Pharmacology – Toxicology

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Science of detection, mechanisms, adverse effects of chemicals upon living organisms including symptoms and treatments
Toxicology

The rate at which drugs are absorbed, distributed, metabolized, and eliminated by the body
Toxokinetics

Actions and interactions of an exogenous compound within an organism, including the compound’s affects on processes at the organ, cellular, and molecular levels
Toxicodynamics

Specialties of toxicology
Clinical, genetic and genomic, environmental, occupational, forensic

Study of symptoms, detection, mechanisms, treatments
Clinical toxicology

Deals with the collection, interpretation, and storage of information about gene and protein activity within particular cell or tissue of an organism in response to toxic substances
Genetic and genomic toxicology (Toxicogenomics)

Prevention and effects of pollutants on living organisms (EPA regulates pesticides, chemicals, and all other pollutants, hazardous waste in the water and air)
Environmental toxicology

Prevention and effects of toxins in the work place (OSHA determines whether employers provide safe working conditions)
Occupational toxicology

Detection of toxins investigation of death, poisoning, and drug use for legal purposes (DEA)
Forensic toxicology

Greek physician in ancient Rome that classified plants according to their toxic and therapeutic effects
Dioscorides

Babylonian physician in the IXth century that wrote the Book on Poisons
Ibn Wahshiya

“All things are poisons and nothing is without poison, only the dose permits something not to be poisonous”
Paracelsus – Theophrastus Phillipus Auroleus Bombastus von Hohenheim the SVth Century

Toxicological assessments
Hazard assessment, exposure assessment, dose response, risk assessment

Likelihood that injury will occur, what depends upon the inherent toxicity of substance and amount that an individual is exposed to
Hazard assessment

How much, how often, which route toxins were delivered
Exposure assessment

Effects in response to the dose, evaluation of how the molecules, cells, organisms will respond to a dose of a poison
Dose response

1. Toxic effects can be
Pharmacological, phatological, genotoxic

2. Toxic reactions can be
Acute, subacute, chronic

3. Toxic effects occur
Locally, systemically

4. Toxic effects can be
Reversible, irreversible, delayed, allergic, idiosyncratic

Examples of Pharmacological toxic efffects? Pathological toxic effects? Genotoxic effects?
Barbituaries > CNS depression
Acetaminophen (tylenol) > analgesic, antipyretic medication > liver damage
Cisplatin > crosslinking DNA

Examples of toxic reactions that are acute? Subacute? Chronic?
Large dose, rapid
Repeated exposure up to weeks
Repeated exposure months to years

Toxic effects that are local? Systemical?
At site of first contact, SO2
Absorption & distribution often affects one or a few organs

Examples of toxic effects that are reversible? irreversible? delayed? allergic? idiosyncratic?
Liver
CNS
Aplastic anemia weeks
Previous sensitization
Genetically determined abnormal reactivity to low or high drug dose

Three routes of entry for toxins
Air pollutants enter through respiratory system, water and food pollutants through GI, solid objects pollutants acting locally or/and entering through skin

Examples of air pollutants entering through respiratory system
Ozone, CO, SO2, NO2, particles less than 2.5 nm, DGP (aircrafts, ships, 18 wheelers), pesticides

Examples of water and food pollutants entering through GI
Cadmium, lead, mercury, pesticides, bisphenols

Examples of solid objeccts pollutants acting locally or/and entering through skin
Cadmium, lead, mercur,y, pesticides, detergent facilitated entries

Principles to deal with poisoned patients exposed to toxins
1. Remove source of toxin and prevent further absorption
2. Antagonize effects of toxin
3. Neutralize toxin
4. Enhance metabolism that reduces toxicity
5. Prevent accumulation
6. Promote excretion
7. Reduce biotransformations that enhance toxicity
8. Provide supportive care

Removing source of toxin and preventing further absorption
Pulmonary route, dermal route, parenteral, oral, emesis, absorption, altering re circulation, repeated charcoal administration, limiting distribution

Remove victim from site of exposure
Pulmonary route

Minimizes absorption, removes contaminated clothing, wash with cold water but not hot water
Dermal route

Constrictive bands, restriction of movement
Parenteral route

Remove toxin from stomach and prevent absorption
Oral route

Emesis
1. Ipecac syrup
2. Gastric lavage stomach pump gastric irrigation
3. Apomorphine subcutaneous injection

Absorption
1. Activated charcoal
2. Colestyramine
3. Sorbitol
4. Specific antidotes/ antibodies for a few classes of toxins

Not used in coma, convulsion, petroleum swallowing
Ipecac syrup

Strongly absorbs water, not binding Fe, K, Li, Poorly binds alcohol, cyanide
Activated charcoal

Binds a limited number of toxins
Colestyramine

Cathartic accelerates defecation
Sorbitol

Nonionized morphine enters stomach from blood. Charcoal can help to remove morphone from stomach
Specific antidotes/antibodies for a few classes of toxins

Eg. for drugs with long enterohpeatic circulation like phenobarbital
Altering re-circulation

Eg. nonionized morphine enters stomach from blood
Repeated charcoal administration

What removes morphine from stomach?
Charcoal

Eg. for drugs changing pH like salicylate poisoning > acidemia pH = 7.0
Normalize to pH 7.4 NaHCO3 & administer loop diuretic – Furosemide

Antagonizing effects of absorbed toxin is a standard ER procedure to maintain
Heart beat, BP and circulation
Respiration
Control of CNS, suppress seizures
Control thermoregulation

Neutralize toxins (metals = chelation)
Competitive antagonists
Specific antagonists
Antihistamine
Chelates
Chemical neutralization
Noncompetitive antagonists

Competitive antagonists
Naloxone
Flumazenil
Ethanol

For morphine iv reverses sedation, respiratory depression
Naloxone

For overdose of benzodiazepines
Flumazenil

In methanol poisoning
Ethanol

Specific antagonists
Antibodies

High affinity for toxins and venoms
Antibodies

Antihistamine
Cimetidine

A histamine H2-receptor antagonist in anaphylaxis = hypersensitivity, degranulation of mast cells, histamines (symptoms: skin, respiratory, gastrointestinal, vasculature, heart, CNS)
Cimetidine

Chelates
Dimercaprol (BAL)
Calcium disodium EDTA ethylenediaminetetraacetic acid
Deferoxamine
Penicillamine
sDOTA
rMTT

Acute poisoning by arsenic, inorganic or elemental Hg
Severe Pb in conjunction with EDTA, well absorbed from IM, succimer is a water soluble analog of dimercaprol, oral of the treatment of Pb
Dimercaprol (BAL)

Does not cause hypocalcemia higher affinity for Mn(II), Cu(II), Fe(III), Pb(II) and Co(III), does not penetrate membrane chelates extracellular metal ions
Calcium disodium EDTA ethylenediaminetetraacetic acid

When plasma concentration of Fe exceeds the binding capacity of transferrin (apotransferring) (toxic or genetic autoomal recessive atransferrinemia) free ferrous iron reacts with peroxides to produce free radicals > damage DNA, proteins, lipids used for treatment of Fe poisoning IV, IM, not oral
Deferoxamine

Water soluble derivative of penicillin, used orally for treatment of Cu and Pb poisoning
Penicillamine

Highly specific for Cu, Ni, Zn, Cd
sDOTA, rMTT

Chemical neutralization
Sodium nitrite

In cyanide poisoning binds cyanides. The thiocyanate is then excrete in the urine
Sodium nitrite

Noncompetitive antagonists
Cyclothiazide, atropine

Non competitive antagonist of mGluR1 receptor (bind to a separate binding site from the agonist)
Cyclothiazide

In poisoning with organophosphate insecticides (900 Bug killers effective also on humans) block AChE
Atropine

No effective way to increase toxin specific metabolism into benign metabolites in acute intoxications
Enhanced or competitive metabolism

Introducing competitive inhibition, eg. methanol 10 mL > 10-30h can cause permanent blindness by destruction of the optic nerve and 30 mL; acts directly onto CNS and as metabolites to formic acid by alcohol dehydrogenase (ADH) (with reduction of NAD+ to NADH); competing with ethanol; Zn binding pocket
Enhanced or competitive metabolism

Acetaminophen 95% metabolized in liver into inactive sulfate and glucuronide conjugates > excreted by kidneys 5% metabolized by cytochrome P450 (polymorphisms)into toxic N-acetyl benzoquinone (NAPQI) NAPQ detoxified by SH groups of glutathione to be secreted by kidneys P450 metabolic route is preferred one in Tylenol overdose and polymorphisms, hence accumulation of toxic NAPQI. Glutathione poorly absorbed from GIT, therefore precursors cytseine or N-acetyl-cysteine administered
Prevent accumulation

Severe intoxication, kidney failure, lethal
Promote excretion of toxin, dialysis, hemoperfusion

Manage: respiration, hypotension, seizures, thermoregulation
Provide supportive care

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