Toxicology

Toxicology

Therapeutic Drug Monitoring (TDM)

Toxicology

 

Overdoses

- may be from loss of tolerance (just outta jail)

- variation in drug purity

- additional drugs added (ie fentanyl to heroin)

 

Inc sensitivity to drug

- may be a factor c stimulant drugs

- Excited Delirium Syndrome (ExDS)

 

Drug levels in blood highly variable and cannot be used on their own as indicator of toxicity

- tolerance; individual var in response to drug, drug metabolism, time when drug taken, route of administration, effects of tx in ER, postmortem redistribution

 

Postmortem Redistribution

After death some drugs (ie meth) leach outta tissue into blood; as a result the drug levels measured at autopsy may be considerably higher than they were at time of death

- blood in heart and major central vessels most affected

- femoral blood considered best type of sample for testing postmortem

 

Prescription drugs

- 36 k deaths / year

- overprescribing and drug interactions

 

Deaths from drug withdrawal

May cause death

- most dangerous with EtOH and benzodiazepine withdrawl

- sx: shaking, loss of appetite, agitation, delirium, dehydration

- death usually from seizures

 

Therapeutic Drug Monitoring (TDM)

 

- direct relationship bwt drug level and drug effect

-- not always true (delayed effects 2/2 need to induce some biologic change (warfarin, valproic acid, and tricyclic antidepressants)

-- digoxin response affected by plasma K+ and Mg++

 

TDM is needed when

1) not possible to directly measure drug effect (such as blood pressure in patients c HTN)

 

2) pt is still c signs of dz and questionable if pt is taking drug or abnormal absorption / metabolism

 

3) sx may be 2/2 lack of drug or drug toxicity

 

Toxicity versus Therapy

TDM needed if toxicity at plasma levels just above their therapeutic range

- therapeutic index is ratio of average toxic dose divided by average therapeutic dose

- lower therapeutic index = more dangerous drug

 

Free Drug Levels

Many drugs bind to serum proteins and (similar to hormones) only the fraction of drug remaining free is able to bind receptors

- in highly protein bound drugs, a decrease in binding protein lowers total drug concentration in serum, but

increase free drug concentration and, thus, drug effect.

- increased binding proteins have opposite effect, increasing total drug levels but lowering drug effect

 

The most important drugs having high protein binding are phenytoin (dilantin), carbamazepine, valproic acid, and lidocaine

-- phenytoin binds albumin, lidocaine binds orosomucoid, an acute phase response

protein

- in albumin bound drugs, major conditions mandating measurement of free drug levels are low levels of albumin (< 3 g/dL) or presence of factors decreasing protein binding (a in s renal failure).

 

Pharmacokinetics

 

Drugs must enter plasma and equilibrate c tissue

- drugs given PO or IM, variable fractions of drug absorbed and enter plasma; this fraction is called bioavailability.

- time taken for drug to equilibrate c tissue is distribution phase. (usually minutes; except digoxin, 6-8 hours)

- Blood levels drawn before distribution complete are falsely high.

After distribution complete, can calc volume of distribution (Vd); apparent volume in which the drug is located, calculated from the concentration of drug before the dose (Cbefore) and that after the dose (Cafter) as Clearance (the rate at which drug is removed from plasma by liver metabolism or renal excretion)

- Most drugs c first order kinetics (rate of clearance of drug related to drug concentration; a constant proportion of drug is removed per unit time)

- fractional clearance constant, kd, predicts concentration at any time, t, (Ct) after distribution from the initial concentration (C0)

- time for concentration to fall to half of its orginal value (Ct/C0 = ½) is half-life; calculated as 0.693/kd (0.693 = ln 2)

 

· Some drugs (metabolized by the liver) can saturate metabolic enzymes; at which point, clearance reaches Vmax and is independent of concentration, and a constant amount of drug is removed per unit time = zero order kinetics.

- zero order kinetics include phenytoin (dilantin),

ethanol, salicylates, and theophylline.

 

Steady State

After drug started, levels rise gradually. Unless an initial loading dose is given, it takes 5 half-lives for drug concentration to reach steady state

- once steady state is achieved, ~5 half-lives to cleared drugs

 

Pharmacogenetics

 

= differences in rate of metabolism based on genetic differences in activity of metabolic enzymes

- many drug metabolizing enzymes have point mutations that alter enzymatic activity, causing differences in response to doses of drugs

- thiopurine methyltransferase (TPMT), metabolizes 6-mercaptopurine and azathioprine. Variants other than TMPT*1 have reduced activity and lead to accumulation of toxic levels.

- warfarin metabolism, cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1), have mutations that are linked to high rates of dangerously prolonged INR with standard doses of warfarin.

 

Specific Drug Information

 

Barbiturates often classified based on duration of action: ultrashort (such as ), short, and long (such as phenobarbital, half-life of several days).

- generic method to detect barbiturates uses UV spectrophotometry at two different pH’s; which changes their absorbance spectrum (the only class of compounds measured in this way)

 

Digoxin equilibrates very slowly with tissue; taking 6-8 hours distribution to tissue to be complete, at which time 98% of digoxin is bound to receptors on cardiac and skeletal muscle.

- If levels are drawn before this time, plasma levels will be inappropriately high.

- Secondly, there are endogenous substances that behave like digoxin (such as ouabain); high levels of these occur in renal failure, shock, preeclampsia, and in neonates.

-- These digoxin-like substances cross-react in digoxin assays. Finally, digoxin overdosage is treated using Fab fragments of anti-digoxin antibodies (Digibind, DigiFab®), which work by pulling digoxin off of receptors and allowing its renal excretion. The digoxin-Digibind complex reacts variably in digoxin assays; some measure the complex, with resulting levels often 50-100x normal therapeutic levels; some do not measure it at all; and some show interference from any free Digibind, causing variable results

 

Phenytoin is MC drug to show zero order kinetics; thus, even small changes in dosage may cause

markedly elevated phenytoin levels

- Secondly, a new form of phenytoin is now available, fosphenytoin, which can be given intravenously. This pro-drug reacts variably in phenytoin assays, in some not being measured at all, while in others showing variable cross-reactivity. Thirdly, generic forms of phenytoin show rapid absorption, while DilantinÒ is absorbed slowly over about 24 hours. Fourth, phenytoin is highly protein bound; low albumin, renal failure, and salicylate cause increased free phenytoin and may produce toxicity at lower total plasma concentrations. Finally, because phenytoin is metabolized, other drugs may change its rate of clearance; carbamazepine and phenobarbital decrease its concentration, while cimetidine, warfarin, and INH increase its concentration.

 

Acetaminophen is generally a safe analgesic, but with

intentional overdosage (average toxic dosage 15 grams) or with depletion of glutathione (alcohol abuse, starvation) and increased activity of oxidant enzymes (induced by alcohol), toxicity can occur with even therapeutic doses. After ingestion, toxicity is best evaluated using the Rumack nomogram, plotting log of acetaminophen concentration on the y-axis and time after ingestion on the x-axis (Figure 3). The Rumack nomogram is ONLY useful in cases of single dose ingestion of regular release formulations, and cannot be used with sustained release forms or in accidental, cumulative overdosage in persons with depleted glutathione.

 

Alcohols

– Ethanol is the most common drug causing toxicity. The units of ethanol are often given in one of two ways: mg/dL and %; to convert from mg/dL, divide

by 1000. For example, a common limit for defining

toxicity is 100 mg/dL or 0.10%. Ethanol shows zero

order kinetics at concentrations above 100 mg/dL;

above this level, ethanol concentrations fall by an

average of 18 mg/dL/hr (a common question on the

boards). In general, levels above 350-400 mg/dL

produce coma

- The most important other alcohols are methanol and ethylene glycol, which produce both metabolic acidosis and increased anion and osmotic gaps. Ethylene glycol also causes renal failure as well as cardiac and pulmonary toxicity, while methanol primarily causes blindness and CNS toxicity.

- The metabolites of both are more dangerous than the parent compound (ethylene glycol: oxalate and

glycolate; methanol: formic acid). Isopropanol and

ethanol cause increased osmotic gap, but not an anion gap. Treatment of these alcohol/glycol poisonings typically involves use of an inhibitor of alcohol dehydrogenase (formerly ethanol, currently 4-

methylpyrazole or Fomepizole®)

 

Carbon monoxide, an odorless, colorless gas made from incomplete combustion of fuels, is the

most common cause of accidental and suicidal

poisoning. Carbon monoxide cannot be measured

readily, but carboxyhemoglobin can be quantified by

differential spectrophotometry. At low levels, carbon

monoxide produces no or mild symptoms such as

weakness and headache. Once more than 20% of

hemoglobin is carboxyhemoglobin, symptoms of viral

illness such as fatigue, irritation, nausea, vomiting, and headache occur; levels over 40-50% may produce coma and death. In chronic poisoning, neurologic and psychiatric symptoms predominate.

 

Iron is the most common cause of fatal overdose in

children, usually from accidental ingestion of iron

supplements. Common symptoms include nausea,

vomiting, GI bleeding, and in severe cases shock and

lactic acidosis. Serum iron levels > 500 mg/dL are

associated with significant toxicity, and those > 1000

mg/dL can be fatal if not treated.

 

Lead is MCC of chronic poisoning in kiddos and MC source of poisoning is peeling paint from houses built before 1970, when lead was removed from house paints. Home renovation of older houses generates paint dust that is also dangerous.

- Any detectable blood lead level (usually > 5 mg/dL) is associated with learning disability in children.

- Classic toxicity, including anemia, abdominal pain, peripheral neuropathy, and neurologic changes occur at levels over 40-60 mg/dL. Other tests for lead poisoning, such as zinc (free erythrocyte porphyrin), and urine d- aminolevulinic acid, are not as sensitive as whole blood lead levels for detecting lower levels of exposure (< 25 mg/dL. Urine lead excretion after EDTA chelation is a good measure of chronic lead toxicity; over 1 mg lead per mg EDTA indicates high body lead burden.

 

Organophosphates (in insecticides) inhibit acetylcholinesterase.

- Tests for exposure to these agents measure red

cell (true) acetylcholinesterase and serum

(pseudo)cholinesterase.

- Plasma levels decrease first with acute exposure, and return to normal more quickly with recovery from poisoning. Toxicity occurs with levels < 50% of normal.

 

References

 

1. Osler notes