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DWT Exam 3 > Toxicology 2: ADME & Physiological factors > Flashcards

Toxicology 2: ADME & Physiological factors Flashcards

1
Q

What does ADME stand for?

A

Absorption

Disposition

Metabolism

Excretion

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2
Q

Absorption is?

A

Process by which toxins/toxicants cross membranes and enter blood stream

GI TRACT
LUNGS
SKIN
eye
uterus

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3
Q

Absorption solubility?

A

LIPID solubility of the neutral or non-ionized form of the drug

Lipophilic toxicants
* Organophosphate/Carbamate insecticides
Insoluble salts
* Barium sulfate (contrast radiography)

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4
Q

Absorption depends on degree on what?

A

Depends on degree of ionization as related to the pH and pKa relationship of the toxicant
*pKa
-Acid dissociation constant measuring strength of an acid
- The lower the pKa, the stronger the acid

  • Ionized Compounds
    -More water soluble in general – not passively absorbed
  • Un-ionized Compounds
    -More lipid soluble in general – passively absorb
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5
Q

Absorption in general?

A
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6
Q

Does morphologic and functional differences with absorption of toxins?

ruminants vs monogastric

A

YES it plays a part!

  1. Rumen (pH = 5.4 – 6.8)
    -Fermentation by microflora
  2. Omasum (pH = 2)
    -Absorption of fluids
  3. Reticulum (pH = 5.4 – 6.8)
    -Fermentation
  4. Abomasum (pH = 2 – 4)
    -“True Stomach”
    -Digestion of proteins
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7
Q

Rumen microflora with absorbed toxins?

A

Nitrate -> Nitrite -> Ammonia -> Protein

Intake of nitrate and conversion to nitrite exceed microflora’s capacity to reduce
nitrite
-Nitrites absorbed into blood and oxidize hemoglobin (Fe+2  Fe+3)
- Methemoglobin and RBCs cannot carry oxygen to tissues
–>Vasodilation, methemoglobinemia, hypoxia, cyanosis

  • Gastric motility, secretion, and the rate of gastric emptying
    -Decreased gastric motility/emptying can increase absorption of toxins,
    toxicants, drugs
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8
Q

Prevention of absorption– Decontamination Protocols

A

Induce emesis (hydrogen peroxide, apomorphine)

Activated charcoal (with or without cathartic)

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9
Q

Dermal absorption

A

Lipid soluble compounds well- absorbed
-formulation in solvnets can facillitate absorption

Fipronil- blocks GABA- gated Cl channels in insects
Methoprene – insect, juvenile growth hormone analog
Ethanol – vehicle for product

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10
Q

Distribution
Depends on several things:

A
  • Perfusion/blood flow through tissues
  • Protein binding of drug
    -Acidic drugs may bind protein and remain in circulation -> low volume of distribution
    -Basic drugs tend not to bind protein and are extensively taken up by tissues -> larger volume of distribution
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11
Q

Distribution

A

Toxicant/Drug distributed via bloodstream
-Portal blood circulation  Liver
-Poisons/drugs not equally distributed throughout body
- Tend to accumulate in specific tissues/fluids
-Blood-brain barrier tends to exclude hydrophilic poisons/drugs

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12
Q

Distribution BBB and GI?

A

Blood-brain barrier (BBB)
-Younger animals more at risk due to immature BBB
- Lead poisoning in kittens – vertical nystagmus; muscle tremors/seizures

Gastrointestinal Tract
-Younger animals more readily absorb lead from the GI tract
- GI motility immature

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13
Q

Distribution Ivermectin toxicity in collies?

A

Deficient in multi-drug resistance gene (MDR1)  P-glycoprotein
 P-glycoprotein functions as an efflux drug transport pump at the blood-brain barrier

 Ivermectin cannot be transported out of the brain in MDR1 deficient animals  acts as a
GABA agonist
-Drug accumulates in brain causing CNS depression
-Ataxia, CNS depression, mydriasis

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14
Q

Distribution
Lead

A

GI irritant, neurotoxicant (V/D, blindness, nystagmus)
-Liver and kidney damage

Blood -> Liver, Kidney, Brain -> Bone

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15
Q

Metabolism means?

A

Conversion of lipophilic toxins/toxicants -> hydrophilic chemicals

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16
Q

Phase 1 and 2 reaction with metabolism?

A

Phase I Reaction: Functionalization reactions
-Converts xenobiotic to a more polar metabolite through hydrolysis, reduction, or oxidation
- In some cases, makes it more amenable to phase II biotransformation

Phase II Reaction: Conjugation reactions
-Conjugation of large, polar molecule to render xenobiotic hydrophilic for excretion
- Does not always result in less toxicity or inactivation

17
Q

What is something both phase reactions can do?

A

Inactivate (detoxify) xenobiotic agent

Activate xenobiotic agent to pharmacologically active metabolite

18
Q

Phase 1 reaction unique qualities?

A

 May metabolize a xenobiotic agent to a toxic metabolite
-Drug or chemical converted to a more toxic agent

19
Q

Acetaminophen can be metabolized to what?

A

Toxic metabolite

20
Q

Excretion organs and excretions?

A

Kidneys -> Urine
Bile -> Feces
Milk

The route of excretion of the toxin/toxicant can affect the degree of toxicosis in the animal

21
Q

Milks relation to excretion?

A

Milk of cows tends to be slightly acidic + milk fat
-pH 6.5 to 6.9 (relative to plasma – 7.2 to 7.4)

Tends to concentrate basic, fat soluble toxicants/drugs

Relay in toxicants to nursing calves, humans

22
Q

White snakeroot poisoning relation to toxicology?

A

Toxin (tremetol or tremetone, or related chemical) metabolized and excreted in milk

Milk Sickness
White snakeroot toxicosis through drinking of
milk from lactating cows eating white snakeroot.

Calves affected with muscle tremors and death.
Lactating, adult cow may remain unaffected.

23
Q

Can rate of excretion affect toxicity?

A

YES

24
Q

What is Ion trapping?
what are the principles of this?

A

Altering the urine pH to inhibit reabsorption of toxicants across the renal tubular membranes into the blood stream

Principle:
-To “trap” the toxicants in its ionized form in the urine so it will be excreted
-Non-ionized toxicants can diffuse across cell membranes because of their lipid
solubility; whereas ionized molecules cannot diffuse across lipid membranes

25
Q

Methamphetamine is what acid or base?
why does this matter?

A

WEAK base

If you give sodium bicarbonate to alkalinize the urine, the % un-ionized (uncharged) methamphetamine increases.
Only 1% of the drug is excreted in urine.

If you give ammonium chloride to acidify the urine, the% ionized (charged) methamphetamine increases.
≈ 70% of drug excreted in the urine.

26
Q

What do we need to consider with toxicology and animals?

A

Animals explore environment

  • Tasting what they find
  • Drink from streams, puddles, wells not suited for drinking
  • Roaming increases likelihood of exposure to poisons
  • Overgrazing can increase likelihood of ingesting poisonous plants
    -When they are hungry, they eat what is available
27
Q

Physiological factors

A

Genetic or species differences

Individual variation

Age of the animal

Pregnancy

Lactation

Disease conditions

Nutritional status (quality of food, etc.)

28
Q

What are the 3 main Physiological factors?

A

Genetic or species differences

Behavioral
-Dogs & cats lap up liquids – chemical burns on tongue & lips

Species Differences
-Cats deficient in glucuronyltransferase – Acetaminophen
-Dogs slow in metabolizing theobromine = Long half-life

29
Q

Chocolate toxicity in dogs

A

Adenosine
-Prepares body for sleep – decreasing
catecholamine release and causing
vasodilation
-Receptors on nerve brain cells can’t tell the
difference between adenosine and caffeine,
theobromine.
- Without adenosine brain activity increases =
stimulation.

Caffeine, Theobromine, Theophylline
-Inhibit adenosine and increase catecholamine
release resulting in CNS stimulation, tachycardia, diuresis, smooth muscle contraction, vasoconstriction
-Cause release of dopamine and glutamate ->
excitatory neurotransmitters

30
Q

Why are dogs predisposed to toxicity when talking about choclate?

A

Long half-life of Theobromine
T1/2= 17.5 hours
–> Caffeine t1/2= 4.5 hours

Theobromine is metabolized into xanthine  methyluric acid by hepatic CYP450

31
Q

What are the clinical signs of chocolate toxicity?

A

1-2 hours (start)

Tachycardia, hypertension
Hyperactivity, CNS excitability, muscle tremors
Vomiting, diarrhea
Tachypnea, respiratory failure

Clinical signs can last for 1-3 days

32
Q

Treatment for chocolate toxicity treatment?

A

Tachyarrhythmias: If persistent
-β-Blockers: Metoprolol, Propranolol

Anti-arrhythmics:
-Lidocaine, Atropine

Emesis induction 2 – 6 hrs post-ingestion

Methylxanthines undergo enterohepatic recirculation
 Activated charcoal/cathartic x 1 dose
 AC (no cathartic) repeat doses for ≥ 3 days

 Gastric lavage if large quantities ingested

Anticonvulsants:
 Diazepam (0.5 – 2 mg/kg IV)
 Barbiturates or propofol

33
Q

Age of animal part in physiological factors of toxicity?

A

Younger animals
 Blood brain barrier still immature – more permeable than adult
 GI motility immature
 Lower glomerular filtration rate
 Rumen microflora low

Older animals (longer t1/2 of xenobiotics)
 Decreased metabolic capacity
 Decreased kidney function

34
Q

Pregnancy or lactation plating a part in physiological factors in toxicity?

A

Hormone changes can affect metabolism

Circulatory changes can alter distribution

Increased susceptibility of fetus to some toxicants

Excretion of fat soluble chemicals in milk
 Organochlorines, fat soluble pesticides
 Lead
 Tremetone (White snakeroot toxins)

35
Q

Disease conditions playing a part of physiological factors in toxocity?

A

Heart disease- cardiotoxic plants, feed additives

Kidney disease- decreased excretion

Liver disease
-decreased metabolic detoxification
-decreased proteins, e.g., albumin and clotting factors

36
Q

Physiological factors dietary factors and nutritional status play a part in toxicity?

A

YES

Selenium deficiency or toxicity

DWT Exam 3 (8 decks)

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