Toxicology Recap Flashcards
Label the diagram about drug plasma levels.
A= Toxic range
B = Therapeutic range
C= Subtherapeutic range
D = minimum effective concentration
E = maximum effective concentration
Explain the difference between efficacy of a drug and potency.
Give an example.
Efficacy is the maximum effect a drug can have
Potency is the amount of drug required to get a given amount of efficacy/response.
For example, Buprenex is a very low dose required compared to methadone to get a small amount of pain control so is very potent.
However, it is not very efficacious- pure mu opioids will give a much higher level of pain control when given at full doses.
Explain the following diagram, including what each of the letters indicates.
- This diagram shows the difference between giving a loading dose and just starting routine dosing of a medication.
- At the top (dotted line- A), a loading dose was given so the drug quickly reaches therapeutic levels.
- At the bottom (solid line) routine dosing of the medication was started.
- At point B, the initial peak level for the first dose (Peak 0), therapeutic levels were not reached.
- It is not until point C that therapeutic levels are first reached and sustained through the entire dosing interval (after 9 doses in this instance).
- Point D indicates steady state (overall curve is no longer rising, peak levels are consistent from dose to dose).
- It takes 3 to 5 half lives for a drug to reach steady state.
- Drugs with long-half lives should typically be loaded if they need to be immediately effective (phenobarbital 50 hours or KBr 24 days).
- Drugs with short half-lives do not usually need to be loaded (keppra 2-4 hours).
Define Therapeutic index.
ratio of adverse event EC50 to the therapeutic effect EC50.
The larger the index, the safer the drug
Define Bioavailability
The percentage of an administered dose that reaches systemic circulation
Define first pass metabolism
The amount of a drug that is metabolized before it reaches circulation (ie in the GI tract or liver).
Define enterohepatic recirculation
when a drug is metabolized by the liver, re-excreted in bile, and then reabsorbed again by the GI tract. This can prolong the activity of the drug since it is not immediately eliminated.
Define elimination half life
The time necessary for half the drug to be eliminated from the body. It takes 5 half lives to eliminate 97% of a drug.
Define volume of distribution.
- Theoretical volume in which the total amount of drug would need to be distributed to produce the desired blood concentration. AKA the amount of tissue to which a drug is distributed.
- There are high and low volume of distribution drugs
- VD affects half life- smaller VD – lower rate of elimination
Explain high volume of distribution drugs.
lipid soluble (non-polar), easily enter cells/tissues.
Low rates of ionization, low plasma binding
Explain low volume of distribution drugs.
water soluble (polar)
high rates of ionization, high plasma binding
Name 4 reasons to avoid inducing emesis:
- Corrosive agent, (bleach, batteries, lye)
- Hydrocarbon toxicant (kerosene, gasoline)
- Symptomatic patients (neurologic in any way, agitated, weak, collapsed, hypoglycemic)
- Patients at risk for aspiration pneumonia (megaesophagus, lar par)
Name the 7 toxins that do NOT bind to activated charcoal
- Ethylene glycol
- Xylitol
- Ethanol/other alcohols
- Hydrocarbons (petroleum distillates, etc)
- Metals (lead, coper, iron, arsenic, lithium)
- Inorganic toxins (cyanide, ammonia, nitrates, nitrites, phosphorus, bromide)
- Corrosive/caustic agents
Name some possible complications of activated charcoal administration.
- Aspiration
- Electrolyte changes- most concerning is hypernatremia which can be fatal due to hyperosmolarity
- Dehydration
- Constipation/impaction
Is multiple dose charcoal administration recommended in humans? Are cathartics recommended in humans.
Multiple dose charcoal and cathartics are not recommended in humans per the toxicology position statements.
List the 2 main theories for the mechanism of action of intralipids in toxicology.
Improves myocardial function
Lipid sink theory
Discuss the theory that intralipids improve myocardial function.
- FFA are the preferred energy source of myocardial energy production
- Increase intracellular calcium
- Alpha adrenergic recpetor mediated increased vasopressor effect
- Reduction of NO and insulin induced vasodilation
Discuss the lipid sink theory for intralipids
Lipophilic compounds are compartmentalized intravascularly preventing drug absorption into tissue decreasing toxic effects
Discuss Organophosphates and Aldicarb.
MOA:
Clinical signs:
MOA: Inhibit acetylcholinesterase causing parasympathetic stimulation
CS:
Muscarinic: SLUDGE, bronchorrhea
Nicotinic: tremors/twitching
Discuss Bromethalin.
MOA:
Clinical signs:
MOA: Inhibits oxidative phosphorylation in CNS -> malfunction of ATP dependent ion pumps -> cerebral edema
CS: Tremors, seizures, coma, death
Discuss Ivermectin.
MOA:
Clinical signs:
MOA:
Agonist of glutamate-activated inhibitory chloride channels in invertebrates.
At high concentrations it stimulates Gaba-A channels in mammals -> hyperpolarization of cell membranes -> no depolarization.
CS: Ataxia, weakness, blindness, mydriasis, GI upset, bradycardia, coma, hypoventilation, seizures, death
Discuss Pyrethrins.
MOA:
Clinical signs:
MOA: Disrupts voltage-sensitive Na channels -> easier or extended depolarization.
CS: Muscle tremors/seizures, hypersalivation, hyperesthesia
Discuss Strichnine.
MOA:
Clinical signs:
MOA: Inhibits the inhibitory neurotransmitter glyceine in the inhibitory interneurons (renshaw cells) in the spinal cord -> net excitatory effect on all striated muscles
CS: Generalized rigidity and tonic-clonic seizures
Explain the 3 stages of ethylene glycol toxicity including duration after ingestion, what is happening in the body, clinical signs, and possible treatment options at each stage.
Stage 1:
- 0.5-12 hrs
- Due to EG itself
- GI upset, PU/PD, ataxia, muscle fasciculations, high AG, metabolic acidosis, hyperosmolarity, crystalluria.
- This is potentially reversible- prior to metabolite formation. Treat with ethanol or 4-MP to prevent metabolite formation or with dialysis to remove EG and metabolites before they cause ARF.
Stage 2:
- 8-24 hrs
- Most signs resolve, tachycardia/tachypnea, depression. Metabolites are doing their thing.
- Likely not treatable by this point.
Stage 3:
- 24-72 hrs
- Depression, decreased UOP, vomiting, seizures, halitosis/oral ulcers, azotemia → Anuria.
- Can try dialysis for weeks until kidneys possibly heal, but mostly doomed
Name a few tremorgenic mycotoxins
- penitrem-A
- roquefortine C
- verruculogen
- aflatrem
- thomitrems
- cyclopiazonic acid
Draw a basic chart showing the phospholipid pathway and where NSAIDS and steroids work.
Explain COX 1 vs COX 2 NSAIDS
COX 1 is the “good” COX. It helps with GI protection via increased mucous production, decreased gastric acid secretion, increased mucosal turnover.
COX 2 is the predominant mediator of inflammation and fevers.
Prefer NSAID drugs that are more COX 2 specific, sparing COX 1.
In overdose situations, all NSAIDS lose specificity and are both COX 1 and COX 2 inhibiting.
Explain the pathophysiology of Acetaminophen toxicity.
- Acetaminophen is conjugated in the liver with glucuronide (primarily) and sulfate (to a lesser degree)- the conjugated product is non toxic and excreted in bile/urine
- Unconjugated drug is metabolized by phase 1 microsomal enzymes (cytochrome p450 system) to cytotoxic oxidative metabolites which are usually scavenged by intracellular glutathione
- N-acetyl-P-benzoquinone-imine (NAPQI)- initially thought to be the causative metabolite, but this is questioned in recent research
- Para-aminophenol (PAP)- now thought to be the causative metabolite of methemoglobinemia - If overdose or glucuronide deficiency (ie cats), the toxic metabolites overwhelm the glutathione scavenging system resulting in toxicity
Explain the effects of Acetaminophen toxicity.
- Methemoglobinemia: cannot carry oxygen and the remaining ferrous Hb will have an increased affinity for oxygen (shifts curve to the left), so oxygen is not released to the tissues.
- Heinz body anemia/hemolysis
- Centrolobar hepatocellular necrosis: NAPQI binds to sulfhydryl groups in the hepatocyte
- Renal injury: less common, similar mechanism to hepatic injury
- GI injury: secondary to hepatotoxicity (not primary)
- CNS injury: usually secondary to hepatic encephalopathy, but primary CNS injury is rarely reported.
What is the difference between a local burn and severe burn injury?
Local burns are < 20% body surface area and do not result in systemic effects. Severe burn injury is >20-30% body surface area and results in “Burn Shock”.
What are the 2 phases of “Burn Shock”?
- Resuscitation phase (“hypodynamic or ebb phase”)
- Hyperdynamic hypermetabolic phase( “flow phase”)
Explain what happens in the Resuscitation phase of “Burn Shock”.
- “hypodymanic or ebb phase”
- Occurs immediately after severe burn injury and lasts for 24-72 hours
- Characterized by increased vascular permeability (due to direct vascular thermal injury and inflammation), fluid shifts (intravascular volume depletion), edema formation (mostly within or surrounding burn tissue), and decreased cardiac output. “Hypodynamic” phase.
- Difficult to restore cardiac output/hypovolemia during this phase, difficult to monitor tissue perfusion.
Explain what happens in the Hyperdynamic hypermetabolic of “Burn Shock”.
- “flow phase”
- Begins 3-5 days after injury and can persist for up to 24 months post-burn (in people)
- Characterized by decreased vascular permeability, increased HR, and decreased peripheral vascular resistance -> Increased cardiac output
- Also see an increased metabolic rate
- Increased counter-regulatory hormones (cortisol, glucagon, and catecholamines)
- Protein catabolism, gluconeogenesis, glycogenolysis, lipolysis, hepatic insulin resistance, increased Glu and O2 consumption, decreased lean body mass, fever
- Hyperglycemia with concurrent hyperinsulinemia is common
What are the physical effects of smoke inhalation?
Physical effects due to heat: acute upper airway obstruction due to edema, bronchospasm, small airway occlusion with mucous/sloughing cells, pulmonary infection/pneumonia, direct pulmonary injury (edema, impaired surfactant)
What toxins are in smoke?
Carbon monoxide
Cyanide
Irritant gasses
Effects of carbon monoxide
Competitively and reversibly binds to hemoglobin at the same sites as oxygen, but binds with an affinity 230-270 times greater than oxygen -> causes anemic hypoxia.
Can’t monitor SPO2, it will look normal.
Effects of cyanide
Binds to cytochrome oxidase and impairs tissue oxygenation by converting intracellular aerobic metabolism to anaerobic metabolism-> causes histotoxic hypoxia
Effects and examples of irritant gasses in smoke.
ammonia, hydrogen chloride, benzene.
These are converted into acids which directly damage the respiratory tract.
Name some of the most common effects of electrocution.
- Surface thermal burns (usually mouth)
- Cardiac arrhythmias
- Non-cardiogenic/neurogenic pulmonary edema
- Respiratory arrest from tetanic contractions of respiratory muscles during contact with electrical source
- Neurologic injury from direct neuron electrical stimulation
- GI ileus
How do you tell a coral snake from a non-venomous snake? What does the coral snake venom do (short answer)?
“Red on yellow kill a fellow”.
Neurotoxin that causes paralysis by blocking the nicotinic ACH receptors at the neuromuscular junction.
What are the main effects of pit viper venom?
List some of the toxins present
Enzymatic and nonenzymatic proteins (purpose is to immobilize and pre-digest rather than kill suddenly)- tissue and hemotoxic effects.
- Phospholipase A2
- Thromboxane
- Endopeptidase
- Hyaluronidase and collagenase
- Proteases
- Metalloproteinase
Effects of Phospholipase A2 in pit viper venom.
- contributes to RBC hemolysis and accumulation of inflammatory cells: echinocytes , spherocytes, ghost cells
- Echinocytosis is transient and only in 89-92% of dog ; resolved by 48 hours; not studied in cats
Effects of Thromboxane in pit viper venom.
involved in marked platelet activation (consumptive) and aggregation; causes thrombocytopenia commonly seen
Effects of Endopeptidase in pit viper venom.
toxic to vasculature, contributes to the soft tissue damage, also contributes to RBC damage and hemolysis
Effects of Hyaluronidase and collagenase in pit viper venom.
necrosis and destruction of tissue; this also allows dissemination of venom
Effects of proteases in pit viper venom.
destruction of tissue (breaks down peptide bonds), contributes to coagulopathies
Effects of metalloproteinase in pit viper venom
activation of TNF-alpha, influx of inflammatory cells
What is different about the Mojave rattlesnake compared to other rattlesnakes?
Many Mojave rattlesnakes contain Mojave toxin which is a neurotoxin that inhibits Ach release → weakness/paralysis.
Some also have typical proteolytic enzymes as well and also have local tissue effects.
Explain the abnormalities typically seen with “Venom Induced Coagulopathy”
- Low fibrinogen
- Thrombocytopenia
- Increased FDP’s
- Normal D-dimers (FXIII not activated so there is no cross linked fibrin, normal D-Dimers)
- Prolonged PT/PTT.
What are the components of the snake bite severity score for humans?
What are the components of the snake bite severity score for dogs?
Which of the following treatments that have research evidence or current recommendations for routine use in rattlesnake envenomation:
Steroids
Benadryl
Antibiotics
Antivenom
Tourniquet
Pressure immobilization
Supportive care measures
Rattlesnake vaccine for prevention in high-risk animals
Antivenom
Supportive care measures
Discuss Albuterol
MOA:
CS:
MOA: Selective B-2 receptor agonist 🡪 non selective B agonist when overdosed.
CS: Tachycardia, hypo or hypertension, tremors, arrhythmias, hypokalemia
Discuss Baclofen
MOA:
CS:
MOA: Mimics the GABA-b agonist to relax skeletal muscle (acts centrally)
CS: Flaccid muscles, CNS depression/coma, respiratory depression, hypotension, hypothermia
Discuss Bread dough
MOA:
CS:
MOA: Yeast expands -> physical obstruction from gastric distension. Fermentation -> ethanol -> metabolic acidosis and intoxication.
CS: Abdominal distention, CNS depression, weakness, recumbency, coma, hypothermia, Sz
Discuss Chocolate
MOA:
CS:
MOA: Theobromines (methylxanthine + caffeine) -> increase intracellular calcium levels -> increased strength of muscle contraction, increased catecholamines
CS: GI signs, tachycardia, arrhythmias, hyperexciteability, tremors, rarely seizures
Discuss Vitamin D
MOA:
CS:
MOA: Increases calcium absorption (GI, bone, kidneys) as well as Phosphorus absorption -> hypercalcemia, hyperphosphatemia -> tissue mineralization
CS: PU/PD, anorexia, vomiting, acute renal failure/anuria, arrhythmias
Discuss Onions/garlic
MOA:
CS:
MOA: Oxidative damage to RBC’s
CS: Anemia, methemoglobinemia
Discuss Paintballs
MOA:
CS:
MOA: High sodium content -> hyperosmolarity
CS: Vomiting, PU/PD, coma, seizures
Explain how calcium channel blockers and B-blockers have similar effects.
- Calcium is needed for impulse transmission in the heart and for contractility of cardiac muscle and smooth muscle of vasculature.
- Calcium channel blockers inhibit the voltage-sensitive channels that open during depolarization → decreased intracellular calcium.
- B-blockers inhibit B-receptors, which stimulate cAMP, which phosphorylates L-type calcium channels → decreased calcium entry into cells and decreased calcium release from sarcoplasmic reticulum.
- Decreased muscular intracellular calcium → bradycardia, impaired cardiac contractility (inotropy), impaired vascular contractility (vasodilation), hypotension.
- Impaired pancreatic calcium channels → impaired insulin release → hyperglycemia and less energy available to cells → worsening cardiovascular function and shock
- Impaired fatty acid use by myocardium with CCBs and B-blockers, so they must use glucose for energy.
Explain why intravenous calcium may be helpful for treatment of calcium channel blocker and B-blocker toxicosis:
increases calcium available to move into cells
Explain why atropine may be helpful for treatment of calcium channel blocker and B-blocker toxicosis:
may help with bradycardia if mild (parasympatholytic)
Explain why vasopressors may be helpful for treatment of calcium channel blocker and B-blocker toxicosis:
Stimulate B receptors to help with cardiac effects/counteract B-blocker.
Stimulate alpha receptors to help with peripheral vasodilation.
Explain why glucagon CRIs may be helpful for treatment of calcium channel blocker and B-blocker toxicosis:
binds to a unique receptor that stimulates conversion of ATP to cAMP (similar to the one B-blockers and Ca Channel blockers are obstructing)- basically bypassing the blocked B-receptor -> improved HR and contractility
Explain why Insulin/dextrose CRIs may be helpful for treatment of calcium channel blocker and B-blocker toxicosis:
Lack of insulin prevents glucose uptake into the myocardial cells leading to loss of inotropy and shock.
Insulin can improve contractility and increase peripheral vascular resistance by improving uptake of carbohydrates and oxidation for use by the myocytes and smooth muscle cells.
Explain why Intralipids may be helpful for treatment of calcium channel blocker and B-blocker toxicosis:
CCB’s are generally fat-soluble, so lipid sink theory may apply.
Likely the main mechanism for why lipids help with CCB’s is that it supplements fatty acids available to cardiac myocytes, so improves energy stores and increases intracellular calcium → improved inotropy.
