Lecture 9: Neurotoxicants medications

What does an SSRI inhibit?

Re-uptake of serotonin at the presynaptic membrane

What does SNRI inhibit?

Re-uptake of serotonin and norepinephrine at presynaptic membrane

For which conditions are some SSRIs/SNRIs used in veterinary medicine?

Urine spraying, canine separation anxiety, aggression, noise phobias

-rapidly absorbed → rapid onset of signs

At what SSRI or SNRI overdose are clinical signs more likely?

2-3 times the therapeutic dose

What CNS effect does serotonin cause?

enhances mood/behavior, increases central respiratory drive

What ophthalmic effect does serotonin cause?

activates ciliary muscle fibers (M3 muscarinic receptors) causing mydriasis

What cardiovascular effects does serotonin have?

Positive inotropic and chronotropic effects- increases intracellular calcium in cardiac myocytes

What gastrointestinal effects does serotonin have?

Increased gastric motility and colonic tone through enteric neurons

What thermoregulation (CNS) effects does serotonin have?

serotonin receptors in hypothalamus play role in increasing and decreasing body temp

what type of drugs are ADD drugs?

sympathomimetic drugs

-structurally related to norepinephrine

What is the mechanism of action of ADD drugs?

Increase release and inhibit re-uptake of dopamine, norepinephrine and serotonin

What CNS effect does dopamine cause?

Regulates motor neurons, spatial memory function, motivation, reward/pleasure center

What ophthalmic effect does dopamine cause?

Excitation of alpha-adrenergic receptors of the dilator pupillae muscle causing mydriasis

What cardiovascular effect does dopamine cause?

positive inotropic and chronotropic effects on cardiomyocytes

What gastrointestinal effects does dopamine have?

Decreased gastric motility and colonic tone through inhibiting acetylcholine release

What nervous system signs can occur with SSRI, SNRI and ADD drug toxicity?

Agitation, hyperactivity, head bobbing, flicking ears or tail

What neuromuscular signs can occur with SSRI, SNRI and ADD drug toxicity?

Tremors, seizures

What cardiovascular signs can occur with SSRI, SNRI and ADD drug toxicity?

Tachycardia, hypertension

What gastrointestinal signs can occur with SSRI, SNRI and ADD drug toxicity?

Vomiting, diarrhea, hypersalivation

What pulmonary sign can occur with SSRI, SNRI and ADD drug toxicity?

Tachypnea

When can signs from extended or delayed-release drugs begin?

4-8 hours after exposure and can persist up to 2 days

-otherwise, 1-4 hours post-exposure

SSRI, SNRI, and ADD drugs treatment

• decontamination

  • emesis

  • AC

Which drugs are listed for treatment of SSRI, SNRI and ADD drugs?

• Acepromazine, chlorpromazine

  • agitation, hyperactivity, head bobbing

• Phenobarb

  • muscle tremors, seizures

• Propranolol

  • tachycardia

• Cyproheptadine

  • serotonin syndrome

• IVF

  • adjust for BP changes

SSRIs, SNRIs and ADD drugs diagnosis

Detection of drugs in urine, blood, serum, stomach contents

What are the two forms of MDMA named in the lecture?

Ecstasy (pills) and Molly (crystal powder)

Mechanism of action for amphetamines/methamphetamines

• increase release of catecholamines

  • dopamine, norepinephrine, epinephrine

• increased amt of catecholamine at nerve endings → overstimulation of CNS and cardiovascular system thru increasing release and inhibiting reuptake of neurotransmitters

mechanism of action of MDMA

Increases serotonin release and inhibits serotonin reuptake

what drugs are potent sympathomimetics

amphetamines sympathomimetics

-CNS and cardiovascular system stimulants

What are medical uses of amphetamines?

• Appetite suppression, ADD drugs, narcolepsy

• old weight loss products

How might an animal be exposed to amphetamines?

• Accidental ingestion or inhalation of smoke

• drug-detecting animals

amphetamines metabolism

• rapidly absorbed in GI tract, peaks in plasma in 1-2 hrs

• crosses BBB

amphetamines clinical signs

• agitation, hyperactivity

• hyperthermia

• mydriasis

• tachycardia, cardiac arrhythmias, hypertension

• tachypnea

• coma, death

How is amphetamine toxicity diagnosed?

Exposure history, clinical signs, and urine or serum testing

amphetamines treatment

• emesis if early enough

• GL if large dose

• AC

• monitor ECG, BP

• IVF

• maintain body temp

What is crack cocaine?

A solid, processed, more potent form of cocaine (“free basing”)

What is a speedball?

Cocaine and heroin

what does a solid powder of cocaine contain?

12-18% cocaine salts and adulterants (caffeine, amphetamine)

-highly abused

How might a pet be exposed to cocaine?

• Ingestion or sniffing residue

• well-absorbed across oral and nasal mucosa

What is a medical use of cocaine?

Topical local anesthetic on mucous membranes

cocaine mechanism of action

• Sympathetic nervous system stimulation

  • Blocks reuptake of norepinephrine, serotonin and dopamine

  • increases catecholamine release

clinical signs with cocaine (12-15 mins)

• excitation, hyperactivity, agitation

• ataxia

• mydriasis

• tachycardia

• muscle tremors

cocaine toxicity:

• any amount may result in toxicosis

• rapid absorption → rapid onset of clin signs

  • peaks in plasms 12-15 mins after exposure

  • readily crosses BBB

cocaine diagnosis

• hx and clin signs

• OTC test kit for urine

• detected in urine, stomach contents, plasma/serum

Which treatments are listed for cocaine?

• emesis if asymptomatic or AC and GL

• control hyperthermia

• excess CNS stimulation:

  • Diazepam, phenobarbital, propofol, methocarbamol

  • a dark room

How do benzodiazepines and non-benzodiazepine hypnotics affect GABA?

Both potentiate GABA, inhibiting neuronal excitation.

What are the therapeutic effects of benzodiazepines?

Anxiolytic, muscle relaxant, anticonvulsant

how does GABA work?

• binds receptors in plasma membrane pre-synaptic and post-synaptic nerves

• opens ion channels allowing more chloride ions into cell

• causes hyperpolarization of nerve makes cell more negative

• inhibits action potential

What are common signs of benzodiazepine or sleep aid toxicity?

• CNS depression, ataxia

• resp depression

• bradycardia, hypotension

• hypothermia

• icterus (fulminant hepatic necrosis- CATS)

Benzodiazepines & Non-Benzodiazepine Hypnotics: paradoxical CNS stimulation

• paradoxical CNS stim in ~50% in dogs and cats

• low doses = CNS depression; higher doses can cause paradoxical stimulation

clinical signs of benzos and non-benzo hypnotics

• Hyperactivity

• agitation, aggression

• panting, pacing

• tremors

• hyperthermia

• vocalization

Which antidote is listed for severe CNS depression from benzodiazepine overdose?

Flumazenil

Treatment for paradoxical CNS stimulation w/ benzos and sleep aids

Ace (blocks serotonin receptors) - do not use Diazepam

benzos and sleep aids toxicity diagnosis

• hx of exposure

• detection of drugs in urine, blood, serum, stomach contents from animal

where do opiates come from?

poppy plants

-sap contains morphine, codeine, and other alkaloids

What is the primary medical use of opiates and opioids?

• Analgesia

• cough suppressants, pre-op sedation, anesthetic supplement, prevent diarrhea

• well-absorbed: orally, parenteral routes, rectal

Which lipophilic opioids can be absorbed through nasal, buccal and respiratory routes?

Heroin, fentanyl, buprenorphine

Where are opioid receptors found?

• opioid receptors are a group of inhibitory G-protein coupled receptors

• in brain (BBB), spinal cord, peripheral neurons, digestive tract

What effects are associated with μ receptors on the lecture slide?

Analgesia, physical dependence, respiratory depression, decreased GI motility, euphoria

What effects are associated with κ receptors on the lecture slide?

Sedation, miosis

What effects are associated with δ receptors on the lecture slide?

analgesia, antidepressant, physical dependence

What is opiate and opioid metabolism?

• undergo extensive first-pass metabolism

  • P.O. dose: extensively altered or metabolized before entering systemic circulation

• some opiates are glucuronidated in the liver → renal excretion

  • cats are deficient in glucuronyltransferase

Why may cats have difficulty metabolizing some opiates?

Cats are deficient in glucuronyltransferase.

What CNS effect do opioids commonly cause in dogs?

CNS depression and lethargy

-dogs have a higher number of opioid receptors in amygdala and frontal cortex

What CNS effect can opioids cause in cats, horses, cattle and swine?

CNS excitation and aggressiveness

-cats have fewer opioid receptors

opiates and opioids clinical signs

• ataxia, drowsiness

• hypothermia

• miosis (dogs), mydriasis (cats)

• vomiting

• resp depression

• hypotension

• constipation

• seizures, coma

Which antidote is listed for opioid toxicity?

Naloxone (Narcan)

-binds all 3 opioid receptors but strongest binding at mu receptor

Why might naloxone doses need to be repeated?

It has a short half-life of 30-60 minutes.

opiate/opioid diagnosis

• hx of exposure and clin signs

• detected in urine or serum

• can use OTC in human illicit drug kits

Is the prognosis for opioid toxicity good?

• depends on amt ingested and time of tx

• good if cardiovascular fxn maintained

• poor to guarded if seizing