Neuro (pt 3/4) Methanol, Ethylene Glycol, Anti-Seizures, Anti-Psych Flashcards
What is Methanol?
-Used in the industrial production of synthetic organic compounds and as a constituent of many commercial solvents
-Absorbed through the skin, respiratory or GI tract
-Eliminated in humans by oxidation to formaldehyde, formic acid and CO2
-Metabolism is slow…6-30 hours before toxicity develops
What are the toxic metabolites that Methanol is oxidized to?
Formaldehyde, formic acid & CO2 = toxic metabolites
How long does it take for Methanol toxicity to develop?
6-30 hours
What are the mild characteristics of Methanol toxicity?
Inebriation, gastritis, elevated osmolal gap
What is the Osmolal Gap?
The difference between measured serum osmolality and calculated serum osmolality
-97% of patients will have OG in the range +10 to -10.
-The presence of low blood pH, elevated anion gap and greatly elevated OG is a medical emergency that requires prompt treatment
An Osmolal Gap value greater than ____ is considered a critical value or cutoff.
15
-The presence of low blood pH, elevated anion gap and _________ OG is a medical emergency that requires prompt treatment
A greatly elevated OG
What are the Severe characteristics of Methanol toxicity?
-Odor of formaldehyde on the breath
-Visual disturbances (most characteristic symptom)
-Metabolic Acidosis
-Can cause blindness
-Bradycardia, prolonged coma, seizures, resistant acidosis
-Fatalities attributed to sudden cessation of respiration
What is the treatment for Methanol Toxicity?
-Dialysis in severe cases (blood levels >50mL/dl)
-Support respiration
-Suppress metabolism of methanol by alcohol dehydrogenase
-Alkalization to counteract metabolic acidosis
(Bicarbonate)
-Meds: Fomepizole, IV Ethanol
What is Fomepizole?
-Alcohol dehydrogenase inhibitor
-Alcohol dehydrogenase is the enzyme responsible for methanol oxidation in the liver
-Approved for Methanol and Ethylene Glycol poisoning
-Rapidly induces its own metabolism by CYP450’s after 48 hours (Increase the dose)
Why is IV Ethanol utilized as an alternative to Fomepizole in the treatment of Methanol toxicity?
Because it has a higher affinity for alcohol dehydrogenase than Methanol (!!!!)
-Used In Methanol and Ethylene Glycol poisoning
-Methanol stays in primary form, doesn’t create toxic metabolites. Still has to be dialyzed off.
-Decreases the formation of methanol’s toxic metabolites
-Used as heat exchangers, in antifreeze formations, and as industrial solvents
-Metabolized to toxic aldehydes and oxalate
Ethylene Glycol
Describe the 3 stages of Ethylene Glycol Overdose.
First few hours – transient excitation followed by CNS depression
4-12 hours – severe metabolic acidosis develops from accumulation of acid metabolites and lactate
After 12 hours – delayed renal insufficiency follows the deposition of oxalate in renal tubules
-Oxalate can lead to crystal formation and kidney stones
What is the treatment for Ethylene Glycol Overdose?
Treatment the same as for Methanol Toxicity (still needs dialysis to pull off metabolites and offending agents)
A finite episode of brain dysfunction resulting from abnormal discharge of cerebral neurons.
-Aberrant signaling in the brain, can be due to disorders, tumors, high fevers, etc.
Seizures
A heterogenous symptom complex disorder (caused by several different factors) characterized as chronic recurrent seizures.
-Approx 1% of the world’s population
Epilepsy
What are the three different mechanisms of Anti-seizure medications?
1) Enhancement of GABAergic (inhibitory) transmission
2) Reduction of excitatory (usually glutaminergic) transmission
3) Modification of ionic conductance (usually K+ hyperpolarization to decrease neuronal firing)
Which anti-seizure drugs have presynaptic targets that diminish Glutamate release?
Na 1.6 voltage-gated sodium channels (carbamazepine, monohydroxy derivative [MHD], phenytoin, lamotrigine, and lacosamide)
K7 voltage-gated potassium channels (retigabine [ezogabine])
α2δ (gabapentin and pregabalin)
Which anti-seizure drugs have postsynaptic targets that diminish Glutamate release?
AMPA receptors (perampanel)
T-type Ca voltage-gated calcium channels (ethosuximide, dimethadione)
Kv7 voltage-gated potassium channels (retigabine [ezogabine]
Which anti-seizure drugs are positive allosteric modulators of synaptic GABA A receptors (promote inhibition)?
Phenobarbital
Benzos
Which seizure type classifications all get the same type of drugs?
Focal Aware, Focal impaired awareness, Focal-to-bilateral tonic-clonic seizure (formerly grand mal), Generalized tonic-clonic seizure (formerly grand mal), and Generalized absence seizures.
Which seizure type classifications each require specific medications?
-Myoclonic
-Atonic
-Epileptic Spasms
What is the Therapeutic Strategy for anti-seizure drugs?
-Use of a single drug is preferred (Fewer adverse effects using monotherapy)
-Multiple drugs can be used simultaneously for patients with hard-to-control seizures
-The therapeutic index for most anti-seizure drugs is low (Toxicity is common)
-Teratogenicity is controversial (Children born to mothers taking anti-seizure drugs have an increased risk of congenital malformations; Must minimize fetal exposure to anti-seizure drugs while ensuring that maternal seizures do not go unchecked)
-Avoid abrupt withdrawal (Increased seizure frequency and severity can occur with accidental or purposeful withdrawal of meds; If a patient is seizure free for 3-4 years, a trial of gradual discontinuance is warranted)
-Most newer drugs (after 1990) have a broader spectrum of activity and many are well tolerated (Newer drugs are preferred to the older ones)
Explain the pharmacokinetics of anti-seizure drugs.
-Well absorbed with approximately 80%-100% of drug reaching circulation
-Not highly protein bound (Except for Phenytoin(Dilantin), Tiagabine(Gabatril), and Valproic Acid (Valproate) )
-Cleared chiefly by hepatic mechanisms
C-onverted to active metabolites that are also cleared by the liver (CYP450 enzyme inducers!!!!)
-Plasma clearance is slow – anti-seizure drugs are considered to be medium to long acting (Some have half-lives longer than 12 hours)
What are the drugs you need to know that treat generalized seizures?
Phenytoin
Fosphenytoin
Carbamazepine
Valproate
Lamotrigine
Levetiracetam
Topiramate
What is the DOC for infantile spasms?
Vigabatrin IM
What are the drugs used to treat Status Epilepticus?
Diazepam, Midazolam, Fosphenytoin, Phenobarbital
Explain the effects of Phenytoin (Dilantin)
-Used for Onset (partial) Seizures and Generalized Tonic-Clonic Seizures
-Alters Na+, K+, Ca2+ conductance, membrane potentials, amino acid concentrations, and neurotransmitters (Epi, Ach, GABA)
-Blocks sustained high frequency action potentials
-Use dependent effect on Na+ conductance (Arises from preferential binding to and prolongation of the inactivated state of the Na+ channel)
-Paradoxically causes excitation in some cerebral neurons
-Decreases the synaptic release of glutamate and increases the release of GABA
-At therapeutic levels – the major action is to block Na+ channels and inhibit the generation of fast, rapidly repetitive AP’s
What is the major action of Phenytoin at therapeutic levels?
At therapeutic levels – the major action is to block Na+ channels and inhibit the generation of rapidly repetitive AP’s (!!!!)
What is the IV form of Phenytoin?
Available in a more soluble IV form as Fosphenytoin. Phosphate ester compound that is rapidly converted to phenytoin in the plasma
Explain the Pharmacokinetics of Phenytoin.
Absorption:
-Oral absorption nearly 100%
-IM absorption unpredictable
-Fosphenytoin is well absorbed IM
Distribution:
-Highly protein bound
-Accumulates in the brain, liver, muscle, and fat
Metabolism:
-Inactive metabolites
Excretion/Elimination:
-Excreted in the urine
-Elimination is dose-dependent( First order kinetics (metabolized by % fraction of the drug); Dose increases after the liver has reached max capacity can result in toxicity)
-Half-life is 12-36 hours( Average 24 hours for most patients
-Takes 5-7 days to reach a steady state after each dose change
-At high doses, it may take as long as 4-6wks
What are the S/Sx of Phenytoin Toxicity?
-Early Signs: Nystagmus and loss of smooth extra-ocular mvmts (not an indicator of a need to decrease dose)
-Diplopia and ataxia (most common dose related adverse effects that require a dose adjustment !!!!)
-Sedation (high doses)
-Gingival hyperplasia
-Hirsutism
What are the effects associated with long-term use of Phenytoin?
-Coarsening of facial features
-Mild peripheral neuropathy (Diminished deep tendon reflexes in the lower extremities)
-Osteomalacia and Vit D deficiencies
-Low folate levels
-Megoblastic anemia (Inhibition of DNA synthesis during RBC production)
What are the Neuroleptic, “Typical” Anti-psychotic drugs?
Anti-psychotic drugs that produce a high incidence of extrapyramidal side effects (EPS) at clinically effective doses (or cataplexy in lab animals).
Examples of the Neuroleptic, “Typical” Anti-psychotic drugs?
Phenothiazines: Ex. Chlorpromazine (Thorazine) is the prototype
Butyrophenone derivatives: Haloperidol (Haldol) - can be used for nausea (not using Droperidol - BBW)
What are examples of Extrapyramidal Symptoms (EPS)?
Pill rolling, tardive dyskinesia. Due to Low Dopamine
What are the “Atypical” Anti-psychotic drugs?
Do NOT cause EPS at clinically effective doses.
-Clozapine is the prototype
Define Psychosis
Denotes a variety of mental disorders.
-The presence of delusions (false beliefs)
-Various types of hallucinations: Auditory, visual, tactile, olfactory
-Grossly disorganized thinking in a clear sensorium
-Excessive limbic dopaminergic activity plays a role in psychosis
Define Schizophrenia
A neurodevelopmental disorder
-Genetic disorder with high inheritability but no single gene is involved
-The most common psychosis
-Psychosis is not present in all patients at all times
-Positive or Negative symptoms
-Other characteristics include cognitive impairments manifested by attention and short term memory deficits
-Diminished cortical or hippocampal activity underlies the cognitive impairment and negative symptoms of schizophrenia
-Studies of glutamate and glycine are in development
-20%-25% of schizophrenics are drug resistant
What are the Positive Symptoms of Schizophrenia? (something is being added that shouldn’t be there)
Delusions, hallucinations, and reality distortions, bizarre/agitated behaviors
-Mediated by D2 receptors
What are the Negative Symptoms of Schizophrenia? (something is removed that is normally there).
Flattened affect, emotional/social withdrawal
-Mediated by 5-HT receptor (many subtypes) but especially the 5-HT2A receptor
What is the MOA of Serotonin Antagonists?
-Blockade of the 5-HT 2A receptor (GPCR of serotonin) and the D2 Receptor
-Blocks 5-HT 2A > D2
-Inverse agonists of 5-HT2A (reverses nl function of the receptor) = Decreases excitation
-Weak D2 antagonism that is linked to positive symptoms
Effects:
-Some alpha blockade and muscarinic blockade
-Also some H1-Receptor blockade
Treatment:
-Schizophrenia – both positive and negative effects
-Some benefits in the agitation of Alzheimer’s and Parkinson’s patients
What is the 5-HT 2A receptor?
The GPCR of serotonin.
-Modulates the effects of Dopa, NE, glutamate, GABA, Ach and other neurotransmitters in the cortex, limbic region, and striatum
What is the prototype drug of the Serotonin Antagonists?
Clozapine (Clozaril)
What are the general pharmacokinetics of anti-psychotics?
-Readily but incompletely absorbed
-Significant first-pass metabolism
-Highly lipid soluble and protein bound
-Large Vd
-Longer clinical duration of action than indicated by their half-lives (Prolonged occupancy of D2 receptors in the brain by the typical anti-psychotic drug)
-Almost completely metabolized by oxidation or demethylation by CYP450 enzymes in the liver (Be aware of potential drug-drug interactions when combination therapy includes drugs that inhibit CYP450 enzymes)
-Time to recurrence of symptoms is highly variable after discontinuation of anti-psychotic drugs
-Average time for relapse in schizophrenic pts who d/c meds is 6 months
-Clozapine is the exception – relapse after d/c is usually rapid and severe
Anti-psychotic that may be excreted in the urine weeks after the last dose of chronically administered drug.
-Long-acting injectable formulations may cause some blockade of D2 receptors 3-6 months after the last injection
Chlorpromazine
What are the general dynamics of anti-psychotics?
-Wide variety of CNS, ANS and endocrine effects
-Efficacy is driven by D2 receptor blockade
-Adverse reactions involve antagonism at alpha receptors, muscarinic receptors, H1 receptors, and 5-HT2 receptors
What is the general MOA of typical anti-psychotics?
Act as D2 antagonists (associated with EPS)
-Primary action at the mesolimbic and mesocortical regions of the brain
-D2 receptor blockade in basal ganglia and tuberoinfundibular pathways mediate some of the SE’s of these drugs
What is the general MOA of Atypical Anti-psychotics?
Mild D2 receptor antagonists (approx. 40% blockade) combined with serotonin 5-HT2 receptor blockade
-Also high affinities for binding to D4 and 5-HT2C
-Fewer dopamine receptor blockade side effects
What are the therapeutic uses for Anti-Psychotics?
Most successful with psychosocial intervention
-Treatment of psychoses
-Treatment of schizophrenia (Typical anti-psychotics for positive symptoms; Atypical anti-psychotics for both positive & negative symptoms)
-Mood stabilizers – Atypical anti-psychotics
-Treatment for the manic phase of bipolar disorder
-Tourette’s Syndrome
-ADD
-Anti-emetics
-Intractable hiccups
What are the general toxicity symptoms of anti-psychotics?
-Severe sedation (Mediated by anti-histamine effects)
-Anti-cholinergic effects (blocking muscarinic receptors): Dry mouth/polydipsia, Constipation
-Parkinsonian like tremors: Tardive dyskinesia (greater with typical anti-psychotics)
-Hyperprolactinemia (see flow chart): D receptor antagonism blocks the inhibitory effects of dopamine on prolactin production by the anterior pituitary gland = Gynecomastia, amenorrhea, galactorrhea (greater with typical anti-psychotics)
-Hypotension (!!!!): Alpha adrenergic receptor antagonism
Know these meds from Chapter 29 Summary
Chlorpromazine (Thorazine)
Haloperidol (Haldol)
Clozapine
Lithium
Carbamazepine (Tergretol)
What is Hyperlactinemia of Anti-Psychotics?
Remember: Dopamine inhibits Ant Pit from releasing Prolactin.
-Dopamine receptor antagonism (DR Antagonist) removes the inhibition of Prolactin. Increases lactation and decreases GnRH.
-Increased Lactation = galactorrhea.
-Decreased GnRH = gynecomastia and Amenorrhea
-greater with typical anti-psychotics
D receptor antagonism blocks the inhibitory effects of dopamine on prolactin production by the anterior pituitary gland
