Toxicology 2: ADME & Physiological factors

Question 1

What does ADME stand for?

Answer 1

Absorption

Disposition

Metabolism

Excretion

Question 2

Absorption is?

Answer 2

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

GI TRACT
LUNGS
SKIN
eye
uterus

Question 3

Absorption solubility?

Answer 3

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

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

Question 4

Absorption depends on degree on what?

Answer 4

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

Question 5

Absorption in general?

Answer 5

Question 6

Does morphologic and functional differences with absorption of toxins?

ruminants vs monogastric

Answer 6

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

Question 7

Rumen microflora with absorbed toxins?

Answer 7

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

Question 8

Prevention of absorption– Decontamination Protocols

Answer 8

Induce emesis (hydrogen peroxide, apomorphine)

Activated charcoal (with or without cathartic)

Question 9

Dermal absorption

Answer 9

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

Question 10

Distribution
Depends on several things:

Answer 10

• 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

Question 11

Distribution

Answer 11

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

Question 12

Distribution BBB and GI?

Answer 12

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

Question 13

Distribution Ivermectin toxicity in collies?

Answer 13

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

Question 14

Distribution
Lead

Answer 14

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

Blood -> Liver, Kidney, Brain -> Bone

Question 15

Metabolism means?

Answer 15

Conversion of lipophilic toxins/toxicants -> hydrophilic chemicals

Question 16

Phase 1 and 2 reaction with metabolism?

Answer 16

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

Question 17

What is something both phase reactions can do?

Answer 17

Inactivate (detoxify) xenobiotic agent

Activate xenobiotic agent to pharmacologically active metabolite

Question 18

Phase 1 reaction unique qualities?

Answer 18

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

Question 19

Acetaminophen can be metabolized to what?

Answer 19

Toxic metabolite

Question 20

Excretion organs and excretions?

Answer 20

Kidneys -> Urine
Bile -> Feces
Milk

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

Question 21

Milks relation to excretion?

Answer 21

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

Question 22

White snakeroot poisoning relation to toxicology?

Answer 22

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.

Question 23

Can rate of excretion affect toxicity?

Answer 23

YES

Question 24

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

Answer 24

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

Question 25

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

Answer 25

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.

Question 26

What do we need to consider with toxicology and animals?

Answer 26

**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

Question 27

Physiological factors

Answer 27

Genetic or species differences Individual variation Age of the animal Pregnancy Lactation Disease conditions Nutritional status (quality of food, etc.)

Question 28

What are the **3** main Physiological factors?

Answer 28

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

Question 29

Chocolate toxicity in dogs

Answer 29

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

Question 30

Why are dogs predisposed to toxicity when talking about choclate?

Answer 30

**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

Question 31

What are the clinical signs of chocolate toxicity?

Answer 31

1-2 hours (start) Tachycardia, hypertension Hyperactivity, CNS excitability, muscle tremors Vomiting, diarrhea Tachypnea, respiratory failure Clinical signs can last for 1-3 days

Question 32

Treatment for chocolate toxicity treatment?

Answer 32

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

Question 33

Age of animal part in physiological factors of toxicity?

Answer 33

**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

Question 34

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

Answer 34

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)

Question 35

Disease conditions playing a part of physiological factors in toxocity?

Answer 35

Heart disease- cardiotoxic plants, feed additives Kidney disease- decreased excretion Liver disease -decreased metabolic detoxification -decreased proteins, e.g., albumin and clotting factors

Question 36

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

Answer 36

YES Selenium deficiency or toxicity