
Fraction unbound
Availability of active transport systems (one for weak acids one for weak bases) -> can be subject to competitive drug interactions and saturatable kinetics
o Reabsorption – passive reabsorption of water in distal tubule means drug reabsorption depends on:
Concentration gradient – determined by urine flow rate, the higher the urine flow rate the higher the drug clearance (as less concentration gradient pulling the drug out of renal tubule)
o Ion trapping - pKa of the drug +/- pH urine
Non-ionised drugs pass through the cell membrane
Ionized drugs stay in water (and get trapped as they do not pass through the membrane)
This principle can be used by alkalizing/ acidifying urine
• Weak acid drugs are ionized in basic solution
• Weak basic drugs are ionized in acidic solution
Alkalinization of urine
• Helps to excrete weak acids that are renally excreted (eg aspirin)
• This can be achieved by administering bicarbonate
Dose adjustment in renal failure
• Renal clearance reduced in proportion with reduction in GCF (Cr clearance)
• Adjustment of drug doses only necessary when drug is >50% cleared by renal elimination and renal function is reduced to half or less
• Dose rate is reduced proportional to reduction in creatinine clearance either by –
o Reducing the dose
o Increasing the dose interval
o E.g. if a drug is 50% renally cleared, and Cr clearance is 10% usual (90% reduction), then renal clearance reduced from 50% to 5% and total clearance is 55%, therefore dose rate should be decreased to 55% normal
• Factors to consider
o Therapeutic index – if wide may not need dose adjustment
o Metabolites renally cleared
Example
• Dose renally cleared = usual dose x new GFR/old GFR
• Eg – if the dose is usually 100mg for a drug which is 20% hepatically cleared and the GFR is 25%
• Renal dose = 80 x 0.25 = 20, liver dose = 20 x 1 = 20 – therefore dose = 40mg
Elimination kinetics
• Zero order kinetics
o Definition = elimination occurs at the same irrespective of the concentration
o Amount of drug in the body determined by volume a constant amount of drug is eliminated per unit time
o Examples = alcohol, phenytoin, aspirin (high dose), theophylline
o NO half life
o Consequences
Large increases in drug concentration with small increases in drug doses
High risk of drug toxicity
• First order kinetics
o Most common
o Definition = elimination rate proportional to the concentration of drug in body
o If more drug is present, elimination is more rapid a constant proportion of the drug is eliminated per unit time
o The elimination rate can be represented by a constant k
o Drugs will have a consistent half life
o Time to steady state (or >95% drug elimination) = five half lives
o Most drugs are first order kinetics - do not saturate the elimination pathway
• Saturable kinetics
o Some drugs will demonstrate first order kinetics at low doses, and zero order kinetics at higher doses
Renal elimination theoretically uncapped
Hepatic metabolism – eventually reach maximum metabolic pathway
• Only when enzyme pathway is saturated – zero order kinetics
• Michaelis-Mentin kinetics = low dose 1st order, high dose zero order kinetic
o Examples = phenytoin, theophylline, aspirin
Half life
• Definition = the time for post-absorption blood/ plasma concentration to be reduced by 50%
o There will be < 5% of drug left after 5 half lives
• Plasma half-life determines
o Duration of action after a single dose
The longer the half-life, the longer the drug will stay in therapeutic range
Increasing the dose is an ineffective way of increasing duration of action as log scale therefore proportionate clearance (not constant)
o Time required to reach steady state with repeated dosing
5 half-lives until steady state
5 half-lives until elimination
Loading dose will not change time until steady state, will only increase starting concentration closer to steady state
o Dose frequency required to avoid large fluctuations in concentration in the dosing interval
If drug given every half-life, the concentration falls to half the peak concentration – peak concentration double the trough (pre-dose)
Drug given more frequently than half-life then there will be minimal fluctuation in dose in interval
Steady state
• Definition
o Level of drug accumulation in the blood and tissue after multiple doses where the rate of input and output are at equilibrium; therefore, the plasma drug concentration remains constant
o If a drug follows first order kinetics, this will be reached after five half lives
• NOTE:
o This is NOT the same as a therapeutic level
o Dosing interval does NOT influence steady state
o Loading dose does NOT influence steady state – reduces the amount of time until in therapeutic range
• Clearance determines the maintenance dose rate required to achieve a desire plasma concentration at steady state
More frequent dosing = more time in the therapeutic range
Amount of time to reach steady state does NOT change based on dosing interval
Half-life does NOT relate to dosing interval
Affinity
• Affinity – Kd
o Concentration of drug required to bind 50% of receptor sites
o The lower the Kd, the lower the drug concentration needed to bind 50% receptor sites correlating with increased affinity for receptor
• Spare receptors
o Maximal response obtained at less than maximal occupation of receptors
o Work this out by comparing EC50 with Kd
o If Kd > EC50 = less than 50% of receptors must be activated to achieve EC50 therefore there are some spare receptors
The parameter EC50 abbreviates for ‘half maximal effective concentration’. In a pharmacological context, this can be the concentration of a drug that is necessary to cause half of the maximum possible effect.
Efficacy and potency
• Definitions
o Emax = the maximal effect that a drug produces irrespective of drug concentration
o EC50 = dose at which a drug achieves 50% of its maximum effectiveness
• Efficacy = defined by maximum effect
• Potency = defined by EC50
o The amount of drug needed to produce a given effect
o Usually this is defined as the amount of drug dose that produces a quantal effect in 50% of the population OR the amount of drug required to produce 50% of its maximal drug effect
o A highly potent drug: larger response at lower concentrations
Agonists and antagonists
• Full agonist = affinity and efficacy
o Can produce a maximal response at low occupancy
• Partial agonist = affinity and less efficacy
o Response at a given receptor occupancy always less than that of a full agonist
o ALSO have the capacity to act as antagonists if in the presence of the full agonist
At low concentrations acts as an agonist
At high concentrations occupies receptors preventing full agonist binding – therefore acts as antagonist
• Antagonist = affinity but no efficacy (efficacy of 0)
o Requires the presence of an agonist to exert an effect
o Competitive = reversible
Competitive inhibition does not change the maximum response of the tissue
Surmountable (ie. no depression of the maximum response)
Parallel shifts in log CR curves
o Non-competitive antagonist = irreversible (eg. aspirin)
Essentially insurmountable
Essentially irreversible – receptors have been blocked by antagonist molecules OR bind at a different site and cannot be displaced by the agonist
Unable to reach maximum effect
Lowers maximum response in log CR curve
Therapeutic range and index
Therapeutic range
• Range of effect between minimal effective concentration and minimally toxic concentration
• Increasing the dose does NOT necessarily increase time spent in the therapeutic window
• Increasing the frequency of dosing increases time in therapeutic range
Therapeutic index
• Definition margin of safety of a drug
• Ratio of lethal or toxic dose to the therapeutically effective dose.
• In animal experiments, TI is the ratio of LD50 (dose at which lethal to 50% of the animal population) to ED50 (effective dose in 50% of animal population)
• Examples
o Broad = penicillins, beta 2 agonists, and thiazide diuretics
o Narrow = digoxin, theophylline, lithium and phenytoin
The therapeutic index is an important ratio to determine how close a toxic dose is to an effective one.
The therapeutic window (or pharmaceutical window) of a drug is the range of drug dosages which can treat disease effectively without having toxic effects.
Adverse drug reactions - classification
a. Type A = predictable (85-90%)
i. Dose dependent
ii. Can be related to known pharmacological actions of the drug
iii. Occur in patients with susceptibility – can occur in any individual given sufficient dose and exposure
iv. Include
1. Drug toxicity/ overdose
2. Drug interactions
3. Adverse effects
b. Type B = unpredictable (10-15%)
i. Dose independent
ii. Often not related to pharmacological actions of the drug
iii. Occur in patients genetically predisposed
iv. Include
1. Idiosyncratic reactions
2. Allergic reactions
3. Pseudoallergic reactions - caused by non-IgE release of mediators from mast cells and basophils (eg. anaphylactoid reaction after radiocontrast media)
Types of hypersensitivities
Type 1 - IgE-mediated, immediate-type hypersensitivity • Mechanism: Antigen exposure causes IgE-mediated activation of mast cells and basophils, with release of vasoactive substances, such as histamine, prostaglandins, and leukotrienes - IgE against soluble antigen Features: • Anaphylaxis • Angioedema • Bronchospasm • Urticaria (hives) • Hypotension Drugs: • Beta-lactams • Neuromuscular blocking agents • Quniolones • Carboplatin • Immunologics – rituximab
Type 2
- Antibody-dependent cytotoxicity
• Mechanism: An antigen or hapten that is intimately associated with a cell binds to antibody, leading to cell or tissue injury
- IgG/IgM against cell surface antigen
• Hemolytic anemia – cephalosporins, penicillins, NSAIDs, quinine-quinidine
• Thrombocytopenia - heparin, abciximaab, quinine, quinidine, sulphonamides, vancomycin, gold, beta-lactams, carbamazepine, NSAIDs
• Neutropenia – PTU, antimalarial, flecainide
Type 3
- Immune complex disease
• Mechanism: Damage is caused by formation or deposition of antigen-antibody complexes in vessels or tissue. Deposition of immune complexes causes complement activation and/or recruitment of neutrophils by interaction of immune complexes with Fc IgG receptors
- IgG to soluble antigen
Examples:
• Serum sickness – antitoxins
• Vasculitis – penicillins, cephalosporins, sulphonamides, phenytoin, allopurinol
• Arthus reaction- tetanus, diphtheria, hepatitis B
Type 4
- Cell-mediated or delayed hypersensitivity
• Mechanism: Antigen exposure activates T cells, which then mediate tissue injury
• Depending upon the type of T cell activation and the other effector cells recruited, different subtypes can be differentiated (ie, types IVa to IVd).
- T cells against soluble/cellular antigen
Examples:
• Contact dermatitis – opcial antihistamine
• Some morbilliform reactions
• Severe exfoliative dermatoses (eg, SJS/TEN)
• AGEP
• DRESS/DiHS
• Interstitial nephritis
• Drug-induced hepatitis
Adverse drug reaction - assessment and rx
- Assessment
a. History = underlying illness, time course, systemic involvement
b. Investigations
i. Skin prick test (often negative in setting of drug allergy)
ii. Intradermal tests - Intradermal injection of drug, measure wheal 2-3 minutes later
- Much more painful than skin prick testing, risk of anaphylaxis
- Penicillin intradermal testing useful for IgE mediated reactions due to its NPT value
a. 1-3% of patients with negative skin test have a reaction (which is mild) when re-exposed to penicillin
b. Skin testing for penicillin should be performed using the major determinant (penicilloyl polysine) and minor determinants (penicilin G, penicilloate and penilloate)
c. Skin prick testing to penicillin does NOT predict non-IgE mediated reactions
iii. Drug provocation test - Gold standard
- Graded exposure in hospital UNLESS hx of SJS/ TENS/ DRESS
iv. NOTE: - Serum sIgE not adequately validated, rarely used for drug allergy
- Basophil activation assay poor sen/ spec compared to skin testing (uses flow cytometry to quantify expression of activation markers after stimulation with allergen)
- Patch testing – more relevant for non IgE mediated disease, may be useful for AGEP etc
- Management = drug desensitization
a. Amount of drug tolerated by patient determines safe initial dose
b. Double dose every 15 minutes
c. Requires regular administration to maintain desensitization
d. Contraindications = history of DRESS, SJS/TEN
e. Indications
i. Drug allergy – when no alternative treatment for temporary tolerance during course of treatment – E.g. penicillin and vancomycin
ii. Anaphylaxis – bee sting
iii. Allergic rhinitis and asthma – refractory – dustmite, pollens, animal
DRESS - general
“drug rash with eosinophilia and systemic symptoms”
- Key points
a. Rare, potentially life-threatening drug reaction
b. In 10-20% of cases drug cannot be identified - Aetiology
a. Anticonvulsants – phenytoin, phenobarbital, carbamazepine, lamotrigine
i. 75% cross reactivity
b. NSAIDs
c. Sulphonamides
d. Dapsone
e. Allopurinol
f. Penicillin
g. Minocycline - Risk factors
a. HLA-B*58:01 (Han Chinese) strongly associated with allopurinol associated DRESS - Clinical manifestations
a. Timing = 2-8 weeks between drug exposure and disease onset
i. Usually begins with high fevers and lymphadenopathy
b. Skin
i. Eruption; diffuse, confluent, and infiltrated erythema
ii. Facial edema common
iii. Can have erythema multiforme
c. Systemic: Fever, Malaise, Lymphadenopathy
d. Haematological
i. Atypical lymphocytosis – early
ii. Eosinophilia
iii. Pancytopaenia less common
e. Internal organ involvement (hepatitis, nephritis, pneumonitis, encephalitis, carditis, hypothyroidism) - Investigations
a. Eosinophilia
b. Atypical lymphocytosis
c. UEC, urine microscopy, LFT, CXR, ECG
d. If symptoms – TSH, echo, LP - Natural history
a. Skin eruption and visceral involvement resolve gradually after drug withdrawal
b. Average time 6-9 weeks
c. Up to 20% of cases disease persists for several months
- 10% mortality - Management
a. Removal of drug
b. Systemic corticosteroids
c. Topical corticosteroids
AGEP - general
“Acute generalized exanthematous pustulosis” - pustules**
- Key points
a. Rare, acute eruption - Aetiology
a. Drugs
i. Antibiotics – aminopenicillins, macrolides
ii. Antifungals
iii. CCB
iv. Anti-malarials
b. Other
i. Viral infection – parvovirus B19, CMV, coxsackie
ii. Mycoplasma
iii. Spider bite - Clinical manifestations
a. Timing = few days after administration
b. Numerous non-follicular sterile pustules on a background of edematous erythema
i. Prominent in flexures
ii. Usually begins on the face and intertriginous areas and rapidly extends
c. Fever
d. Leukocytosis
e. Organ involvement uncommon - Natural history
a. Skin symptoms resolve without treatment in one to two weeks after discontinuation of the offending drug
b. Pustular eruption is followed by desquamation with characteristic collarettes of scale
c. Courses >2 weeks are rare - Treatment
a. Cessation of drug
b. Supportive
SJS/TEN - bg
- Key points
a. Severe mucocutaneous reactions
b. Most commonly triggered by medications
c. Characterised by extensive necrosis and detachment of the epidermis (full thickness)
d. Mucous membranes are affected in >90% of patients
e. NOTE = erythema multiforme is a SEPARATE condition - Similar histology, Typically target lesions only – no widespread coalesce - Definitions
a. SJS = skin detachment <10% BSA
b. TEN = skin detachment >30% BSA
c. All TEN will start as SJS - Epidemiology
a. F>M, any age
c. Mortality 30% - 10% for SJS to >30% for TEN - Pathogenesis
a. Drug specific CD8+ cytotoxic T cells and NK cells major inducers of keratinocyte apoptosis - Atiology
a. Drugs = most common
i. Allopurinol
ii. Aromatic anticonvulsants = phenobarbital, carbamazepine, lamotrigine
iii. Antibacterial sulphonamides = commonest in adults
v. NSAIDs
vi. Penicillins
b. Mycoplasma pneumoniae infection = second most common trigger, particularly in children
c. Other (after BMT, vaccinations, AI) - Risk factors
a. HIV
b. Genetic factors e.g. HLA-B*15:02 and 11
c. Underlying immunological disease or malignancies
SJS/TEN - sx
- Natural history
a. Acute phase lasts 8-12 days
b. Characterised by persistent fever, severe mucous membrane involvement and epidermal sloughing
c. Re-epithelialization begins after several days and typically takes 2-4 weeks - Clinical manifestations
a. Prodrome = 2 days to 2 weeks
i. Fever and influenza like symptoms
ii. Photophobia, conjunctival itching or burning and pain with swallowing
iii. Mild to moderate skin tenderness or burning
iv. May have oral mucositis
b. Cutaneous lesions
i. Ill-defined, coalescing, erythematous macules with purpuric centres
ii. Skin tender to touch
iii. Lesions start on face and thorax before spreading
iv. Symmetrically distributed
v. Scalp, palms and soles rarely involved
vi. Bullae begin to form which then slough
vii. Nikolsky sign (ability to extend the area of superficial sloughing by applying gentle lateral pressure on the surface of the skin at an apparently uninvolved site)
viii. Bullae spread sign (lateral extension of bullae with pressure)
c. Mucosal lesions
i. Occur in 90% of cases
ii. Can proceed or follow skin eruption
iii. Oral = almost invariably involved; painful haemorrhagic erosions with grayish-white membrane
iv. Ocular = present in 80%; most commonly severe conjunctivitis with purulent discharge
1. Eye changes may regress completely
2. At least 50% of patients have late eye seqeuale includeing pain, dryness and scarring with development of synechiae between eyelids and conjunctiva
v. Urogenital = 2/3 of patients
1. Vulvovaginal involvement may lead to long-term anatomical sequelae
