Toxicology 2: ADME & Physiological factors Flashcards
What does ADME stand for?
Absorption
Disposition
Metabolism
Excretion
Absorption is?
Process by which toxins/toxicants cross membranes and enter blood stream
GI TRACT
LUNGS
SKIN
eye
uterus
Absorption solubility?
LIPID solubility of the neutral or non-ionized form of the drug
Lipophilic toxicants
* Organophosphate/Carbamate insecticides
Insoluble salts
* Barium sulfate (contrast radiography)
Absorption depends on degree on what?
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
Absorption in general?
Does morphologic and functional differences with absorption of toxins?
ruminants vs monogastric
YES it plays a part!
- Rumen (pH = 5.4 – 6.8)
-Fermentation by microflora - Omasum (pH = 2)
-Absorption of fluids - Reticulum (pH = 5.4 – 6.8)
-Fermentation - Abomasum (pH = 2 – 4)
-“True Stomach”
-Digestion of proteins
Rumen microflora with absorbed toxins?
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
Prevention of absorption– Decontamination Protocols
Induce emesis (hydrogen peroxide, apomorphine)
Activated charcoal (with or without cathartic)
Dermal absorption
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
Distribution
Depends on several things:
- 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
Distribution
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
Distribution BBB and GI?
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
Distribution Ivermectin toxicity in collies?
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
Distribution
Lead
GI irritant, neurotoxicant (V/D, blindness, nystagmus)
-Liver and kidney damage
Blood -> Liver, Kidney, Brain -> Bone
Metabolism means?
Conversion of lipophilic toxins/toxicants -> hydrophilic chemicals
Phase 1 and 2 reaction with metabolism?
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
What is something both phase reactions can do?
Inactivate (detoxify) xenobiotic agent
Activate xenobiotic agent to pharmacologically active metabolite
Phase 1 reaction unique qualities?
May metabolize a xenobiotic agent to a toxic metabolite
-Drug or chemical converted to a more toxic agent
Acetaminophen can be metabolized to what?
Toxic metabolite
Excretion organs and excretions?
Kidneys -> Urine
Bile -> Feces
Milk
The route of excretion of the toxin/toxicant can affect the degree of toxicosis in the animal
Milks relation to excretion?
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
White snakeroot poisoning relation to toxicology?
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.
Can rate of excretion affect toxicity?
YES
What is Ion trapping?
what are the principles of this?
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
Methamphetamine is what acid or base?
why does this matter?
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.
What do we need to consider with toxicology and animals?
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
Physiological factors
Genetic or species differences
Individual variation
Age of the animal
Pregnancy
Lactation
Disease conditions
Nutritional status (quality of food, etc.)
What are the 3 main Physiological factors?
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
Chocolate toxicity in dogs
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
Why are dogs predisposed to toxicity when talking about choclate?
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
What are the clinical signs of chocolate toxicity?
1-2 hours (start)
Tachycardia, hypertension
Hyperactivity, CNS excitability, muscle tremors
Vomiting, diarrhea
Tachypnea, respiratory failure
Clinical signs can last for 1-3 days
Treatment for chocolate toxicity treatment?
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
Age of animal part in physiological factors of toxicity?
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
Pregnancy or lactation plating a part in physiological factors in toxicity?
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)
Disease conditions playing a part of physiological factors in toxocity?
Heart disease- cardiotoxic plants, feed additives
Kidney disease- decreased excretion
Liver disease
-decreased metabolic detoxification
-decreased proteins, e.g., albumin and clotting factors
Physiological factors dietary factors and nutritional status play a part in toxicity?
YES
Selenium deficiency or toxicity
