Module 3-PHAR 370

mechanism of seizures

-sudden repeated spontaneous discharge of groups of excitatory neurons in the CNS -glutamate input exceeds the GABA input -most excitatory neurons in the CNS are glutamatergic neurons

pharmacokinetics of benzos

-taken a capsule or tablet -can be intravenous -action is determined by the rate of liver metabolism and formation of or lack of pharmacologically active metabolites.

major depression (endogenous)

-tends to recur throughout life -characteristic disturbances in sleep, hunger and appetite -loss of pleasure and interest in most activities -genetically determined biochemical disorder -response to antidepressant therapy

why should Z drugs and Benzos be used with caution in the elderly ?

-they can produce cognitive dysfunction -they metabolize them slower then younger adults -leads to over sedation, falls and injury

amyloid plaques

A structural change in the cerebral cortex associated with Alzheimer's disease, in which dense deposits of a deteriorated protein called amyloid develop, surrounded by clumps of dead nerve and glial cells.

Parkinson's disease is characterized by 4 main clinical features which are:

Bradykinesia (slow and poor movement) • Muscle rigidity • Tremor at rest • Poor postural balance and a shuffling/impaired gait

Which one of the statements regarding bipolar disorder is correct? a) The depressive phase of bipolar disorder is the exact same as major depression. b) Mood stabilizers are rarely used in the treatment of bipolar disorder. c) Bipolar disorder is usually associated with manic and depressive phases. d) Lithium carbonate has very few adverse effects.

C

Antipsychotics

class of drugs used to reduce psychotic symptoms caused by a variety of disorders, including bipolar disorder, schizophrenia, and drug-induced psychoses

is MAO-A or MAO-B responsible for most of the oxidative metabolism of dopamine in the brain?

MAO-B bc it is the predominant form of the enzyme in the striatum.

Memantine

NMDA receptor antagonist This drug may slow the rate of destruction of neurons by inhibiting the excitatory responses to glutamate, preventing glutamate-induced excitatory neuronal death.

can you develop a dependence on anticonvulsant drugs?

Yes -withdrawal does occur -severity depends on the drug being withdrawn

electroconvulsive therapy (ECT)

a biomedical therapy for severely depressed patients in which a brief electric current is sent through the brain of an anesthetized patient

drug classes

a class of drugs is a group of drugs that have the same mechanism of action and similar pharmacological properties

Amyotrophic Lateral Sclerosis (ALS) (Lou Gehrig's Disease)

a disorder of the motor neurons in the spinal cord, brain stem, and brain. -targets motor neurons and limits their ability to carry signals from the CNS to the skeletal muscles

how does Huntingtons present?

a gradual onset of motor incoordination, impairment of balance, and a decline in cognitive function that usually appears in midlife -depression -memory loss (but they dont forget their friends and fam)

lithium carbonate

a mood-stabilizing agent used to prevent mood swings in patients with bipolar disorder. It is also used to treat mania

Brain-derived neurotrophic factor (BDNF)

a protein required for neural growth and axon sprouting within the nervous system

mood stabilizers

commonly used to prevent the mania (highs) and depression (lows) associated with bipolar disorder.

Haloperidol

competitively blocks dopamine receptors

diclofenac

currently only available by prescription. Clinically, it is used as an ophthalmic preparation for prevention of postoperative ophthalmic inflammation and as a topical gel for solar keratosis (i.e. a skin condition caused by damage from the sun). Additionally, diclofenac can be used as a rectal suppository for preemptive analgesia and postoperative nausea. Diclofenac is a relatively non-selective inhibitor of COX-1 and COX2.

all non-opioid analgesic drugs function by inhibiting the enzymes _________ and _________ thereby reducing the amount of prostaglandins.

cyclooxygenase (COX)-1 and/or COX-2

Dopamine receptor agonist

an approach to increasing dopaminergic activity in the substantia nigra (synthetic dopamine agonist to supplement the decreased endogenous dopamine)

adverse effects that limit the usefulness of TCA's include:

anticholinergic effects (dry mouth, urinary retention, constipation, and blurred vision) • antiadrenergic (alpha) effects (hypotension when standing up) • antihistaminic actions (sedation) • block sodium channels (arrhythmias, seizures, fatal in overdose) • weight gain

postictal period

just after the seizure, the individual may be confused, fatigued, and fall into a deep sleep

what part of the brain controls emotion and behavior?

limbic system

Parkinson's disease is when there is a loss of _____________________in the region of the brain called the substantia nigra pars

dopaminergic neurons

Prostaglandins

endogenous substances that sensitize the nerve endings to mediators of pain, reducing fever, and inhibiting the propagation of inflammation.

what do treatment strategies of Parkinson's aim to do?

enhancing the function of the remaining dopaminergic neurons by increasing the amount of dopamine, inhibiting the breakdown of dopamine, and/or administering dopamine agonists.

abuse potential of barbiturates

equal to or greater than alcohol

what creates anxiety and insomnia

excessive CNS excitation

treatment for ALS

no cure -Riluzole a glutamate receptor (kainate and NMDA) blocker, is thought to decrease the rate of excitotoxic cell death induced by glutamate. This drug increases survival by several months. symptom control of muscle spasticity and respiratory assistance.

NSAIDs

nonsteroidal anti-inflammatory drugs These drugs have analgesic (reduces pain), antipyretic (reduces fever), and antiinflammatory (reduces inflammation) effects

are anticonvulsants lethal?

rarely

desirable short term effects of benzo

relaxation calmness relief from tension or anxiety

what's the most dangerous effect of anticonvulsants

respiratory depression

sex __________ are also implicated in major depression.

steroids (deficiency in estrogen and testosterone)

regardless of the cause of depression, all current effective antidepressants have their primary actions on the ....

storage, metabolism, or reuptake of serotonin or norepinephrine (and in some cases dopamine).

dopaminergic neurons provide input to the ...

striatum (an areas of the brain involved in motor coordination and movement)

how is Alzheimer's treated?

symptom control or drugs that modify cholinergic transmission or attempt to enhance transmission in the remaining cholinergic neurons.

consequences of long term use of benzo

symptoms of chronic sedative-hypnotic intoxication -impaired thinking, poor memory and judgement -disorientation, incoordination -slurred speech

where do barbiturates bind?

the barbiturate receptor on the chloride channel

sedation

used to relieve anxiety, decrease activity, moderate excitement and generally calm the individual

anti-anxiety effect

used to treat anxiety disorders such as obsessive-compulsive disorder

Naxproxen

useful for rheumatologic indications, such as rheumatoid arthritis. Naproxen is also available as an ophthalmic solution and a topical preparation. Naproxen reversibly inhibits both COX-1 and COX-2.

neurofibrillary tangles

-occur later in disease progression -cognitive impairment -aggregated tau protein within the neuron

Ibuprofen

-one of the most efficacious over-the-counter agents on the market. -The mechanism of action of ibuprofen is reversible inhibition of COX-1 and COX-2 enzymes -A 200 mg dose of ibuprofen is more effective than a 325 mg dose of ASA

Second-Generation Antipsychotics (i.e. atypical antipsychotics)

-produce less extrapyramidal side effects -dual action by blocking dopamine and serotonin receptors.

treatment for Huntington's

-relieve symptoms -antidepressants treat depression -antipsychotics treat paranoia, psychosis or delusional states -use of drugs to deplete the storage of catecholamines in the vesicles of neurons may help in controlling the motor symptoms.

what's the risk of substance dependence with benzos?

-risk is low for short time use -with chronic use (one year or more) sudden discontinuation may lead to withdrawals -therefore addiction is possible but unlikely

pharmacokinetics of anticonvulsants

-absorption after oral administration is about 80-100% -drugs are cleared primarily by the liver

partial seizures

-aka focal -involves the focal areas of the brain -more restricted symptoms -may involve motor disturbances -alterations of perceptions (ex. taste, smell) or behavior (ex. violence)

Catechol-o-methyltransferase inhibitors

-enzyme that breaks down dopamine

adverse effects of cholinesterase

-gastrointestinal effects -muscle cramping -abnormal dreams

how and were is dopamine synthesized ?

-in the brain -from dietary phenylalanine after conversion to tyrosine.

generalized seizures

-involve the entire CNS -arises in both cerebral hemispheres -accompanied by a loss of consciousness -subdivided into several classes based on the type of movement and duration of loss of consciousness.

Name some steps a healthcare worker could take when prescribing anticonvulsants to a patient to minimize potential drug-drug interactions

-limit co-administration; prescribe additional medication only when there is a clear clinical indication -monitor response: carefully monitor clinical response after addition or removal of drugs -if necessary adjust the dose

clinical use of barbiturates

-limited use -it has been replaced with safer alternatives. -induces anesthesia -anti-seizure use

barbiturates are classified according to their duration of action:

-long acting (1-2 days) -short-acting (2-8 hours ultra short acting (20 mins)

is there abuse potential with taking benzos?

-low abuse liability bc weaker enforcing properties then opioids and alcohol

pharmacology of barbiturates

-low therapeutic index -suppresses REM sleep -lethality is common especially when combined with alc -

MAO inhibitors and their drug and food interactions include:

-many over counter and prescription drugs -tyramine-containing foods (causes a hypertensive crisis) -use of TCA, SSRI or cough suppressant in a patient taking a MAO can cause serotonin syndrome

depression associated with bipolar disorder

-mood stabilizer is used to minimize atypical shifts in mood associated with this disorder and the depression is sometimes managed with antidepressants.

benefits of electroconvulsive therapy

-more effective than drug therapies -beneficial effects are seen in 1-2 weeks instead of 4-6 weeks for drugs. -minimal adverse effects -increases BDNF levels and neurogenesis in animal models

reactive (secondary) depression

-most common -occurs in response to real stimuli such as grief and illness -may resolve spontaneously or to a variety of treatments

idiopathic Parkinson's disease

-most common -no known or confirmed cause

Selective Serotonin Reuptake Inhibitors (SSRIs)

-most widely used class of drugs in the treatment of depression -The SSRI's are relatively selective for blocking the serotonin transporter protein in the presynaptic terminal. -less toxicity then TCAs

adverse effects of SSRI's

-nausea -headache -nervousness -insomnia -high incidence of sexual dysfunction

pharmacological properties of benzodiazepines

-they have a high therapeutic index -they relieve anxiety -they produce sedation and amnesia -they can decrease aggression -some members of this group are effective hypnotics -they produce minimal suppression of REM type sleep -they produce skeletal muscle relaxation -they have anticonvulsant action

substance dependence of barbiturates

-tolerance develops vary rapidly to the sleep induction and mood effects. -tolerance to the anticonvulsant actions develops more slowly and is not a major problem clinically. -addiction can result from regular use -you need to be withdrawn slowly bc withdrawal symptoms can be fatal

symptoms of ALS

-twitching -muscle cramps -weakness of an arm or leg -difficulty in swallowing -rapid progression of muscle atrophy leading to increased weakness, spasticity and death results from compromised respiration -behavioral changes and cognitive dysfunction

Acetylsalicylic Acid (ASA)

-used for mild to moderate pain and for fever -prevention of strokes and myocardial infarcts

What are the two main pathological features of Alzheimer's disease?

1) amyloid plaques 2) Neurofibrillary tangles

types of sedative hypnotic agents include:

1) anti-anxiety effect 2) sedation 3) hypnosis 4) general anesthesia

three main classes of sedative-hypnotic drugs

1) benzodiazepines 2) barbiturates 3) the 'Z' drugs

what two populations do benzos have an increased likelihood of producing adverse effects?

1) elderly 2) pregnant/breastfeedign

three mechanism that control seizures

1) increasing the inhibitory input to the neuron to suppress firing (increasing the GABA) 2) blocking electrical activity of the nerve to slow the nerve impulse (blocking sodium channel electrical activity to slow the conduction of nerve impulse) 3) Decreasing excitatory transmission (decreasing the release of glutamate at the synapse)

Two categories of drugs commonly used as mood stabilizers:

1) lithium carbonate 2) anticonvulsants

drugs that treat pain are divided into two categories:

1) opioid analgesics 2) non-opioid analgesics

types of depression

1) reactive (secondary) depression 2) major depression (endogenous) 3) depression associated with bipolar disorder

what are the 5 common features of neurodegenerative diseases?

1) selective areas affected 2) distinct genetic forms 3) inappropriate protein 4) increased likelihood with age 5) treatment controls the system

what two drug interaction can SSRI therapy cause?

1)Decreased metabolism: SSRIs inhibit the CYP450 enzymes, therefore the metabolism of concurrently administered drugs is altered. This may lead to drug toxicity or loss of drug efficacy. Some SSRIs have minimal inhibition, while others have major interactions. 2) Serotonin Syndrome: This syndrome occurs due to concurrent use of multiple drugs that increase serotonin. Monoamine oxidase inhibitors are the major culprit, but TCAs and other drugs that increase serotonin can also contribute. Serotonin syndrome is characterized by muscle rigidity, elevated body temp, and mental status changes (i.e. confusion, agitation). The syndrome can lead to coma and death.

Antidepressants work in 1 of three ways..

1. Block neurotransmitter reuptake systems. a. TCAs, SSRIs, SNRIs 2. Block neurotransmitter metabolism, thereby increasing the amount of neurotransmitter released. a. MAOi 3. Directly increase the amount of neurotransmitter released a. Autoreceptor antagonists

three classes of antipsychotics

1. Phenothiazine antipsychotics 2.Haloperidol 3. Atypical antipsychotics

Treatment of the manic phase of bipolar disorder is a two step process that involves:

1. Reduce the patient's mood to a "normal" range with antipsychotic medications such as haloperidol, chlorpromazine, or new atypical antipsychotics. 2. Stabilize the patient's mood within "normal" range with a mood stabilizer.

Which one of the statements regarding the selective serotonin reuptake inhibitors is correct? a) The SSRIS are more selective than the tricyclic antidepressants b) The SSRIs and tricyclic antidepressants have the exact same adverse effects c) The SSRIs are equally effective in blocking the reuptake of serotonin and norepinephrine d) The SSRIs are rarely used clinically

A

what does antagonism of dopamine receptors do?

Antagonism of dopamine receptors in the mesolimbic and mesofrontal regions of the brain helps to alleviate some of the symptoms associated with psychosis, such as unusual or bizarre behaviour, thought disorder, and delusions.

explain the ways in which anticonvulsants can have adverse effects in all individuals and then in pregnant women specifically

Anticonvulsants can cause a variety of adverse effects including severe skin rashes, g.i. disruption, and cognitive and visual impairment. Pregnant women should be especially cautious, as some anticonvulsants are teratogenic and can cause neural tube defects in the fetus.

anxiolytic effects

Anxiety-reducing effects

what receptors in the brain can phenothiazine antipsychotics also antagonize ?

Blockade of Cholinergic (muscarinic) receptors: • Therapeutic effects: Reduction of extrapyramidal adverse effects. Adverse effects: Blurred vision, dry mouth, constipation, difficulty urinating. Blockade of Histamine Receptors: • Adverse effects: Sedation, drowsiness, and weight gain. Blockade of α-adrenoceptors: • Adverse effects: Postural hypotension, dizziness, reflex tachycardia.

sedative-hypnotic agents

CNS depressants

adverse effects of anticonvulsants

CNS: sedation, tremor, anxiety, cognitive and visual impairment Gastrointestinal: nausea, vomiting, and diarrhea hepatic: elevated hepatic enzymes, generally asymptomatic, periodic monitoring of liver function is required. immune system: benign skin rashes (prompts discontinuation)

Cholinesterase inhibitors

Cholinesterase inhibitors block the enzyme acetylcholinesterase, reducing the rate of breakdown of acetylcholine. This enhances the activity of acetylcholine at the receptors and potentially improves memory and cognition

Alzheimer's disease is characterized by a loss of? a. Cholinergic neurons from the brain stem. b. Dopaminergic neurons from the cerebellum. c. Dopaminergic neurons from the spinal cord. d. Cholinergic neurons from the cerebral cortex.

D

Parkinson's Disease is characterized by? a. The loss of adrenergic neurons from the substantia nigra. b. The gain of cholinergic neurons in the substantia nigra. c. The deposition of amyloid protein into the substantia nigra. d. The loss of dopaminergic neurons from the substantia nigra.

D

which one of the statements best describes the mechanism of seizures? a. Seizures result from sudden CNS depression b. Generalized seizures involve only a specific area of the brain c. All seizures involve the entire brain d. Decreasing glutamate release will help to control a seizure

D

neurotrophic hypothesis

Depression may be due to a loss of neurotrophic support characterized by a decrease in neurogenesis and synaptic connectivity.

amine hypothesis

Depression may be due to a reduction in the activity of one or more neurotransmitter systems in the CNS. (serotonin, norepinephrine, dopamine)

neuroendocrine hypothesis

Depression may be due to an abnormality in hormones affecting mood.

what's the antidote for benzo overdose ?

Flumazenil

what is the primary inhibitory neurotransmitter in the brain?

GABA

Where does GABA bind?

GABA binds to the chloride ion channel on the membrane of neurons in the brain and spinal cord.

Huntington's disease

Huntington's disease is an inherited neurodegenerative disease characterized by a loss of neurons in the striatum of the brain. Specifically, there is a loss of nerve projections from the striatum, leading to a decrease in GABA concentrations.

Monoamine oxidase (MAO) inhibitors

MAO-A and MAO-B. MAO-A is the enzyme primarily responsible for metabolism of norepinephrine, serotonin, and tyramine. MAO-B is more selective for metabolism of dopamine. By blocking a major metabolic pathway for the monoamine neurotransmitters. the MAO inhibitors allow more amines to accumulate in presynaptic stores, resulting in more to be released when the nerve impulse reaches the presynaptic neuron.

Non-opioid analgesics

Substances that act independently of the opioid receptors to relieve pain. For example, ibuprofen

opiod analgesics

Substances that are derived from opium and act on the opioid receptors in the brain to relieve pain. For example, morphine.

Anticonvulsants as Mood Stabilizers

The anticonvulsants, such as valproic acid, have been found to be useful agents as mood stabilizers. These agents have a more rapid onset of action than lithium, and are often preferred.

why are mood stabilizer used instead of antidepressants for bipolar?

The depressive phase of bipolar disorder is not the same as major depression. antidepressants are sometimes used, but may actually make matters worse. Mood stabilizers tend to be effective in the depressive phase.

what enzyme breaks down and inactivates dopamine?

The enzymes monoamine oxidase and catechol-o-methyltransferase.

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

This class of drugs block transporters for both serotonin and norepinephrine, and have fairly good safety profiles. Unlike the TCAs, these drugs do not have effects at autonomic and histaminic receptors.

Autoreceptor antagonists

This newer type of antidepressant drug inhibits the activation of α2 receptors As such, drugs that block α2 autoreceptors remove this negative feedback loop, allowing the presynaptic neuron to release more neurotransmitter into the synaptic cleft. ex: mirtazapine

Benzodiazepines

bind to benzodiazepine receptor they increase the frequency of the opening of the chloride channel enhancing the effect of GABA

lithium has a narrow therapeutic index, how is the safety and efficacy of lithium enhanced ??

by monitoring serum lithium concentration.

what two drugs are combined to treat parkinsons?

carbidopa and levodopa

Alzheimer's disease

characterized by progressive loss of memory and cognitive function. In the early stages of Alzheimer's disease, the person may be forgetful, but as the disease progresses, there is a loss of cognitive function that affects daily activities and can result in a vegetative state

strategies for controlling seizures aim to ______________.

decrease glutamate-induced excitation

what is the primary excitatory neurotransmitter in the brain?

glutamate

major depression is associated with _____________levels.

increased cortisol

what does activation of the barbiturate receptor do?

increases the duration of the opening of the chloride channel, increasing the effects of GABA

symptoms of Bipolar disorder

manic phase: -elation -excitement -hyperactivity -disinhibition -aggression -some psychotic symptoms depressive phase: -symptoms are similar to major depressive disorder -depressed mood -sleep disturbances -anxiety

Antagonism of dopamine receptors in the nigrostriatal system of the brain results in extrapyramidal movement disorders. These include:

o tremor o rigidity of limbs and slowing of movement o reduction in spontaneous activity o dystonia (involuntary muscle spasms) o akathisia (anxiety, restlessness, and repetitive purposeless action) o Tardive dyskinesia is a serious movement disorder that can occur and is characterized by involuntary movements of the face, tongue, trunk, and limbs, and can be severely disabling. This adverse effect may limit the therapeutic use of these drugs.

where do most Sedative-hypnotic agents bind?

on the chloride channel and they mimic the inhibitory effects of GABA

adverse effects of MOA inhibitors

orthostatic hypotension, agitation, and insomnia.

Barbiturates

potent CNS depressants

CNS Degenerative Diseases

progressive and irreversible loss of neurons from selected regions of the brain and spinal cord

Antagonism of dopamine receptors in the hypothalamus will result in excess release of ________.

prolactin In women, this will result in the flow of milk from the breast and menstrual changes In men it will cause sexual dysfunction

adverse effects of SNRI's

same as SSRI's and some effects from norepinephrine including an increase in bp and HR

which calls of drug do benzodiazepines fall into?

they are allosteric activators

how do sedative-hypnotic drugs control CNS excitation?

they reduce the amount of glutamate-induced neural excitation....most do this by increasing the GABA inhibitory signaling in the brain

what's the common end goal of all antidepressants?

to increase the amount of neurotransmitter within the synaptic cleft.

what are sedative-hypnotic drugs used for ?

to treat acute and chronic anxiety disorders including: 1) generalized anxiety disorder 2) OCD 3) panic disorder 4) PTSD 5) a number of phobias

A period of _________________of lithium administration may be required for lithium to have a full therapeutic effect.

two to four weeks

sleep hypnosis

used to produce drowsiness and aid in the onset and maintenance of sleep

Prominent side effects of the second-generation antipsychotics are:

weight gain, increased risk of developing diabetes, and sudden cardiac death due to an abnormality in the rhythm of the heart.

inhibitory effect

when GABA binds to the chloride ion channel it opens and negatively charged ions flow into the cell resulting in an inhibitory effect.

when do neurons in the brain "fire"

when excitatory inputs exceed the inhibitory inputs

Phenothiazine Antipsychotics

work by blocking dopamine receptors

TCAs (tricyclic antidepressants)

work by inhibiting the reuptake transporters of both serotonin and norepinephrine (i.e. SERT and NET) into the presynaptic axon, causing an increased concentration of these neurotransmitters to be present in the synaptic cleft.

what are the "Z" drugs ?

zolpidem, zopiclone and similar drugs with letter Z bind to a subset of the GABA receptors, causing sedation.

adverse effects for NSAIDs

• Gastrointestinal: abdominal pain, nausea, vomiting, and ulcers (rare) • Hepatic: liver function abnormalities, liver failure (rare) • Renal: renal insufficiency, renal failure • Pulmonary: individuals with asthma are at a higher risk for experiencing an allergic reaction to NSAIDs • Cardiovascular: fluid retention, edema, hypertension • CNS: headaches, tinnitus, dizziness • Skin: rashes

Adverse Effects of Lithium:

• Tremor, thirst, excessive urination, edema, and weight gain may persist for the duration of treatment. • Confusion and loss of muscle coordination. • Mild hypothyroidism • Toxic kidney effects are observed in some individuals treated chronically with lithium, but are uncommon. •When taken during pregnancy, it can, as a rare event, cause cardiac malformations in the fetus.