Toxicology General Principles Flashcards by Philip Tarnowski

Why is toxicology important?

Among Canadians of all ages, poisoning is the fourth-leading cause of injury deaths and the fifth-leading cause of hospitalizations.
Overall, the most common cause of poisoning is prescription medication

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Define toxicology

The study of poisons

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Toxicology is the study of adverse effects of chemicals on living systems, including: (5)

Mechanisms of action and exposure to chemicals as a cause of acute and chronic illness.
Understanding physiology and pharmacology by using toxic agents as chemical probes.
Recognition, identification, quantification of hazards from occupational exposure to chemicals.
Discovery of new drugs and pesticides.
Development of standards and regulations to protect humans and the environment from adverse effects of chemicals

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Define ED50

Dose at which 50% of the population therapeutically responds

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Define TD50

Dose at which 50% of the population experiences toxicity

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Define LD50

Dose at which 50% of the population dies

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What is NOAEL?

Highest dose at which - No Observed Adverse Effect Level

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What is LOAEL?

Lowest dose at which - Observed Adverse Effect Level

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How is therapeutic index (TI) calculated?

TI = LD50/ED50
TI = TD50/ED50

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What is therapeutic index?

TI is the ratio of the doses of the toxic and the desired responses

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What do you need to know about TI and ratio?

The larger the ratio, the greater the relative safety

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Who is the father of toxicology?

Paracelsus

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What are the branches of toxicology? (6)

Mechanistic
Forensic
Clinical
Environmental
Food
Regulatory

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What are 3 major factors affecting toxicity?

Route and site of exposure
Duration of exposure
Elimination rate and frequency of exposure

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Major poisons access the body via: (6)

GI (77%)
Lungs
Skin
Parenteral routes - most toxic and rapid response (BYPASS FIRST PASS METABOLISM)
Ocular
GU and other routes

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Should know the timeframes for the following exposure classes:
Acute
Subacute
Subchronic
Chronic

Acute - within previous 24 hours
Subacute - repeated exposure x 14 days
Subchronic - repeated exposure x 3 months
Chronic - repeated exposure > 6 months

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Pharmacologic effects of the toxicant itself may affect the toxicokinetics. Such as? (2)

Gastric hypomobility or delayed gastric emptying from anticholinergic effect
Pathophysiologic consequences: hypotension, hypothermia –> hypoperfusion

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Why is absorption important to know about in toxicology?

Rate and extent (bioavailability) of absorption are important because they determine concentration and ultimately, the likelihood of toxic effect

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Should know whether Cmax and Tmax is high or low in the following routes of drug absorption:
GI
IV
Inhalation (lungs)

GI - Cmax is low and Tmax is large
IV - Drug does not undergo first pass metabolism. Cmax is larger and Tmax is smaller. Even though the conc of the drug administered is the same
Inhalation - Cmax is even large and Tmax is further smaller e.g., anaesthetics

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True or False? Different routes may cause different Cmax and Tmax at same conc of the drug

True - AUC is same (body is exposed to same amount of drug - bioavailability) but some routes spread the exposure to the drug over greater time

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Thinking back to the chart with the 3 curves, why does the fast and high peak curve fall faster than the other curves?

Rate of excretion is proportional to the current conc of the drug as the drug follows first order kinetics

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True or False? Half-life of the drug depends on route of administration

False - t1/2 is same regardless of route of administration. T1/2 is drug characteristics and not route based

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What are pharmacobezoars and why are they bad?

Clumps of medications that build up in the GI that have not dissolved properly, resulting in a mega tablet.
If that bezoar were to dissolve it would cause a whole lot of other toxicant effects.
It can also cause obstruction in the GI, causing secondary adverse effects due to lack of blood flow and oxygen to the tissues

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How do high Vd drugs act? How does that affect dosing?

Have a propensity to leave the plasma and enter the extravascular compartments of the body, meaning that a higher dose of a drug is required to achieve a given plasma conc. (High Vd –> more distribution to other tissues)

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How do low Vd drugs act? How does that affect dosing?

Low Vd drugs like to remain in the plasma, meaning a lower dose of a drug is required to achieve a given plasma conc (Low Vd --> less distribution to other tissues)

What are factors that affect distribution of a drug? (5)

1. Blood flow 2. Plasma protein binding 3. Vd - how much of a drug needs to be in the body to reach a certain plasma conc 4. Transporters 5. pH of the blood (affects how the toxicant is moving through the body)

What does onset of toxcity depend on?

The rate of distribution to the toxic effect compartment

What are 3 factors that affect metabolism?

1. Saturation 2. Genetic polymorphism 3. Variation - Rate of blood flow, protein binding, and the intrinsic ability (organ clearance)

Should know the difference between first order and zero order kinetics

- First order is a conc-dependent process (i.e., the higher the conc, the faster the clearance) - Zero order elimination rate is independent of conc

Drug clearance is defined as?

The volume of plasma cleared of a drug over a specified time period

The renal excretion of drugs is the result of different mechanisms: (4)

1. Glomerular filtration 2. Passive back diffusion 3. Tubular secretion 4. Tubular reabsorption (saturable)

What are 3 things to consider for renal excretion?

1. Passive filtration relies on filtrate pH and blood flow rate 2. Changes to blood pH may cause ion trapping 3. Saturation of active secretion may lead to accumulation

What are the 7 steps to approaching a poisoned patient?

1. Resuscitation and stabilization 2. History and physical exam 3. Symptomatic and supportive care 4. Diagnostic testing 5. Decontamination 6. Elimination 7. Antidote

What are the ABCs of resuscitation and stabilization?

Airway - non-obstructed and maintained --> intubation Breathing - respiratory - rate and depth and oxygen level --> provide/ensure adequate ventilation/oxygen Circulation - BP and heart rate and temp --> maintain adequate vital signs by IV

Drug-induced hyperthermia can be caused by what 2 mechanisms?

1. Increased heat production (increased muscle activity or metabolic rate) 2. Decreased heat loss (impaired perspiration response, vasoconstriction)

Drug-induced hypothermia can be caused by what mechanism? Who is at special risk here?

1. Inhibition of shivering, vasodilation 2. At special risk: very young, very old, immobile, intoxicated, unconscious

Drug-induced fever - what happens in the brain?

Thermal set point in hypothalamus is increased

What toxicants can cause hyperthermia? (9)

1. TCAs 2. Amphetamines 3. Methamphetamines 4. MDMA 5. Cocaine 6. Salicylates 7. Lithium 8. Anti-cholinergics 9. MOAIs

What toxicants can cause fever?

Pyrogens such as microorganisms, some drugs

What toxicants can cause hypothermia? (5)

1. Ethanol 2. Phenothiazines 3. Barbiturates 4. Antidepressants 5. Organophosphates

Respiration can be parsed into 2 categories. What are they?

1. Rate (frequency) 2. Depth (amplitude)

What effect do anticholinergics have on the following vital signs? BP Pulse Respiration Temp

BP - change unlikely/maybe increase Pulse - increase Resp - variable Temp - increase

What effect do cholinergics have on the following vital signs? BP Pulse Respiration Temp

BP - variable Pulse - variable Resp - change unlikely/maybe increase Temp - change unlikely

What effect do ethanol or sedative-hypnotics have on the following vital signs? BP Pulse Respiration Temp

BP - decrease Pulse - decrease Resp - decrease Temp - change unlikely/maybe decrease

What effect do opioids have on the following vital signs? BP Pulse Respiration Temp

BP - decrease Pulse - decrease Resp - decrease Temp - decrease

What effect do sympathomimetics have on the following vital signs? BP Pulse Respiration Temp

BP - increase Pulse - increase Resp - increase Temp - increase

What effect do wihtdrawal from ethanol or sedative-hypnotics have on the following vital signs? BP Pulse Respiration Temp

BP - increase Pulse - increase Resp - increase Temp - increase

What effect do withdrawal from opioids have on the following vital signs? BP Pulse Respiration Temp

BP - increase Pulse - increase Resp - change unlikely Temp - change unlikely

What neurologic signs are you looking at for a poisoned patient? (2)

1. Altered mental status 2. Seizures

What movement signs are you looking at for a poisoned patient? (4)

1. Tremors 2. Dystonia 3. Myoclonus** 4. Asterixis

What is myoclonus and what 2 drugs/classes can it be caused by?

Brief, shock-like involuntary movements 1. Lithium 2. Anticholinergics

What dermatologic signs are we looking at for a poisoned patient? (2)

1. Cyanosis 2. Erythema 3. Others - Jaundice, diaphoresis, etc.

What is methemoglobinemia?

The hemoglobin can carry oxygen, but is not able to release

When doing a physical exam of a poisoned patient, should know what the following breath odors are caused by: 1. Fruity or "nail-polish remover" 2. Garlic 3. Mothballs 4. Wintergreen

1. Acetone 2. Organophosphates 3. Naphthalene 4. Methylsalicylate (sports cream)

Vomiting/hematemesis (poisoned patient) is due to what 3 things?

1. Direct GI mucosal irritation - salicylates, colchicine, alkali, acids 2. Chemoreceptor trigger zone (CTZ) stimulation - Opioids, carbon monoxide, nicotin, salicylates 3. Intracranial hemorrhage (pressure) - Presents as vomiting - Amphetamines, cocaine

Should know what happens when the parasympathetic nervous system is activated. Rest and digest type shi (8)

1. Constrict pupils 2. Stimulate saliva 3. Slow heartbeat 4. Constrict airways 5. Stimulate activity of stomach 6. Stimulate gallbladder 7. Stimulate activity of intestines 8. Contract bladder

Should know what happens when the sympathetic nervous system is activated. Fight or flight type shi (9)

1. Dilate pupils 2. Inhibit salivation 3. Increase heartbeat 4. Relax airways 5. Inhibit activity of stomach 6. Inhibit gallbladder 7. Inhibit activity of intestines 8. Secrete epinephrine and norepinephrine 9. Relax bladder

Should know the anticholinergic saying for symptoms i.e., hot as a ... etc. (5)

Hot as a Hare Blind as a Bat Dry as a Bone Red as a Beet Mad as a Hatter

The sympathomimetic and anticholinergic toxidromes may present very similarly. How do we distinguish between the two then?

1. The sympathomimetic toxidrome presents with diaphoresis and hyperactive bowel sounds 2. Anticholinergic toxidrome presents with dry skin and hypoactive bowel sounds

IV sodium bicarb may be indicated when...

pH is very low

Should know diaphoresis toxidromes 1. Anticholinergics 2. Cholinergics 3. Opioid 4. Sympathomimetics 5. Sedative-hypnotic

1. Anticholinergics - dry skin 2. Cholinergics - sweat 3. Opioid - dry skin 4. Sympathomimetics - sweat 5. Sedative-hypnotic - dry skin

How is Subchronic exposure defined? A. One-time exposure in the last 48 hours B. Repeated exposure for 3 months C. Repeated exposure for > 6 months D. Two-time exposure in 2 weeks

What is the main difference between hyperthermia and fever? A. They have different temperature set points B. Hyperthermia occurs from toxicants and fever occurs from xenobiotics C. Fever is a dysregulation of the temperature centres of the brain, while hyperthermia is either an over-production of heat or the body’s inability to cool off. D. Hyperthermia is caused by viruses and fever is caused by drugs.

What is indicated by breath that smells like garlic? A. Organophosphates B. Naphthalene C. Ethanol D. Acetone

The toxidrome for anticholinergic poisoning is as follows: __ HR, __ BR, __ BT, __ bowel sounds, __ pupils: A. Increased, No change, Increased, Decreased/Quiet, Dilated B. Decreased, Increased, Decreased, Decreased/Quiet, Dilated C. Increased, Increased, Decreased, Increased/Loud, Constricted D. Increased, No change, Increased, Increased/Loud, Dilated

What is the main difference between the toxidromes of anticholinergics and that of sympathomimetics? A. Anticholinergics cause dry skin, while sympathomimetics cause diaphoresis B. Sympathomimetics cause mydriasis, while anticholinergics cause miosis C. Anticholinergics cause constipation, while sympathomimetics cause diarrhea D. Answers A and C are correct

Dystonia is defined as: A. Involuntary, slow, twisting spasms B. Quick and jerk-like the movement C. Memory loss D. Nerve pain

What is meant by tachypnea? A. Deeper than normal breathing B. Rapid respiratory rate C. Decreased respiratory rate D. Hyperventilation

What factors affect the distribution of a drug in the body: A. Blood flow B. Plasma protein binding C. pH of the blood D. All of the above

What factors affect toxicity of a drug: A. Route and Site of Exposure B. Duration of Exposure C. Elimination rate and Frequency of exposure D. All of the above

Which statement about half life of a drug is true: A. Half-life of a drug is same regardless of the route of administration B. Half life of a drug depends on route of administration C. Half life of an orally administered drugs is less D. Half life of drugs administered by parenteral route is less