Pharmacology Antidepressants / Antipsychotics and epilepsy drugs II

How do drugs used to treat schizophrenia differ in action from those used to treat depression?

• Antidepressants are thought mainly to increase norepinephrine and/or serotonin levels by blocking reuptake

• Antipsychotics are thought to work mainly by decreasing dopamine activity by acting as dopamine receptor antagonists in the dopaminergic tracts in the brain, especially to mesocorticolimbic tract

what are some medical uses of antipsychotic medications?

• Management of Schizophrenia

• Bipolar disorder

• Treatment of Agitated Depression, Acute Mania, and Atypical Psychiatric Disorders (following surgery or MI)

• Tourette’s Syndrome (Haloperidol, Pimozide, Atypicals)

• Prevention of Cancer Chemotherapy-Induced Severe Nausea and Vomiting (Prochlorperazine (Compazine))

• Pre and Postsurgical Prophylaxis Against Aspiration (Metoclopromide, Droperidol)

• Treatment of Intractable Hiccups (Promethazine)

• Motion Sickness (Promethazine)

Worldwide, the prevalence of schizophrenia appears to be %

1%

t/f: Schizophrenia is more prevalent than Alzheimer's disease, diabetes, or multiple sclerosis

true

(prevalence greater among lower SES in urban areas and comparable among men and women_

what is the peak age of onset of schizophrenia?

18-25 years in men

26 to 45 yeara in women

A person with a parent or sibling with schizophrenia has approximately a % risk of developing the disorder compared with a % risk for a person with no family history of schizophrenia.

10%

1%

Research suggests that schizophrenia may be a developmental disorder resulting from…?

impaired migration of neurons in the brain during fetal development (nongenetic factors like environmental stress during fetal development/birth may also contribute)

what are positive symptoms of schizophrenia?

• Delusions

• Disorganized speech

• Hallucinations

• Behavior disturbance

what are negative symptoms of schizophrenia?

• Avolition (lack of goal directed behavior)

• Flattened affect

• Anhedonia

• Social withdrawal

what are 3 typical antipsychotics (D2 antagonists) used to treat schizophrenia?

• Phenothiazines: Chlorpromazine (Thorazine)

• thioxanthines

• Butyrophenones: Haloperidol (Haldol)

  • 1st choice typical

how do typical antipsychotics like Phenothiazines: Chlorpromazine (Thorazine), thioxanthines, and Butyrophenones: Haloperidol (Haldol) work?

block D2 > D1 (dopamine receptors) with varying degrees of selectivity for 3 dopaminergic tracts in the CNS

• phenothiazines affect all tracts = lots of side effects

what are the 3 dopaminergic tracts in the CNS that are targets of typical antipsychotics (D2 antagonists)?

• nigrostriatial

• mesocorticolimbic

• tuberinfundibular

antipsychotic agents that act on the nigrostriatal dopaminergic tract helps with…?

extrapyramidal movement disorders (EPS)

antipsychotic agents that act on the mesocorticolimbic dopaminergic tract helps with…?

relief of hallucinations and delusions

antipsychotic agents that act on the tuberinfundibular dopaminergic tract helps with…?

increased prolactin release

• galactorrhea

• gynecomastia

• sexual dysfunction

• menstrual irregularities

early antipsychotic drugs also act on other receptors (non-dopamine) which can explain side effect such as…?

• anticholinergic

  • xerostomia, urinary retention, blurred vision, constipation

• antihistamine

  • sedation

• anti-alpha-1 adrenergic

  • orthostatic hypotension

what are atypical antipsychotics?

block serotonin AND dopamine receptors (decreased side effects like EPS)

• dibenzepines

  • clozapine (Clozaril)

  • Olanzapine (Zyprexa)

  • Quetiapine (Seroquel)

• benzisoxazoles

  • Risperidone (Risperidal)

what is one potentially dangerous side effect of Clozapine (atypical antipsychotics)?

agranulocytosis (bleeding disorder)

what are some dental management issues that may arise with patients using antipsychotic drugs?

• poor oral hygiene (caries, periodontal disease)

• anticholinergic side effects (xerostomia)

• EPS and dystonias, postural hypotension

• heightened sensitivity to light

• informed consent may be issue if pt has trouble understanding oral care instructions

• fixed dental appliances preferred to removable appliances

• lack of patient compliance

About % of men and % of women suffer from anxiety disorders

6% men

13% women

# Americans have had an anxiety disorder but only % receive treatment

30 million

25%

A typical Dentist will see how many patients per day with some kind of anxiety?

at least one

what is the emotional state in which people feel uneasy, apprehensive, or fearful about events they cannot control or predict, or about events that seem threatening or dangerous?

anxiety (feeling of vulnerability, can persist and become disabling)

what is fear? how is it different from anxiety?

• fear: a normal reaction to a known, external source of danger

• anxiety: individual is frightened but source of danger not known, recognized, or inadequate to account for symptoms

• physiological manifestations are similar

what are phobias?

fear response to a neutral stimulus (unrealistic fears)

what are panic attacks?

A period of intense fear or discomfort that is associated with numerous physical and psychological symptoms such as :

• Palpitations,

• sweating,

• trembling,

• shortness of breath,

• choking,

• chest pain

• nausea

what are anxiolytics used for?

• to treat acute anxiety reactions/agitation

• adjunctive to other medications to enhance sedation prior to procedures

• management of chronic anxiety disorders (generalized anxiety disorder, panic disorder, PTSD, social phobias)

what are some common antianxiety drug classifications?

• benzodiazepines (diazepam, flurazepam, etc.)

what is the benzodiazepine antagonist?

flumazenil (important because you could overdose on benzodiazepine antianxiety drug so it is good that there is a antagonist that can help reverse effects)

Diazepam, Midazolam, Lorazepam, Alprazolam, Triazolam are all examples of …? how do they work?

benzodiazepines

• enhance effect of GABA (inhibitory neurotransmitter)

what are the effects of benzodiazepines?

Anxiolytic in low doses, higher doses lead to more general sedation and sleep

• acute use well estabilshed

• chronic use discouraged (tolerance, withdrawal, addiction)

what is a cautionary warning DDI for benzodiazepines?

Synergistic sedating and respiratory depressant effects with opioids, ETOH and other “CNS depressants”

what are some adverse effects of benzodiazepenes?

• Sedation

  • Tolerance to sedative effects usually in ~2 weeks of daily use, synergistic with opioids

• Cognitive impairment

  • short AND long term use especially in elderly

• Ataxia

  • Increase in falls especially in the elderly and synergistic with opioids

• Respiratory depression

  • In high doses or when combined with other CNS depressants such as EtOH, opioids, barbiturates

• Anterograde amnesia

• Reduce dose in elderly!

which benzodiazepine drug is often used in pediatric dental procedures?

midazolam (so patients already on long term benzodiazepines may exhibit tolerance and require higher doses (monitor respiration))

what does the FDA black box warning indicate with benzodiazepine use?

FDA black box warning for opioid analgesics, prescription opioid cough products, and benzodiazepine labeling related to serious risks and death from combined use (2016)

There are 3 dopamine tracts in the brain that are acted upon by antipsychotic drugs. Nigrostriatal, mesocorticolimbic, and tuberoinfundibular.

Which tract mediates the relief of the positive symptoms like hallucinations?

Mesocorticolimbic

There are 3 dopamine tracts in the brain that are acted upon by antipsychotic drugs. Nigrostriatal, mesocorticolimbic, and tuberoinfundibular.

Which mediates the extrapyramidal movement disorders caused by antipsychotic drugs?

Nigrostriatal

How do atypical or 2nd generation antipsychotics differ from 1st generation?

• They supposedly reduce the negative symptoms in addition to the positive symptoms

• They block serotonin 5-HT2 Receptors in addition to dopamine receptors

• More selective for DA receptors in mesocorticolimbic system

• Reduced EPS side effects

What are some problematic side effects or dental concerns in treating a patient taking antipsychotic drugs?

• Patient may have EPS movement disorder like Tardive dyskinesia or akathisia

• Drugs cause xerostomia

• Patients show poor oral hygiene

• May show orthostatic hypotension

• Increased sensitivity to light

Benzodiazepines are typically used as anxiolytics. Name 3.

Diazepam

Lorazepam

Midazolam

what is the MOA of benzodiazepines?

they enhance the action of GABA

describe 3 adverse side effects of benzodiazepines?

sedation

cognitive impairment

respiratory depression

anterograde amnesia

what is the FDA warning for benzodiazapenes?

Risk of death when combined with opioids due to severe respiratory depression

Anticonvulsants are typically used to manage the symptoms of _______, which derive from …?

epilepsy

the recurrence of an abnormal discharge of cerebral neurons

what are type 1 anticonvulsants?

sodium channel inactivators

• Phenytoin (Dilantin), Carbamazepine (Tegretol)

what are type 2 anticonvulsants?

GABA facilitators

• Barbiturates (Phenobarbital), Benzodiazepines: Diazepam (Valium), Lorazepam (Ativan), Clonazepam (Klonopin)

what are type 3 anticonvulsants?

T-calcium current blockers

• Ethosuximide (Zarontin)

what are type IV anticonvulsants?

mixed acting (combination of type 1/2/3 with inhibition of EAA activity)

• Topiramate (Topamax), Lamotrigine(Lamictal), Valproic Acid (Valproate)

how do type I (sodium channel inactivator) anticonsulsants work? (MOA)

• These agents inhibit synaptic transmission and stabilize hyperexcitable neurons by altering sodium ion influx and efflux

• This dampens only abnormally high neuronal activity, allowing normal conduction of action potentials to occur

Examples: Phenytoin (Dilantin), carbamazepine (Tegretol)

what are some notable side effects of Phenytoin (Dilantin)?

(this is a type I sodium channel inactivator anticonvulsant)

• gingival hyperplasia hypertrichosis

• teratogenic (cleft palate)

what are some notable side effects of Carbamazepine (Tegretol)?

no dilantin type adverse effects other than 3A4 induction

what are some DDIs of type 1 sodium channel inactivator anticonvulsants?

Induce liver metabolism (3A4) of some drugs

GABA is the major inhibitory neurotransmitter in the CNS.

Enhancing the activity of GABA has the dual action of …?

1. preventing the spread of the abnormal neuronal activity from its focus

2. but also raises the threshold for setting off the focus

which type II anticonvulsants work via faciliation of GABA binding?

Phenobarbital, Benzodiazepines

which type II anticonvulsants work via decreased GABA breakdown and increased GABA synthesis?

valproic acid

what is the MOA of benzodiazapenes?

• BDZ receptors are part of a complex containing a CL-channel, GABA-A receptors for the major inhibitory neurotransmitter GABA, and receptors that bind barbiturates.

• GABA binds to its receptor, opens the CL-channel, CL- goes into the neuron, hyperpolarizing the cell, decreasing the neuronal firing ability.

• BDZs work indirectly via allosteric modification, increasing the affinity of GABA for the GABA receptor and thus enhancing GABA’s inhibitory action.

what are side effects of type II anticonvulsant (barbiturates: phenobarbital)?

Sedation and cognitive slowing. Children and elderly patients may show paradoxical excitement

what are potential drug interactions of type II anticonvulsant (barbiturates: phenobarbital)?

• additive respiratory depression

• generalized inducer of liver enzymes

_______ is the drug of choice (sometimes diazepam due to its wider availability outside the medical setting) for terminating status epilepticus (given IV) and to treat local anesthetic induced seizures

Lorazepam (Ativan)

what is a key DDI with type II gaba enhancing benzodiazepines ?

Opioid abuse combined with BDZs is lethal due to additive respiratory depression

what is the drug of choice for absence seizures?

type III T-calcium current blockers (ethosuximide)

what is the MOA of ethosuximide? (type III T-calcium current blocker)

ethosuximide elevates the firing threshold for seizures and depresses the firing of epileptic foci by blocking low threshold, T calcium channel currents in thalamic relay neurons

what are some side effects of ethosuximide? (type III T-calcium current blocker)

drowsiness, nausea and vomiting, blood dyscrasia, bone marrow depression, dizziness and skin rashes

MOA of Lamotrigine (Lamictal)? (type IV mixed acting anticonvulsant)

Na+ channel inactivator and decreased EAA (glutamate) activity

MOA of Topiramate (Topamax) (type IV mixed acting anticonvulsant)

• Na+ channel inactivator

• enhancement of GABA

• decreased EAA activity

what are some non-seizure related uses of Topiramate (Topamax) (type IV mixed acting anticonvulsant)?

• migraine prophylaxis

• bipolar disorder

• managing alcohol dependence

• obesity

• binge eating

• smoking cessation

what are some adverse effects of Topiramate (Topamax) (type IV mixed acting anticonvulsant)?

• Can produce speech, language and behavioral problems in children

• Increased incidence of cleft palate

what are some Adverse Side Effects/ DDIs involving anti-seizure drugs?

• Additive CNS depression (most)

• Drug-produced gingival hyperplasia (Dilantin)

• Drug-induced blood dyscrasias may increase susceptibility to infection. (ethosuximide, dilantin, tegretol, valproic acid)

• Induction of drug metabolizing enzymes (Phenobarbital, Dilantin, Tegretol)

• Additive effects on bleeding (Valproic acid)

• Dry mouth resulting in bleeding gums and tooth pain

MOA of Gabapentin and Pregabalin (Lyrica)?

Both bind to the α2δ (alpha2delta) subunit of the voltage dependent calcium channel in the CNS. This reduces calcium influx into the nerve terminals

• used for neuropathic pain, depression, bipolar, anxiety

what is a disorder that affects nerve cells in the part of the brain controlling muscle movement and can result in trembling, muscle rigidity, difficulty walking, problems with balance, and slowed movement?

Parkinson’s disease

Many of the signs and symptoms of Parkinson's disease develop when certain nerve cells in an area of the brain called the _______ are damaged or destroyed

substantia nigra

what is the cause of Parkinson’s disease?

• Many signs/symptoms develop when half or more of certain nerve cells in the substantia nigra are damaged or destroyed.

• Normally, these nerve cells release dopamine — a chemical that transmits signals between the substantia nigra and the corpus striatum.

• These signals cause muscles to make smooth, controlled movements.

• combination of genetic and environmental factors

• Certain drugs, diseases and toxins also may cause similar symptoms

what is the main drug used to treat Parkinson’s disease?

Sinemet (Levodopa + Carbidopa)

how does sinemet work to treat Parkinson’s disease?

• Levodopa converts into dopamine by nerve cells in brain (crosses BBB but only small amount actually reach brain)

  • increase in dopamine may reverse many disabling symptoms

• Carbidopa blocks carboxylase that breaks down levodopa in periphery

  • helps more levodopa reach the brain + prevent breakdown

what are some other, less common drugs used to treat Parkinson’s disease?

• dopamine agonists like pramipexole (Mirapex)

  • causes compuslive gambling behavior

• MAO-B inhibitors: elegiline (Eldepryl) and rasagline (Azilect)

• Catechol-O-methyltransferase (COMT) inhibitors. (Entacapone)

what are the implications for dentistry for drugs used to treat Parkinson’s disease?

• xerostomia, enamel erosion from frequent nausea and vomiting

• Tremoring (difficult for patient to brush teeth)

  • oral tremors

wjat are problematic DDIs with drugs used to treat Parkinson’s disease?

• Levodopa and COMT inhibitors may sensitize heart to epinephrine induced arrhythmias,

  • avoid use of vasoconstrictor containing local anesthetics

• Selegilene is metabolized to amphetamine and metahamphetamine

  • avoid epi!

• Selegilene is an MAOI

  • avoid meperidine

what are generalized seizures?

• both hemispheres of brain involved leading to tonic - clonic symptoms

• consciousness and postural control loss

what are absence seizures?

Short loss of consciousness but no loss of postural control (More common in children)

what is status epilepticus?

continuous seizure lasting more than 5 minutes - need to intervene with BDZ (Can be caused by local anesthetic)

how do dopamine agonists (“Miradex”) work to treat Parkinson’s?

gets into CNS and stimulates dopamine receptors

how do MAO-B inhibitors (“selegiline”) work to treat Parkinson’s?

combined with sinemet helps reduce breakdown of DA