Introduction to Toxicology (Lynn R. Panganiban, MD) Flashcards
It is the science of adverse effects of chemical, physical and biological agents on living organisms.
Toxicology
What are the physical agents toxicology is concerned with?
Radiation and heat waves
What are the biological agents toxicology is concerned with?
Parasites and infectious disease etiologic agents
Define: Toxicity
Ability of a substance to cause harm in an organism
T/F: Toxicity is an innate property of the substance.
True
While we cannot control a drug’s toxicity, we can control its toxicity during (1).
Manufacture
Define: Toxicodynamics
- Mechanisms of actions of chemicals
2. Extension of definition of pharmacodynamics
Define: Toxicokinetics
ADME of substances in their toxic statess
i.e. changes from 1st order to 0 order
Define: Poison
Any agent capable of producing a deleterious effect leading to injury or death
What is the more medically acceptable term for “poison”?
Toxicant
T/F: Toxins are artificial substances.
False
They are naturally occurring substances of endogenous plant or animal origin.
What are used for substances that are synthetically manufactured?
Xenobiotics
What is the state of being overdosed on drugs, medicaments, chemicals and biological substances?
Poisoning
What is the difference between an adverse reaction and poisoning?
An adverse reaction always occurs within therapeutic doses.
Enumerate the factors affecting responses to toxic agents
- Physical & chemical properties
- Exposure situation
- Individual factors
Enumerate the important physical and chemical properties of toxic agents
- Physical state
- Solubility
- Vapor pressure
- Vapor density
- Reactivity
What physical state is most toxic to humans?
Gas
In terms of solubility, what toxicants are most harmful?
Fat-soluble, non-ionised substances
What values of vapour pressure are considered most toxic?
Greater than or equal to 1 mmHg
What values of vapour density are considered most toxic?
Greater than one (heavier than air)
Dangerous for people on the first floor!
Toxicants with (1) and (2) are more deleterious.
(1) Charged particles
(2) Reactive oxygen species
Define: Acute Exposure
- Exposure happens in less than 24 hours.
- Single dose
- Series of doses within 13hrs if administered orally
- Continuous for 4 hrs via inhalation
- Large volume of drugs
- Effects appear within 14 days
Define: Subacute Exposure
- Repeated daily exposure for 21 ways via specific route
- No need for high dosage
- SSx manifest within 21 days.
Define: Subchronic Exposure
- Repeated daily exposure for 90 days
2. Can be low dose
Define: Chronic Exposure
- Lifetime exposure
- Two years for rat and mice
- Seventy years for humans
- May result in transgenerational effects
What parameter is expressed in terms of exposures/time period?
Frequency
What parameter is critical to the concentration level of substance in biological fluids at the site?
Frequency
Enumerate the major routes by which toxic substances gain access to the body
Ingestion Inhalation Dermal/Percutaneous Parenteral Mucosal
Rank the routes of entry in terms of descending effectiveness toxicity
Parenteral Inahalational Intraperitoneal Intramuscular Subcutaneous Intradermal Oral & Dermal
What is the most critical factor determining whether the intrinsic property of a substance will be expressed?
Dosage
T/F: Dose should not be dependent on the weight of the individual.
False
It should be.
Which tenet may not necessarily apply in cases of toxicity?
The dose makes the poison
What are examples of endocrine disruptive agents?
Bisphenol A (found in plastics and can affect reproductive development of children) DDT (affects reproductive development)
What substances can induce their effects in picograms?
Dioxins
What is the mechanisms of action of carcinogenic or genotoxic substances?
Disrepair of components of the central dogma
Enumerate the individual factors that contribute to toxicity
Age
Sex (pregnant women > women reproductive age group)
Genetic Background (toxicogenomics; G6P deficiency bleeding from nitrates)
Nutritional Status (low protein/albumin)
General Health Status (liver, kidney or heart disease)
ADME
T/F: Toxic action of drug is an exaggeration of its therapeutic action.
False
What happens when a person overdoses on paracetamol?
Develops liver problems
What is the mechanism of action of isoniazid?
Attacks the ribosomes of Mycobacterium
How does isoniazid overdose manifest?
Inhibition of GABA synthesis resulting in seizures and B6 deficiency
T/F: One toxicant may exert several mechanisms of toxic actions.
True
Toxicity may also affect the (1) not just the CNS. Give an example.
blood; lead toxicity
What does lead toxicity do to the body?
- Breakdown of sulfhydryl molecules of myelin sheaths causing neuropathy
- Interference with haemoglobin production by enzyme inhibition leading to multi-organ system effects
e. g. alcohol & tobacco
T/F: Toxic action can only be brought about by the parent compound.
False
What is a metabolite of diazepam that has the same potency as its parent compound?
Oxazepam
When metabolised, what is paracetamol converted to? Is it toxic?
NAPQI; yes
T/F: The mechanism of toxic action in acute exposure is no different from those in chronic exposure.
False
e.g. seizure as a result of acute exposure and cancer as a result of chronic exposure
What substances inhibit acetylcholinesterase?
Organophosphate
Enumerate the clinical signs of cholinergic manifestation
Salivation, diarrhoea, pupil dilation, sweating and bradycardia
Intensity of the toxic effect depends primarily on what properties of the ultimate toxicant?
Concentration and persistence
T/F: The effect of a chemical is dependent solely on the dose administered.
False.
It depends more on the concentration and disposition of the chemical in the target organ.
T/F: Drugs that are normally metabolised through first-order kinetics may change to zero-order kinetics during overdose.
True
Give examples of drugs that exhibit zero-order kinetics when overdosed.
Phenobarbital, theophylline and salicylate
T/F: During overdose, some drugs may change their volume of distribution
True
Enumerate the factors affecting kinetic processes.
- Duration and concentration at the portal of entry.
- Rate and amount of chemical absorbed
- Distribution of the toxicant within the body
- Efficiency of biotransformation and nature of metabolites
- Ability of the chemical or its metabolites to pass through cell membranes and come into contact with specific cell components
- Amount and duration of storage of the chemical or its metabolites in body tissues
- Rate and site of excretion
T/F: The higher the concentration of the chemical at the portal of entry, the greater the damage
True
e.g. concentrated HCl causes greater damaged than diluted HCl
In terms of rate and amount of chemical absorbed, when will toxicity be low?
Slow absorption and small amount of absorption
T/F: Slowly released products have a wide margin of safety.
True
Where are toxicants most highly concentrated?
Brain, heart and kidneys
T/F: The organ where a chemical is most highly concentrated is where the most tissue damage occurs.
False
Describe: Lead as Storage Depot
95% of lead is stored in the bones for years, where it may reach the brain and cause effects to the hematologic and nervous systems.
Describe: DDT as Storage Depot
DDT is converted to DDE and stored in adipose tissue, bones, and plasma proteins for up to 8 years.
What is the half-life of lead?
20 years
T/F: A chemical may be converted into a metabolite that is more toxic than the parent compound.
True
What drugs undergo Michaelis-Menten kinetics at toxic concentrations?
- Paracetamol
2. Alcohol (0 to begin with)
In what conditions will the blood-brain barrier not work?
Hypoglycemia and acidosis
T/F: Heavy metals can’t pass through the placenta.
False
Heck, even nicotine can (fetal tobacco syndrome)
What is the half-life of DDT in the body? In the environment?
30; 100
What is the relationship between rate of excretion and toxicity?
Greater rate, less toxicity
What is responsible for delayed excretion of certain compounds via enterohepatic circulation?
Bacterial flora in distal ileum convert metabolites into lipophilic states
What compounds are recovered via enterohepatic circulation?
Carbamazepine (anti-convulsant) Dapsone (anti-infective; leprosy) Phenobarbital (anti-convulsant) Quinine (for malaria) Theophylline (asthma and lung problems)
What compounds are ionised in alkaline urine? acidic urine?
Weakly acidic drugs; weakly basic drugs
Enumerate the kinetic processes the body adapts to protect itself from toxicants.
Presystemic elimination
Distribution away from target site
Detoxification
Excretion
What is the process that prevents formation of ultimate toxic metabolites and enhances its elimination?
Detoxification
What agents are used in detoxification?
Antioxidants
Glutathione
Superoxide dismutase
What are the modes of excretion?
Liver Kidney Bile GI tract Breast milk
Enumerate the potential stages in development of toxicity after clinical exposure
- Delivery
- Interaction with target molecule
- Cellular dysfunction & injury
- Dysrepair
What are direct injuries usually caused by?
Caustic agents
Ethylene glycol is converted to (1) by (2), which produces (3) and (4), causing damage to (5) and (6).
(1) oxalic acid (potential acute kidney and lung injury)
(2) oxidation
(3) acidosis
(4) hypercalcemia
(5) kidney
(6) GIT
What are the two altered states of cell regulation? Of cell maintenance?
Dysregulation of gene expression
Dysregulation of ongoing cellular activity
Impaired internal maintenance
Impaired external maintenance
What are the forms of interaction with the target molecule?
Non-covalent binding
Covalent binding
Electron transfer (i.e. snake venom)
Enzymatic reactions
Which process is most affected by toxicity? What are its components?
Cellular regulation
Dysregulation of gene expression
Dysregulation of on-going cellular activity
Common endocrine disruptors affect?
Reproductive genes
Thyroid
Obesity
Give examples of compounds that produce transgenerational toxicity
Bisphenol A
DDT
Nonlyphenol
What compounds mimic endogenous estradiol?
Bisphenol A
DDT
Phthalate
What compounds produce inhibitory effect on the M2 and M3 receptors?
Atropine and atropine-like drugs
What causes “Alice in Wonderland” toxidrome?
Datura metel (Angel’s trumpet plant or talampunay)
What are the components of Datura metel?
Scopolamine, atropine, hyoscine and calcium oxalate
Enumerate the manifestations of anticholinergic toxidrome present during the 1st to 6th hour
Mydriasis Decreased bowel sounds Urinary retention Dry mouth Hallucinations/agitation Flushed skin Tachycardia Hyperthermia Blind as bat
T/F: Exaggeration of benzodiazepine stimulation of GABA alpha-receptor leads to sedation and coma.
True
Amphetamine and other sympathomimetic drugs lead to?
Increased release of neurotransmitters
Differentiate anti-cholinergic and sympathomimetic
Sympathomimetic - no dryness of skin
Anti-cholinergic - dry and hot skin and very high-grade fever
What compounds cause enzyme inhibition?
Lead
Organophosphate
Isoniazid
Describe: Isoniazid overdose
It causes seizures and inhibits GABA synthesis.
What enzymes does isoniazid inhibit?
Glutamic acid decarboxylase and pyridoxine phosphokinase
Can you treat isoniazid overdose with benzodiazepine?
No. Seizures will not stop.
What are examples of impaired internal maintenance?
Impaired ATP synthesis
Oxidative stress
Impaired membrane function
What cases fall under impaired ATP synthesis?
Impaired H+ delivery to ECT (fluoroacetate)
Inhibition of electron transport complexes (cyanide)
Inhibition of O2 delivery to ETC
Inhibition of ADP phosphorylation
Paracetamol undergoes (1) and (2) for metabolism and excretion.
(1) Glucuronidation
(2) Sulfation
NAPQI is reduced to (1) by (2).
(1) Mercapturate
(2) Glutathione
Paracetamol overdose manifests as…
Liver toxicity
T/F: Ethanol and organic solvents increased cell membrane fluidity.
True
T/F: Hydrocarbons destroy plasma membrane.
False
They destroy lysosomal membranes.
Describe: Impaired external maintenance by coumarin
Inhibits hepatic synthesis of coagulation factors
What are the different toxicity repair mechanisms?
Molecular (proteins, lipids and DNA)
Cellular
Tissue
How long does it take liver tissue to regenerate?
6 - 8 weeks
Give an example of a chemical allergy
Pyrethroids - insecticides
Refers to a genetically determined abnormal reactivity to a chemical
Chemical idiosyncrasy
Deficiency in NADH-methemoglobin reductase may lead to?
Cyanosis, CNS and GI effects
T/F: Immediate toxicity is acute toxicity, while delayed toxicity is chronic/subchronic toxicity
True
T/F: Neurotoxicity is an example of immediate toxicity caused by organophosphates.
False
Delayed!
Give examples of reversible and irreversible toxicity
Reversible - paracetamol injury
Irreversible - alcoholic binge (2 million neurons lost!)
Give examples of systemic toxicity
Phenol a.k.a. lysol leading to kidney damage
Oxalic acid leading to liver damage
What compound is capable of interrupting formation of NAPQI from paracetamol?
N-acetylcysteine (precursor of glutathione)
What is the antidote for isoniazid overdose?
GABA and exogenous vitamin B6
What are clinical applications in cases of toxicity?
Choose antidotal therapy
Determine magnitude and extent of toxicity
Make effective/adequate treatment plan to address kinetic & dynamic properties
Predict plasma drug concentration
What are the modifications in clinical responses of individual drugs with concurrent use of 2 or more drugs?
Adverse interaction (loss of efficacy) Beneficial interaction (enhancement of efficacy)
T/F: Many drug interactions can be predicted by knowledge of pharmacokinetic & pharmacodynamic properties of the drugs.
True
T/F: Altered pharmacokinetics, pharmacodynamic, drug-induced disease or change in fluids and electrolyte balance may modify response to another drug.
True
T/F: Interactions demonstrated with certain drugs can be extrapolated to closely related drugs.
False
Give examples of drugs with a low therapeutic margin
Oral anticoagulants Hypoglycemics Cardiac glycosides Anti-convulsants Anti-cancer Anti-hypertensives
T/F: Pharmaceutical drug interactions are typically in vitro.
True
T/F: IV fluid does not need to suit the drug.
False
T/F: Certain drugs may be broken down by polyvinyl chloride plastics.
True
T/F: Isoniazid can be converted to toxic forms if stored improperly.
True
When do pharmacodynamic drug interactions occur?
When interactant drug alters effect of object drug at site of action
What is the antidote for opiate overdose? What is the mechanism of action?
Naloxone; antagonism
T/F: Flumazenil and benzodiazepine exhibit antagonism.
True
What substances are used for potentiation of sedation?
Ethanol and CNS depressants
T/F: An antihistamine can enhance the hypotensive effect of an anti-hypertensive.
True
In indirect pharmacodynamic interactions, it is the (1) that interacts with the main drug.
Side effect
Enumerate drugs that cause potassium depletion
Diuretics
Amphotericin
Ampicillin
Carbenicillin
T/F: Furosemide can produce hypokalemia.
True
Give an example of an indirect pharmacodynamic interaction
Cardiac glycosides and potassium-depleting drugs
Define: Pharmacokinetic Drug Interaction
ADME is altered by the interactant drug
Antimuscarinic drugs (1) gastrointestinal motility.
(1) decrease
T/F: Food + isoniazid/penicillin/rifampicin would lead to increased absorption of the drugs.
False
Decreased!
What are the three factors affecting distribution?
Concentration in drug plasma
Relative binding affinity of the drug
Volume of distribution
T/F: Most drug interactions involving inhibition of metabolism occur in liver and are due to competitive inhibition.
True
List potent inducers of the microsomal enzyme system
Barbiturates Imipramine Phenytoin Haloperidol Carbamazpine Rifampicin
List potent inhibitors of the microsomal enzyme system
Cimetidine Isoniazid Phenothiazines Chloramphenicol Metronidazole TCADs
What are the factors involved in excretion drug interactions?
Competition for tubular secretion
Change in urine pH
Define: Object Drugs
Narrow margin of safety
Define: Precipitant Drugs
Highly protein bound and affects metabolism of other drugs
What is the major limitation in interventions?
Cost
