Poisoning : Kinetics to Therapeutics

Epidemiology of Poison Ingestion

Worldwide, the acutely poisoned patient remains a common problem for doctors working in emergency medicine. The causes of acute poisoning change over time. Some substances that were once very common causes of poisoning are now only rarely so, including barbiturates, older types of rodenticide (thallium compounds), and alkyl phosphate insecticides such as parathion. Newer medications, illegal drugs, and poisoning always have been a part of human life. The further scientific understanding of technical products such as cleaning agents and cosmetics such as cleaning agents and cosmetics and new consuming habits (intentional and unintentional) also have changed the overall picture substantially.

Within the United States, since 1983, the American Association of Poison Control Centers has compiled data covering 63 poison centers, which for 2014 reported a total of 2,617,346 cases. Children younger than 3 years were involved in 35.6% of these cases, and 47.7% occurred in children younger than 6 years. A male predominance is found among poison exposure victims younger than 13 years, but the sex distribution is reversed in teenagers and adults. Approximately 93.5% of exposures occurred at home, 1.7% at the workplace, 1.3% at school, 0.3% at healthcare facilities, and 0.2% at restaurants. A total of 1173 fatalities were reported, with analgesics, antidepressants, stimulants and street drugs, sedative-hypnotic-antipsychotic agents, and cardiovascular drugs being the most common agents responsible. Although involved in a majority of poisoning reports, children younger than 6 years incurred just 1.4% of the fatalities; 45.9% of poisoning fatalities occurred in persons 20 to 49 years of age; 24.1% of fatal cases involved two or more drugs or products. The majority of human exposures were acute (55%) or acute on chronic (20.5%). The vast majority (74.7%) of poison exposures were unintentional; a suicidal intent was identified in 11.7% of cases. Therapeutic errors accounted for 12.6% of exposures, with unintentional nonpharmaceutic product misuse accounting for another 5.8% of exposures.

Absorption

Absorption is the process of drug movement from the administration site to the systemic circulation. Drug absorption is determined by physicochemical properties of drugs, their formulations, the physiologic characteristics of the person taking the drug, and routes of administration. When given by most routes, a drug must traverse several semipermeable cell membranes, which act as a lipid barrier with small holes throughout located in various tissue, muscle, or gastrointestinal (GI) epithelium before reaching the systemic circulation. Drugs may cross these membranes selectively by passive diffusion, facilitated passive diffusion, active transport, or pinocytosis. Bioavailability is the most important term used to describe the rate and maximum amount of drug available to the body after its absorption. Drug solubility is a major factor in determining the bioavailablity. Area under the concentration curve, the best measure of bioavailability, is the integrated space under the curve of a plot of concentration of drug versus time. Peak serum level is important to know and will sometimes correlate with symptoms of drug exposure.

Distribution

Drug distribution refers to the movement of drug to and from the blood and various tissues of the body (e.g., fat, muscle, and brain tissue) and the relative proportions of drug in the tissues. Factors that influence distribution include blood perfusion, membrane permeability, plasma protein binding (PPB), regional pH gradients, and accumulation in fat and tissue reservoirs. The one-compartment model assumes rapid distribution, but it does not preclude extensive distribution into various tissues.

Many different plasma proteins such as albumin, various lipoproteins, and α ₁ -acid glycoprotein interact with various drugs primarily by electrostatic interactions. Only unbound drug is thought to be available for passive diffusion to extravascular or tissue sites where pharmacologic effects occur. PPB influences distribution and the apparent relationship between pharmacologic activity and total plasma drug concentration.

Apparent volume of distribution (V _D ) is a measurement of the apparent space in the body containing the drug. V _D is an artificial concept and depends partly on the lipid/water solubility properties of drugs. It is of value in describing whether a drug is predominantly to be found in blood or at other tissue sites. Drugs that bind strongly to plasma protein tend to have lower V _D .

Metabolism

Drug metabolism is the chemical alteration of a drug by the body. The liver is the principal, but not the sole, site of most drug metabolism in the body. The cytochrome P-450 enzyme system is particularly important because many different drugs also can induce or inhibit these enzymes, resulting in changing efficiency of the system in metabolizing drugs, which may enhance toxicity or diminish efficacy of the drug. “First-pass effect,” an important term of metabolism, refers that some drugs are metabolized in the liver immediately after absorption and then are excreted in the bile, leaving less active drug available to the site of action.

Phase I reactions of drug metabolism involve oxidation, reduction, or hydrolysis of the parent drug, resulting in its conversion to a more polar molecule. Phase II reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine. The substances that result from metabolism may be inactive, or they may be similar to or different from the original drug in therapeutic activity or toxicity.

Excretion

Drug excretion is the removal of drugs from the body, either as a metabolite or unchanged drug. There are many different routes of excretion, including urine, bile, sweat, saliva, tears, milk, and stool. By far, the most important excretory organs are the kidney and liver. In kidney, excretion of drugs depends on glomerular filtration, active tubular secretion, and passive tubular absorption. Urine and blood pH and the physical characteristics of the drug molecule are important in determining whether the drug is excreted in the urine or remains in the circulation. Drugs appearing in bile will enter the intestines and may be reabsorbed resulting in enterohepatic circulation. Biliary excretion eliminates substances from the body only to the extent that enterohepatic cycling is incomplete. Drugs with a molecular weight (MW) exceeding 300 daltons and with polar and lipophilic groups are more likely to be excreted in bile. Clearance is a measure of the ability of the body to eliminate a drug. The elimination behavior of a drug is described most simply by its half-life, the time needed for the drugs concentration to be halved.

Exposure Doses

The major difference between pharmacokinetics and toxicokinetics is the different exposure doses. It has been known for 500 years that toxicity is a matter of concentration. Paracelsus (1493–1541), the father of toxicology, stated, “All substances are poisons, there is none which is not a poison. The right dose differentiates a poison from a remedy.” This is known as the dose-response relationship, a fundamental concept of toxicology. It therefore would be unrealistic to assume that the body could handle administered compounds and their metabolites from these very high doses in a way similar to therapeutic or pharmacologic doses.

Solubility

Solubility may occur in the GI tract at toxicologic doses. This could give rise to drug precipitation in biologic fluids and in organs and tissues giving rise to toxicity that may not be associated with the intrinsic pharmacologic or toxicologic effects of the poison.

Bioavailability

Normal absorption behavior and hence normal bioavailability of a drug may change drastically in overdose situations. For example, ethanol and salicylates may paralyze the pyloric sphincter and delay their own absorption, especially when taken in large doses. This can be beneficial because gastric lavage (GL) can be employed long after ingestion when the drug would be expected to have been absorbed already. The overdose behavior of drugs is therefore difficult to predict, and laboratory results will be difficult to interpret because of unusual absorption behavior.

Plasma Protein Binding

PPB is generally reversible and always saturable at toxicologic doses. Measurement of the free fraction is often preferable clinically, especially for drugs with high degrees of PPB. This can in turn influence Vd and penetration into such tissues as the nervous system. It may give rise to different plasma concentration-effect relationships at toxicologic doses compared with pharmacologic doses.

First-Pass Effect

Hepatic clearance of drug during absorption is an enzyme-dependent process and enzymes responsible for first-pass metabolism may become saturated by toxicologic doses. This results in a higher-than-usual fraction of the drug reaching the intended receptors and may be manifested in more toxicity than expected. The metabolic pathways and metabolic effiency may differ at toxicologic doses relative to pharmacologic doses.

Renal Excretion

Renal excretion comprises satuable and nonsaturable mechanisms. It can be influenced dramatically by circulating drug concentrations, giving rise to changes in renal excretion effciency and clearance of drug from the body. This is particularly true for any compound that is actively excreted wholly or partially by the proximal renal tubules.

Physiologic Feedback

Because the toxicologic doses may be toxic to the host, depending on the site and nature of toxic events, this also may have a traumatic effect on physiologic feedback that may affect the ADME processes of drug.