Variability in drug response

Introduction:

There is a wide variability in the response of different pts to identical doses of the
same drug (“variability in response” in graph below). Not only may drugs not
produce the same effects in all pts, they may not even produce identical responses
when given to the same patient on different occasions (“variability in dose” below).
Dose-response curves are thus often used to reflect the results obtained in a sample
from a relatively homogeneous population of subjects.
In these conditions, a sigmoid log dose-response curve may represent the
characteristic results in the population, while vertical and horizontal arrows represent
the interindividual variability.

The vertical arrows illustrate that a range of effects may be observed in the
population after the same dose of a drug.
The horizontal arrows represent the range of drug dosage that may be required to
produce a specific pharmacological effect in individual subjects.

Variability of drug responses can be considered as part of the general phenomenon of

inherent or intrinsic biological variability.
Physiological and pharmacological phenomena are subject to considerable
interindividual variability, which is sometimes expressed by detailed description of
the individual results.

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 Causes of variability in drug response

Can be broadly classified into:

 Physiological/social factors
 Pharmacological factors
 Pathological factors

A) Physiological and social factors causing variability:

 Age
 Pregnancy
 Tobacco
 Alcohol
 Obesity (see phys notes)

 Childhood: (Mainly due to pharmacokinetic differences)

Absorption: Abs is slower in neonatal period due to longer gastric emptying time +
increased intestinal transit time. Gastric contents are less acidic, and some drugs
(penicillins) will have greater overall abs orally.
Distribution: Influenced by various factors eg tissue mass, fat content, blood flow,
membrane permeability and the degree of PPB. Total body water as % of TBWt falls
from 87% in prem to 73% at 3/12, and subsequently decreases to ~ 55% in adults. Thus,
doses of water-sol drugs calculated by scaling down adult doses in prop to weight, can
result in lower tissue [ ]’s in infants /neonates. Drug distribution is also affected by the
lower body fat + the  permeability of the BBB in the neonate, -thus lipid sol drugs may
be relatively concentrated in the CNS. The  in pl protein levels in newborns leads to 
free drug, with  activity and metabolism. Also, the  in pH of plasma in neonates may
affect the degree of ionization of drugs and thus their permeability.
Metabolism: rate depends on both size of liver and the activity of hepatic enzymes. In
early newborns, enzymatic activity is initially immature and only reaches adult levels
over several months. (older kids, most drugs metabolized faster - / due to relatively larger
liver).
GFR ~ adults at 4/12. In neonates however, the GFR is particularly lower (20-40% of
adult) and drugs eliminated by renal route (digoxin, gentamycin) = slowly cleared.

Due to above differences: In neonate, weight-related doses of H2O-sol drugs produce

lower tissue [ ]’s c/f adults. Dose regimes related to BSA are required to produce similar
blood levels. However, the  Vd +  Cl (renal esp)   t1/2 elimin, and dose intervals
should thus be prolonged.
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Dose requirements for NDNMB’s in neonates / very young essentially unchanged
(reasons are complex:  Vd is offset by immaturity of NMJ). Dosing intervals might need
to be prolonged for those with organ dependant elimination.
Re opioids: Abn responses to opioids sometimes seen in neonates. Some may be
relatively insensitive to the analgetic properties, although  sensitivity to the respiratory
depressing effects. These might be due to differences in distribution of mu-1 and mu-2
receptors. Possible increased crossing of the BBB.

Even in older kids (where PPB, liver enzyme activity, renal Fx etc ~ adults), it is best to
calculate drug dosage in terms of BSA, due to the proportional  in body water in
childhood (see addendum for easy calculation rule for drug dosages in kids).
More frequent rates of administration, esp the more lipid sol drugs, may be needed due to
rel  in liver blood flow.

There may be differences in pharmacodynamic activity, but = difficult to assess.

 Elderly: (Mainly pharmacokinetic as well)

Absorption: - not signif different (except for those reliant on active transport eg Fe,
thiamine, calcium)
Distribution: c/f neonate,  in TBWater + relative  in body fat   Vd for water sol
drugs with an  in pl + tissue [ ]’s. Also,  pl albumin   free fraction of some drugs
(eg phenytoin, tolbutamide etc).
Metabolism: at age 65, liver blood flow may be 45% less than N + the activity of the
enzymes  by similar extent. Thus bioavailability of drugs subject to low or high hepatic
clearance is increased.
GFR + tubular secretion  with age  care with water sol drugs (digoxin etc)

Pharmacodynamic factors may also play role in elderly: Changes in R numbers /

sensitivity may account for eg  analgetic effects of opioids with  age. Altered
sensitivity may also occur with BZ’s, warfarin and some beta-antagonists.
MAC of all volatiles progressively declines with age.
Comparable data for IV induction agents follow same trends, indicating likely
pharmacodynamic cause for  sensitivity.

 Pregnancy: (see lecture on obstetric pharmacology for detail)

Abs:  gastric emptying may result in  uptake of drugs abs in stomach (diazepam) +
delayed abs of those absorbed in upper GIT (paracetamol).
Distrib:  pl vol +  CO ( 50 + 30% respectively). Also  PPB of many drugs
( diazepam, pethidine, theophyline etc) esp in 3rd trimester.
Metabolism: the  CO may  clearance of many drugs dependant on hepatic and renal
clearance.
Also the  CO +  VA will enhance both rate of uptake + elimination of the volatiles.
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 Smoking:

Tobacco smoking  induction of some hepatic enzymes (esp CYP 1A2 isoform of P-450). Rates
of drugs eliminated via this route = generally greater.
Studies also show that smokers need more opioids for pain, are less sedated by BZ’s and may get
less relief from anginal pain by beta-blockers and nifedipine (? PD effect).

 Alcohol:

Chronic use of alcohol   capacity of liver to metabolize it + at same time pharmacodynamic

tolerance.
Cross-tolerance b/w many sedatives and alcohol occurs (due to both PK and PD mechanisms).
Resistance to Thiopentone, mainly due to tolerance at cellular level, as its duration of action is
primarily determined by redistribution rather than metabolism.
Changes in availability of GABA with possible alterations in no + nature of GABA-receptors
may play a role.

After the acute ingestion of alcohol, the administration of other CNS depressants may lead to
supra-additive effects. T1/2 of barbiturates may also be increased, ? due to competition with
alcohol for liver enzymes.

B) Pharmacological Variability:

 Idiosyncrasy
 Supersensitivity
 Tolerance / tachyphylaxis (see separate lecture on PD’s)
 Hypersensitivity reactions

 Idiosyncracy:

Definition: Genetically determined abnormal reaction to a drug.

It may present as extreme sensitivity to low doses, or marked insensitivity to high doses
of a drug. Underlying mechanisms are unclear, - possibly immune mediated.
The term has also been used empirically to describe s/e’s ( eg dysphoria, N+V etc)
occurring in certain pts receiving certain drugs ( eg opioids, NSAID’s). These s/e’s may
disappear when closely related drugs are substituted.

NB examples of idiosyncrasy (ie genetically determined) are:

 Sux-apnoea (see elsewhere)
 Malignant Hyperthermia (see addendum)
 Haemolytic drug reactions
 “Slow acetylators”: Toxic effects of eg INH, phenelzine + certain sulpha’s; decreased analgetic
effects of codeine and tramadol (prodrugs)
 "Fast metabolisers": Increased effects of codeine and tramadol (CYP2D6)
 Hereditary resistance to oral anticoagulants (OD)
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  Acute hepatic porphyria: - commonly ppt’ed by certain drugs in genetically susceptible
pts. Implicated drugs are usually inducers of enzyme delta-aminolaevulinic acid (ALA)
synthase. Administration   hepatic prod + urinary excretion of porphyrins.  may
lead to widespread demyelination of peripheral + central nerves  sensory changes and
motor paralyses.
Drugs implicated are barbiturates, phenytoin, alcohol, sulpha’s, sulphonylureas,
OCP’s, certain steroids.

 Supersensitivity:

This term relates to the hyper reactivity to certain drugs where receptor up-regulation has
occurred.
Adrenoreceptors are a prime example: Up-regulation may occur in any decrease in
catecholamine production (either following drug Rx or sympathetic denervation) or after
chronic therapy with B-blockers, clonidine, minoxidil, (thus acute withdrawal of these
drugs may lead to an exaggerated response to exogenous or endogenous substances
acting on adrenoreceptors).
Up-regulation of receptors may also be responsible for the hyperkalaemia after sux in
severe burns or spinal cord injuries (Extrajunctional n-Ach receptors).

 Tolerance: see Pharmacodynamic (mainly PD’s, eg change in number or action of

receptors, depletion of transmitters, but also pharmacokinetics)

 Hypersensitivity:

Hypersensitivity (HS) responses are abnormal responses to drugs that are dependant on
immunological mechanisms, and usually involve the formation of antibodies.
HS reactions have been grouped into 4 main types:

 Type 1 HS (immediate-type HS):

Mediated by IgE antibodies. Require prior exposure to antigen.

Drugs combine covalently with pl or tissue proteins  antigenic drug-prot complex 
gains access to antibody-forming cells ( B lymphocytes, plasma cells)  IgE formed 
becomes attached to mast cells ( eg in skin, bronchial + intestinal mucosa, vascular
capillaries etc). On subsequent exposure to the drug-protein complex, adjacent IgE
molecules on the cytoplasmic membrane of the mast cells are bound by the hapten or
antigen (consequently, type I HS is only commonly seen with drugs that form multivalent
prot complexes, or are inherently divalent due to presence of symmetrical molecular
features eg most muscle relaxants)  calcium enters mast cells  degranulation 
release of mediators (histamine, heparin, 5-HT, leukotrines, PAF, anaphylatoxin
[complement C3a,4a,5a]). Type 1 HS more common with certain drugs (penicillins,
sulpha’s, MR’s) + may also follow insect stings or ingestion of certain proteins.

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Range of reactions seen, from mild itching to “triple response” with generalized urticaria
or angioneurotic oedema to the severe form aka anaphylactic shock (severe hypotension
due to profound peripheral vasodilatation + venous pooling, usually associated with
bronchospasm.)
Emergency Rx ( in brief!): A,B,C, including promotion of venous return + adrenaline (iv
preferably)
Steroids = of no immediate benefit, but may be of long term benefit. H1 and H2
antagonists of little or no use in full-blown anaphylaxis.(role in prevention tho)

 Type 2 HS (cytolytic reactions, antibody mediated):

Depend on reaction of circulating antibodies (either IgE or IgM) with antigens that are
usually associated with blood cell membranes. Drugs combine with prot’s in the cell
membrane of RBC’s, WBC’s or PLT’s  formation of antibodies. The Ig’s E + M then
cross react with the antigenic sites in the cell membrane in presence of complement 
cell lysis or agglutination.

Eg’s: haemolytic anaemia due to sulpha’s or methyldopa

Agranulocytosis due to phenothiazines, antithyroid drugs
Thrombocytopaenia due to thiazide diuretics
Also, evidence that “halothane hepatitis” also a type 2 HS reaction.

 Type 3 HS ( Immune complex-mediated responses):

First describes as the Arthus reaction (localized inflamm response 4-8hr after drug or
toxoid).
Due to formation of precipitin complexes by the reaction of circulating antibodies (IgG +
complement) with soluble antigens (eg bacterial toxins). Normally precipitins are
removed by the RES, but when excess antigen is present, immune complexes are
deposited in the endothelial lining of small vessels, glomerular membranes + connective
tissue of joints, causing an inflammatory response.

May be NB in: Acute glomerulonephritis

Polyarthritis nodosa
RA
Serum sickness : - some drugs may act as haptens ( eg after sulpha’s,
penicillin etc)
NB: no prior exposure to drugs needed, but depends on the continuous prod of antibodies
(esp IgG). Serum sickness usually = self limiting and treatment very rarely needed.

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  Type 4 HS ( cell-mediated or delayed HS):

Antibody formation not involved.

Reaction solely results from combination of antigen with T-cell (killer) lymphocytes.
Antigen or hapten introduced by contact or injection, combines covalently with receptors
on the lymphocyte membrane  lymphocyte mitosis  local release of lymphokines 
 vascular permeability. Local inflammatory reaction usually occurs within 24-48 hrs
(erythema, blistering, exfoliation)

Involved in: Positive Mantoux test

Most forms of contact dermatitis (metals or drugs; latex)

Drug rashes ( erythema multiforme / Stevens-Johnson sy) + morbilliform

rashes sometimes seen with ampicillin / amoxicillin in pts with
glandular fever or CLL.

Anaphylactoid reactions:

Due to release of vasoactive substances (histamine, 5-HT) from mast cells or circulating
basophils after the IV administration of certain drugs.
Mechanism of vasoactive substance release = via direct or non-immunological
mechanisms (specifically do not require immunoglobulin cross-linkage):

 Direct histamine release from mast cells: NMB’s ( esp tubocurarine) + morphine
 Complement activation, either via classical or alternative pathways

As opposed to anaphylaxis:
 Prior exposure not needed
 IgE not involved
 Severity of reactions usually dose dependant (and or rate of injection)
 Can be as severe as anaphylaxis, but usually less severe.

Many drugs implicated including: Iv induction agents, NMB’s, ganglion blockers, certain
contrast media and colloid infusion.

Management = same as for anaphylaxis

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C) Pathological Variability:

Mainly due to:

 Liver disease
 Renal disease
 Respiratory disease
 Cardiac disease
 Neurological disease
 Endocrine disease

 Liver disease:

Liver disease can affect drug clearance as follows:

 Alterations in hepatic blood flow
 Plasma protein binding changes
 Changes in intrinsic clearance
 May also be associated with a  renal flow (hepatorenal syndrome)

These effects can be complex + depend on type + duration of liver pathology.

Pancuronium has been well studied: Obstructive disorders lead to decreased Cl of muscle
relaxants dependent on liver metabolism / bile excretion (eg pancuronium) and prolongation of
duration of action.
If cirrhosis predominates, the  Vd, associated with changes in PPB, results in lower pl
concentrations of pancuronium and decreased uptake at receptor sites.

In chronic liver disease, dose requirements for Thiopentone is also decreased, and duration of
action prolonged. (due to  PPB,  free fraction, and prolonged distr t1/2)

GA also will influence hepatic clearance, due to alterations in CO + redistribution of regional

flow. Elimination of drugs with high hepatic clearance (opioids, LA’s, B-blockers) will be
reduced

 Renal disease:

Many drugs + their metabolites are wholly or partly eliminated by the kidneys, thus prolonged
responses +/- toxic effects can be expected with  renal fx. Nomograms for adjustment of
dosages in renal disease exist and is based on creatinin clearance.
Elimination of acidic drugs (penicillin, NSAIDS) = further complicated by accumulation of
organic acids, which competes with them for active tubular transporters.

Alterations in PPB also possible; - Binding of acidic drugs (normally to albumin) =

usually decreased.
- Basic drugs = more variable response, but an  in free
fraction of some drugs ( diazepam, morphine) may occur .

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Thiopentone: dosage requirements reduced ( free fraction, possibly altered
permeability of BBB, ? abn cerebral metabolism)

Opioids: kidneys partly responsible for Cl of opioids + their metabolites. Dose

requirements are decreased in RF and active metabolites (M6G, nor-pethidine etc) may
accumulate. Fentanyl undergoes rapid / extensive liver metabolism, but its metabolites
have little or no activity / toxicity (thus a good choice in ARF and CRF).

Muscle relaxants: Apparent resistance to onset of blockade. ? Due to altered distribution

with changes in PPB, sometimes seen.
40-50% of pancuronium and > 90% gallamine renally cleared. Tubocurarine (also ~ 40-
50% renally) undergoes reciprocally ’ed biliary excretion if renal Fx decreases.
Vecuronium and Roc duration only slightly increased in RF (mainly liver / bile).
NB: Re-paralysis after reversal = unlikely in renal failure, as the clearance + elimination
of anticholinesterases decreases in parallel with NDNMB’s.
Note: The PK’s of atracurium and mivacurium = unaffected by renal failure.
Laudanosine, breakdown product of both atracurium / cisatracurium, may accumulate to
a limit, but unimportant extent in pts with renal failure.
Variability in response to sux only occurs if there is concomitant hyperkalaemia.

Other: Diazepam: decreased elimination of active metabolites, nordiazepam +

temazepam, with prolonged sedative effects.

 Respiratory disease:

In COPD, respir centre may become insensitive to CO2 and rely more on hypoxic drive.
Thus, the resp depressive effects of opioids, IV induction agents may be exaggerated.
Also, BZD’s in sedative doses (eg for endoscopic procedures), may cause CO2 narcosis.

Acid base changes + electrolyte imbalance associated with chronic resp disease may
result in variable responses to MR’s (eg Resp Acidosis  prolonged duration)

V/Q abnormalities: rate of induction with poorly soluble volatiles (eg desflurane) can be
delayed. Not affected with more soluble agents, as compensatory increases in alveolar
concentrations can be obtained.

 Cardiac disease:

Most general anaesthetics (IV or inhalational) can induce depressant effects on different
CVS parameters (contractility, coronary flow, SVR, baroreflex activity etc) and those
effects can be exaggerated in pt with decreased reserve from various diseases.
Eg, Thiopentone induced myocardial depression in pt with constrictive pericarditis, may
lead to profound hypotension / pulm oedema.

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In some cases of cardiac disease, a beneficial effect can be achieved with some
anaesthetic drugs ( eg  cardiac work and  SVR with moderate [ ]’s of volatiles in CCF)

Pharmacokinetically, -profound changes in distribution + elimination of anaesthetic drugs

can occur in pts with low CO-states. (eg Muscle relaxants’ speed of onset)

Drugs with signif muscarine effects (sux, halothane), can sensitize heart to arrhythmias in
response to circulating catecholamines.

Isoflurane: A potent coronary vasodilator may cause a maldistribution of coronary flow

away from ischaemic areas (‘steal-effect”) The clinical significance of this has been
debated. It seems to be more likely in pts with “steal-prone” coronary artery anatomy.
(this seem not to occur with sevo and des) [Stoelting 754]

Exaggerated changes in BP can occur with induction in hypertensive (poorly ctrl’ed) pts.

 Neurological disease:

Muscle relaxants: Many neurological diseases = associated with abn response to MR’s
 NMJ (eg Myasthenia + Lambert-Eaton): - both show  sensitivity to NDNMB’s
( Sux =variable; eg In MG, - apparent resistance to single dose, but  chance of
ph 2 block. In LE, -  sensitivity to sux)
 Muscle fiber: - Dystrophia myotonica (OD): - prolonged generalized myotonia
following sux, as well as hyperkalaemia (can enhance arrhythmias
in underlying abn myocardium )  Sux absolutely CI’ed !!
Duration of NDNMB’s may be prolonged (give smaller doses).
Also  sensit to resp depressant effects of most anaesthetics
+ opioids. Halothane esp may induce cardiotoxic effects
 Muscle wasting (paralysis, MND, MS): -  sensitivity to sux (extra junct R’s) +
potential malignant arrhythmias sec to hyperkalaemia. (in acute paralysis, -as
soon as ~ 96 hrs  persisting up to ~ 6/12)
 Duchenne muscular dystrophy: Sux abs CI’ed !! ( MH-like response can occur)
 Other (muscular dystrophies other than Duchenne, Friedreich’s ataxia): -
unpredictable responses to both depolarizing and NDNMB’s can occur.

Autonomic disturbances (diabetic auton neuropathy, acute polyneuritis, Shy-Drager)

Enhanced drops in MAP can occur after administration of most anaesthetic drugs, or
drugs with signif CVS effects ( phenothiazines etc). = mostly due to abn baro-reflex
response.

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 Endocrine disease:

 Myxoedema : -  sensitivity to opioids + most general anaesthetic drugs

( multifactorial:  liver enzyme fx, changed Vd due to CCF / bradycardia,
changes in body temperature)
 Thyrotoxicosis: - enhancement of esp the oxidative microsomal drug metabolism.
Also ’ed PPB of both acidic and basic drugs. Variable drug responses can be
expected.
 Adrenal insufficiency: - adrenocorticosteroids exert a permissive effect on
catecholamines, thus exaggerated drop in MAP can occur in drugs with
propensity to  MAP (ie most anaesthetic drugs).
 Phaeochromocytoma: - drugs with ability to release histamine (eg morphine ) or
drugs that can induce arrhythmias ( halothane, enflurane), should be avoided.
 Carcinoid tumours: avoid histamine releasing drugs ( tachycardias + HTN)

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 Mechanisms of Drug Interaction

 Pharmaceutical incompatibility
 Pharmacokinetic reasons
 Pharmacodynamic reasons
 Combined toxicity
 Interactions due to changes in electrolytes / fluids

 Pharmaceutical incompatibility:

 PH: - Drug precipitation can occur if drugs with different pH’s are mixed
together ( eg Thiopentone mixed with midazolam)
- drug inactivation / property changes can occur due to pH differences. Eg
Sux mixed with Thiopentone, leads to rapid alkaline hydrolysis of sux.
Adrenaline can be changed from l- to d-isomer with pH changes
 Calcium: Addition of calcium into infusion-lines with NaHCO3 or blood may
result in precipitation.
 Osmolarity: infusing fluids with differing osmolarities can lead to interactions;
Eg Blood infused with 5% DW or mannitol  haemolysis
 “Salting out”: = when electrolytes are added to supersaturated sol’s (mannitol)
which leads to aggregation / precipitation of mixture.
 “Emulsion cracking”: = when calcium added to fat emulsions  extra cations
alter repelling surface charge on fat globules  coalesce.
 Interaction with administration sets: eg – GTN binds to plastic (sorption)
- Insulin can adsorp to the glass container or plastic syringes’ surfaces,
or drugs in stomach with activated charcoal.

 Pharmacokinetic causes:

Absorption: If one of the drugs has large SA, it can; bind or chelate other drug, alter
gastric pH or motility
Propranolol (weak base) has small very lipid sol unionized fraction that interferes
with the high lung uptake (75%) of fentanyl.
Adrenaline  the abs of LA’s and hylaluronidase  abs of LA’s
Distribution: - due to competition for PPB, displacement from tissue binding sites
(eg  s-digoxin with concurrent quinidine)
- Volatiles enhance NDNMB’s by increasing their blood distribution.

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Metabolism: - Liver enzyme induction (eg by steroids, barbiturates etc) can  duration of
action of concurrent drugs whose metabolism is liver dependant.
- Enzyme inhibition (eg by allopurinol, cimetidine, omeprazole,
haloperidol, erythromycin etc), will have opposite effect.
- Competition: Esmolol, remifentanil, atracurium, etomidate compete
for same pl esterases. Sux, mivacurium, trimethapan, procaine and
propanidid compete for pl-CHE.
Excretion: - renal excretion of weak acids or basis may be influenced by other drugs that
alter urinary pH, or competition with tubular transport (eg probenecide + penicillin) .

 Pharmacodynamic causes:

 Additive (1+1=2) or synergistic (1+1=4) effect when drugs with similar effects
given together.
 Competitive or non-competitive antagonism of concurrent given drugs (see PD’s)

 Combined toxicity:

Combined use of 2 or more drugs with toxic effects on same organ can greatly 
likelihood of organ damage ( eg ACEI’s + gentamycin + NSAIDS on kidneys)

 Alteration in fluids / electrolytes:

eg - Potentiation of digoxin by diuretics due to hypokalaemia or by Na, Ca, Mg due

to other concurrent drugs.
- Digitalis induced arrhythmias due to sux induced hyperkalaemia.

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 Adverse drug reactions ( ADR )
Classified as:

 Predictable (Type A): = extension of expected pharmacological effect

= dose dependant usually
= temporal relationship between administration and effect

 Unpredictable (Type B): - idiosyncratic, - uncommon, - unrelated to known

pharmacological properties of the drug, not dose dependent -usually involving
immune system in some way.

Predictable (type A):

 Abnormally high drug concentration at receptor site:

Eg due to pharmacokinetic variability = most common cause

 Alteration in the Dose-Response Curve:

Eg due to  receptor sensitivity will result in an increase in drug effect at same [ ].
(Warfarin in elderly)

 The shape of the Dose Response Curve:

Eg drugs with steep curve (low therapeutic index) = more likely to be associated with
dose-related toxicity, as only small  in dose to produce effect (eg propofol, digoxin).

 Concomitant drug therapy:

See above, drug interactions, for detail

Unpredictable (Type B)

 Idiosyncratic reactions (see above under “variability in drug response”)

 Cytotoxic reactions: - due to irreversible covalent binding of drug or its

metabolites to tissue macromolecules and hence tissue damage. (Some chemical
carcinogens bind directly with DNA). It is more common for covalent binding to
occur after metabolic activation to reactive metabolites. This activation usually
occurs in the microsomal mixed function oxidase system in liver. These covalent
binding often occurs close to the site of reactive metabolite production (eg
paracetamol and liver), but the MFO-system is found in other tissues as well.
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Addendum:

Easy “rule of 30” for calculating drug dosages in kids:

It has been shown that the following drug calculations follow BSA very closely in kids:

If weight < 30kg  body weight x 2  = % of adult dosage

If weight > 30kg  add 30 to weight  = % of adult dosage

Malignant Hyperthermia (MH)

Definition: State of hypermetabolism due to a calcium imbalance in skeletal muscle in

response to certain triggering agents in genetically susceptible persons.

Etiology / susceptibility: Autosomal dominant inheritance with incomplete penetration.

In 50-70% of affected families the gene predisposing to MH is thought to be on
chromosome 19. This is at or near the gene coding for the ryanodine/dihydropyridine
receptor complex at the T-tubule/sarcoplasmic reticulum complex of skeletal muscle. The
ryanodine receptor is involved in control of calcium flux in and out of the sarcoplasmic
reticulum. Note that the genes for muscular dystrophy and other metabolic disorders lie
nearby that for MH (some, eg Duchene’s MD has a very similar clinical picture to MH
when given suxamethonium for example, but MD thought not to be related to MH).

Incidence of MH 1:5000 to 1:200 000

Triggering agents: A lot has been written on this and there are still contradictions in the
literature, but at present only the following seems to be true triggers for MH in
susceptible patients (assoc with central core disease & King Denborough syndrome):
- the potent Volatiles (Halothane the most. N2O seems to be safe…)
- Suxamethonium (NDNMB’s = safe)

Note: Stress / heat can trigger MH in certain pigs and case report exist for a patient too.

Clinical picture:
Note: hyperthermia is not an early feature…
 Early:
- Sustained muscle contraction (not relieved by NMB’s) and or masseter
spasm.
- Tachypnoea (if SV)
- Tachycardia and or arrhythmias.
- Exhaustion of soda lime / hot soda lime.
 15

 Intermediate:
- pt feels hot / hyperthermia / sweating
- cyanosis
- dark blood in wound
- arrhythmias
 Late:
- generalized muscle rigidity
- prolonged bleeding
- unstable haemodynamics
- dark urine
- oliguria
- death

Laboratory: Electrolyte abnormalities, hyperkalaemia…

ABG: metabolic acidosis (or mixed picture due to hyperventilation if SV)

Management: (prognosis good IF TREATED EARLY: <5% mortality c/f 80% pre
Dantrolene)
- Most important is a high index of suspicion.
- Declare an emergence early if suspect MH (rapid deterioration, lot of hands
needed for mixing dantrolene, cooling measures etc)
- ABC and Discontinue triggering agent immediately / 100% Oxygen.
- Abandon surgery if feasible / safe surgical closure. If not possible, continue
with trigger-free anaesthetic.
- Specific Rx: Dantrolene 1-2mg/kg ivi bolus –repeat up to max 10mg/kg
- Further supportive Mx:
- Hyperventilation with 100% oxygen: to correct metabolic acidosis
- Cooling: by any means possible; eg cold iv fluids, fans, sponging,
packing with ice, irrigation of body cavities etc
- Correction of acidosis: bicarbonate (0.5 – 1 mmol/kg) until ABG back
- Rx hyperkalaemia if severe (insulin/dextrose, CaCl2, NaHCO3)
- Diuretics: +/- urinary alkalinization to reduce renal damage by
myoglobin. Mannitol or frusemide.
- Rx arrhythmias as appropriate
- Corticosteroids (?)
- Close monitoring ICU / Mx renal failure / DIC etc
 16
Dantrolene:

Presentation: Yellow powder, 20mg/vial. Vials also contain 3g mannitol (solubiliser) and
NaOH. Reconstituted with sterile water to 60ml (pH 9.5 = due to NaOH), no
bacteriostatic agent.

MOA: Direct acting skeletal muscle relaxant, probably by interfering with ca++ release
from SR (Ryanodine receptor antagonist).

Clinical uses: MH, Neurolept Malignant syndrome, chronic muscle spasticity, ecstasy
intoxication

Kinetics: A) Poor OBA, given IV

D) 85% PPB
M) Hepatically metabolized to 5 OH-dantrolene (active)
E) Metabolites renally excreted
NB: Elimination half-life 12hrs

Dynamics/Effects: Skeletal muscle weakness

S/E’s: Respiratory m weakness, diuresis, volume overload, hepatic failure
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Old SAQ’s:

1) What factors might explain the inter-individual variability in drug response seen with
the intravenous anaesthetic agents. (2005a: 29% pass…)

2) Discuss the factors contributing to the inter individual variability in the therapeutic
response to opioid analgesic medications. (2007a: 69% pass)

3) Briefly outline the acute management of malignant hyperthermia (during a relaxant general
anaesthetic). Describe the important aspects of dantrolene pharmacology relevant to treating malignant
hyperthermia. (2014b)