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Adv Pharm 1 > Neuro (pt 3/4) Methanol, Ethylene Glycol, Anti-Seizures, Anti-Psych > Flashcards

Neuro (pt 3/4) Methanol, Ethylene Glycol, Anti-Seizures, Anti-Psych Flashcards

1
Q

What is Methanol?

A

-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

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2
Q

What are the toxic metabolites that Methanol is oxidized to?

A

Formaldehyde, formic acid & CO2 = toxic metabolites

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3
Q

How long does it take for Methanol toxicity to develop?

A

6-30 hours

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4
Q

What are the mild characteristics of Methanol toxicity?

A

Inebriation, gastritis, elevated osmolal gap

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5
Q

What is the Osmolal Gap?

A

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

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6
Q

An Osmolal Gap value greater than ____ is considered a critical value or cutoff.

A

15

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7
Q

-The presence of low blood pH, elevated anion gap and _________ OG is a medical emergency that requires prompt treatment

A

A greatly elevated OG

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8
Q

What are the Severe characteristics of Methanol toxicity?

A

-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

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9
Q

What is the treatment for Methanol Toxicity?

A

-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

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10
Q

What is Fomepizole?

A

-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)

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11
Q

Why is IV Ethanol utilized as an alternative to Fomepizole in the treatment of Methanol toxicity?

A

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

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12
Q

-Used as heat exchangers, in antifreeze formations, and as industrial solvents
-Metabolized to toxic aldehydes and oxalate

A

Ethylene Glycol

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13
Q

Describe the 3 stages of Ethylene Glycol Overdose.

A

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

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14
Q

What is the treatment for Ethylene Glycol Overdose?

A

Treatment the same as for Methanol Toxicity (still needs dialysis to pull off metabolites and offending agents)

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15
Q

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.

A

Seizures

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16
Q

A heterogenous symptom complex disorder (caused by several different factors) characterized as chronic recurrent seizures.
-Approx 1% of the world’s population

A

Epilepsy

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17
Q

What are the three different mechanisms of Anti-seizure medications?

A

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)

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18
Q

Which anti-seizure drugs have presynaptic targets that diminish Glutamate release?

A

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)

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19
Q

Which anti-seizure drugs have postsynaptic targets that diminish Glutamate release?

A

AMPA receptors (perampanel)

T-type Ca voltage-gated calcium channels (ethosuximide, dimethadione)

Kv7 voltage-gated potassium channels (retigabine [ezogabine]

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20
Q

Which anti-seizure drugs are positive allosteric modulators of synaptic GABA A receptors (promote inhibition)?

A

Phenobarbital
Benzos

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21
Q

Which seizure type classifications all get the same type of drugs?

A

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.

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22
Q

Which seizure type classifications each require specific medications?

A

-Myoclonic
-Atonic
-Epileptic Spasms

23
Q

What is the Therapeutic Strategy for anti-seizure drugs?

A

-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)

24
Q

Explain the pharmacokinetics of anti-seizure drugs.

A

-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)

25
Q

What are the drugs you need to know that treat generalized seizures?

A

Phenytoin
Fosphenytoin
Carbamazepine
Valproate
Lamotrigine
Levetiracetam
Topiramate

26
Q

What is the DOC for infantile spasms?

A

Vigabatrin IM

27
Q

What are the drugs used to treat Status Epilepticus?

A

Diazepam, Midazolam, Fosphenytoin, Phenobarbital

28
Q

Explain the effects of Phenytoin (Dilantin)

A

-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

29
Q

What is the major action of Phenytoin at therapeutic levels?

A

At therapeutic levels – the major action is to block Na+ channels and inhibit the generation of rapidly repetitive AP’s (!!!!)

30
Q

What is the IV form of Phenytoin?

A

Available in a more soluble IV form as Fosphenytoin. Phosphate ester compound that is rapidly converted to phenytoin in the plasma

31
Q

Explain the Pharmacokinetics of Phenytoin.

A

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

32
Q

What are the S/Sx of Phenytoin Toxicity?

A

-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

33
Q

What are the effects associated with long-term use of Phenytoin?

A

-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)

34
Q

What are the Neuroleptic, “Typical” Anti-psychotic drugs?

A

Anti-psychotic drugs that produce a high incidence of extrapyramidal side effects (EPS) at clinically effective doses (or cataplexy in lab animals).

35
Q

Examples of the Neuroleptic, “Typical” Anti-psychotic drugs?

A

Phenothiazines: Ex. Chlorpromazine (Thorazine) is the prototype

Butyrophenone derivatives: Haloperidol (Haldol) - can be used for nausea (not using Droperidol - BBW)

36
Q

What are examples of Extrapyramidal Symptoms (EPS)?

A

Pill rolling, tardive dyskinesia. Due to Low Dopamine

37
Q

What are the “Atypical” Anti-psychotic drugs?

A

Do NOT cause EPS at clinically effective doses.
-Clozapine is the prototype

38
Q

Define Psychosis

A

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

39
Q

Define Schizophrenia

A

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

40
Q

What are the Positive Symptoms of Schizophrenia? (something is being added that shouldn’t be there)

A

Delusions, hallucinations, and reality distortions, bizarre/agitated behaviors
-Mediated by D2 receptors

41
Q

What are the Negative Symptoms of Schizophrenia? (something is removed that is normally there).

A

Flattened affect, emotional/social withdrawal
-Mediated by 5-HT receptor (many subtypes) but especially the 5-HT2A receptor

42
Q

What is the MOA of Serotonin Antagonists?

A

-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

43
Q

What is the 5-HT 2A receptor?

A

The GPCR of serotonin.
-Modulates the effects of Dopa, NE, glutamate, GABA, Ach and other neurotransmitters in the cortex, limbic region, and striatum

44
Q

What is the prototype drug of the Serotonin Antagonists?

A

Clozapine (Clozaril)

45
Q

What are the general pharmacokinetics of anti-psychotics?

A

-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

46
Q

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

A

Chlorpromazine

47
Q

What are the general dynamics of anti-psychotics?

A

-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

48
Q

What is the general MOA of typical anti-psychotics?

A

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

49
Q

What is the general MOA of Atypical Anti-psychotics?

A

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

50
Q

What are the therapeutic uses for Anti-Psychotics?

A

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

51
Q

What are the general toxicity symptoms of anti-psychotics?

A

-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

52
Q

Know these meds from Chapter 29 Summary

A

Chlorpromazine (Thorazine)
Haloperidol (Haldol)
Clozapine
Lithium
Carbamazepine (Tergretol)

53
Q

What is Hyperlactinemia of Anti-Psychotics?

A

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

Adv Pharm 1 (28 decks)

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