BBH 451 Final (new material)

Drug development on the enzyme is rooted in the idea that increasing acetylcholine levels might be a cognitive enhancer and slow the rate of progression of cognitive decline of Alzheimer's disease. MAO Methyltransferase AChE enzyme TCA

AChE enzyme

I. Three classifications:

ADHD-I (inattentive) HI (hyperactive-impulsive) C (comb.)

Which of the following is NOT one of the drugs used in medical treatment of ADHD? Methylphenidate Dextroamphetamine Benzedrine Acetaminophen

Acetaminophen

Lithium Pharmacokinetics

Administration - primary oral Not metabolized Half-life 18-24 hours (initially, then a second process of slow excretion by diffusion)

mechanism of Benzodiazepines

Allosteric modulator at GABA receptor Increases effect of GABA binding Safer than barbiturates, which act as a direct agonist Works by allowing Cl- to enter cell through receptor pore, and inhibits action potentials (no firing of neuron)

Why was the COMT drug tolcapone (Tasmar) withdrawn from the market? It did not increase the half-life of levodopa and it caused metabolic syndrome It increased the half-life of levodopa but caused metabolic syndrome Although it increases the half-life of levodopa, it caused severe liver toxicity It did not increase the half-life of levodopa and was found to be insufficiently effective

Although it increases the half-life of levodopa, it caused severe liver toxicity

Source of Aβ

An amyloid is any deposited protein\ Mutations in the Aβ gene (Amyloid Precursor Protein - APP) cause early onset Alzheimer's (Goate, 1991, Tanzi, 1992)

classes of sex steroids

Anabolic steroids - male hormones (testosterone and dihydrotestosterone) Estrogens - female hormones...

Second-, Third-, and 4th-Line Drugs

2nd COMT Inhibitors tolcapone (Tasmar), or entacapone 3rd Monoamine Oxidase-B Inhibitors 4th Dopamine Receptor Agonists Pre and/or post use of l-dopa Mirapex problems with gambling

What is the ratio of d-amphetamine to l-amphetamine in the drug known as Adderall? 4:1 2:1 3:1 1:1

3:1

Current research suggests that Parkinson's disease is not only a motor disorder but also presents with nonmotor symptoms that may actually precede the onset of motor deficits by a period of to years. 1;5 10;30 5;20 20;25

5;20

Don't exhibit symptoms of parkinsons until loss of _____ neurons

80%

anabolic steroids

A class of steroid hormones related to the male hormone testosterone or substances that work like testosterone Precursors of testosterone [e.g. Androstendione, and Dehydroepiandrosterone (DHEA)] are active, and included with testosterone in this category Increase protein synthesis within cells Promote general body growth by making muscles bigger and bones stronger. Have androgenic properties which include the development and maintenance of male characteristics.

Antipsychotics

(neuroleptics or major tranquilizers) - drugs primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia and bipolar disorder. Usually block dopamine D2 receptors.

Genes involved in dopaminergic neuron death

-Synuclein Parkin DJ-1

What is the lifetime prevalence of bipolar disorder across all populations globally? 6.5 percent 2 percent 1 percent 0.5 percent

1 percent

two variations of drug-receptor interactions:

1) Facilitation - indirect action to augment the action of a neurotransmitter; 2) Inverse agonist - causes the inverse response of an agonist, not just blocking the agonist's action.

About to percent of ADHD patients do not respond adequately to stimulants and are considered to be treatment-resistant. 0.1;10 10; 30 5;10 20;40

10;30

According to DSM-5, before what age must symptoms of inattention, hyperactivity and impulsivity be present to diagnose the individual with ADHD? 12 years 18 years 8 years 15 years

12 years

Bipolar I:

At least one manic episode, usually followed by depression, but not required

Why are barbiturates considered to be more toxic than benzodiazepines? Barbiturates bind to a separate protein that activates the GABA receptor to facilitate the influx of chloride ions. Benzodiazepines bind separate protein that activates the GABA receptor to facilitate the influx of chloride ions. Barbiturates act directly on the GABA receptor to open the chloride ion channel. Benzodiazepines act directly on the GABA receptor to open the chloride ion channel.

Barbiturates act directly on the GABA receptor to open the chloride ion channel.

Brain Regions Affected in Parkinson's

Basal Ganglia: 3 Indirectly affected areas Sends signals up Extrapyramidal pathway Substantia Nigra: Primary affected area with dopamine cell bodies (~80% death before symptoms appear)

Guanfacine (Intuniv™) and Clonidine (Catapres™)

Both were developed as anti-hypertensives Might improve ADHD symptoms by activating alpha-2-adrenergic receptors (NE receptors) Act in the CNS (probably in the prefrontal cortex) Guanfacine is less sedating and longer acting.

II. Pathology of Alzheimer's Disease

Cell loss is dramatically visible: Cortex and hippocampus are most severely affected.

Androgenic Effects

Changes in primary and secondary sex characteristics. Primary characteristics: Testicular, ovarian, penile, and vaginal development Secondary characteristics: voice change, hair growth, increased aggressiveness, prostate enlargement, breast enlargement

benzo subclasses

Chlordiazepoxide (Librium)- half life 5-30 hr Diazepam (Valium)- half life 20-100 hr

drug therapy: Acute, more severe mania + depression:

Combination of antidepressant (fluoxetine) with antipsychotic (olanzapine), sold together in one pill (Symbyax)

drug therapy: Acute, more severe mania:

Combination of mood stabilizer + 2nd gen antipsychotic (see above)

1st line treatment for parkinsons and limits

Combination with carbidopa (liver decarboxylase inhibitor) Sold as Sinemet limits: As you supply more Dopa, there still aren't many neurons left in brain for conversion to dopamine

APOE Neurobiology

Complexes of Aβ + APOE particles that have ε2 form: Increased cerebral amyloid angiopathy (CAA) (not good)

How do corticosteroids manipulate inflammation?

Corticosteroids suppress the multiple inflammatory genes that are activated in chronic inflammatory diseases, such as asthma, mainly by reversing histone acetylation of activated inflammatory genes through binding of liganded glucocorticoid receptors (GR) to coactivators and recruitment of histone deacetylase-2 (HDAC2) .

Cyclothymia:

Cycling between highs and lows that do not reach criteria for mania or depression for 2 years or more

Ramelteon

First sleep aid that is not a controlled substance (no abuse liability), perhaps because it is an agonist at: Melatonin Receptors (MT1/MT2)

Apolipoprotein E (APOE) and Alzheimer's Disease

Genotypes: ε2 - protective ε3 - comparison group ε4 - risk

Corticosteroids classes

Glucocorticoids - Cortisol (stress hormone) → control carbohydrate metabolism Mineralocorticoids - Aldosterone → control electrolyte (Ca++,K+) and water levels in the bloodstream

Glucocorticoids: How do they reduce inflammation?

Glucocorticoids modulate the inflammatory response by repressing the expression of pro-inflammatory cytokines by immune cells. In addition, glucocorticoids can repress the expression of adhesion molecules, which prevents rolling, adhesion and extravasation of neutrophils to the site of inflammation

What are the two main areas of the brain where cholinergic neurons are lost? Hypothalamus and cerebral cortex Parietal lobe and occipital lobe. Hippocampus and parietal lobe Hippocampus and cerebral cortex

Hippocampus and cerebral cortex

Bipolar II:

Hypomania (mania but less severe) combined with full depression over an extended period of time

Sex steroids

Important for differences in neuronal development for males and females Important for resistance training, building muscle/bone strength, and many medical uses (weight loss prevention)

inverse agonist

In the absence of ligand (GABA) there is some low level of opening of the channel and allowance of Cl- to enter the cell. An inverse agonist takes the receptor to a level of activity that is lower than baseline (ground state).

Symptoms of Alzheimer's

Inability to form new memories, followed by loss of recent memories, and then loss of old memories Emotional outbursts of anger, violence, paranoia, alternating with depression Easily gets lost, even walking in a neighborhood that was familiar for decades...

DSM criteria for ADHD

Inattention: 6 or more symptoms Hyperactivity and impulsivity: 6 or more symptoms Several symptoms present before age 12 Several symptoms are present in 2 or more settings Symptoms must interfere with social, school, or work functioning Symptoms not due to another disorder

effects of benzo

Inhibition of areas in the amygdala and frontal cortex important for anxiolytic effect Effects can be anxiolytic, sedative, and/or hypnotic (sleep-inducing) Also has anticonvulsant and muscle relaxing effects

Which of the following describes the mechanism of Levodopa? It can cross the blood brain barrier and is a precursor for dopamine It can cross the blood brain barrier and it is dopamine It cannot cross the blood brain barrier and is a precursor for dopamine It cannot cross the blood brain barrier and it is dopamine

It can cross the blood brain barrier and is a precursor for dopamine

Compared to d-amphetamine. l-amphetamine is:

Less active for DA release, more for NE Better sustained attention Less control of locomotor effect and impulsivity

marker of Parkinsons disease

Lewy body only seen post mortem Aggregates of -Synuclein protein not degraded by proteasome (removes old proteins)

Which of the following symptoms does NOT describe Parkinson's disease? Loss of dopamine neurons Resting tremor and impairment of postural balance Loss of serotonin and norepinephrine neurons Bradykinesia and muscle rigidity

Loss of serotonin and norepinephrine neurons

Sex steroids made by

Made by testes or ovaries

III. Methylphenidate (MPH, Ritalin™):

Major action is blockade of the dopamine transporter, and norepinephrine transporter to a lesser extent Secondary action may be release via the transporter (similar to amphetamine) given for ADHD

mechanism of corticosteroids

Mechanisms of function involve gene regulation at the molecular, transcriptional level (involving a multitude of transcriptional factors) ultimately resulting from the drug acting as an agonist at the glucocorticoid receptors.

drug therapy: acute, less severe mania + depression:

Monotherapy with 3rd Gen neuromodulator/anticonvulsant (lamotrigine, lamictal), and mood stabilizer if history of severe mania

drug therapy: Acute, less severe mania:

Monotherapy with mood stabilizer lithium, valproate, or 2nd gen antipsychotic (aripiprazole, olanzapine, carbamazepine)

Which of the following is an example of an inhaled anesthetic agent? Alprazolam Zolpidem Midazolam Nitrous oxide

Nitrous oxide

The second most common neurodegenerative disease, with increasing incidence as our population ages

Parkinsons

prevalance of AD

Prevalence increases from 1% at 69 to 50% at 95.

Steroid Receptors action 2; NEW cell mem

SHORT TERM Steroid Receptor embedded in cell membrane can interact with neighboring receptors upon steroid binding leading to other intracellular signaling (e.g. second messengers) downstream.

Steroid Receptors action 1: classic geonomic

SLOW LONG TERM Cytosolic, inactive transcription factor, activated by steroid binding Binding of steroid to receptor causes disassociation of stabilizing cofactors. Conformational change of receptor due to steroid binding allows for nuclear translocation. Dimerization of steroid-receptor complexes allows binding to DNA sequence activating or repressing transcription.

Atomoxetine (Strattera)

Selective Norepinephrine Reuptake Inhibitor with weak dopamine and serotonin effects (compare with methylphenidate) for ADHD

Buspirone (BuSpar)

Serotonin receptor (5-HT1A) partial agonist Some antagonist effect on D2 and D4 dopamine receptors May exert both anxiolytic and antidepressant action No muscle relaxant or sedative effects

Corticosteroids made by

Steroid made by Adrenal Cortex

ADHD medications

Supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD

markers of Alzheimers

The build-up of Amyloid β protein (Aβ) is the hallmark of Alzheimer's, and it has been proposed to be the toxin causing neuronal death. Hyper-phosphorylated Tau is also present;

Which of the following is NOT one of the reason's that barbiturate use has declined? They can result in serotonin syndrome from overuse. They interact dangerously with other drugs They are lethal in overdose. They have a narrow therapeutic-to-toxic range.

They can result in serotonin syndrome from overuse.

Paraldehyde

Very effective anticonvulsant, hypnotic, & sedative

Lithium Side Effects

Very narrow therapeutic window Many common side effects, e.g. tremor, dry mouth, headache, memory problems, nausea, vomiting, GI problems, vertigo Weight gain to the point of obesity Can affect thyroid and kidney function over time Overdose can occur acutely or with chronic use

Psychosis

a severe mental disorder in which thought and emotions are so impaired that contact is lost with external reality.

Benzodiazepines are well absorbed when they are taken orally; peak plasma concentrations are achieved in: 10 hours Two hours 30 min About one hour

about one hur

The most common neurodegenerative disease

alzheimers

Bupropion (Wellbutrin™)

another drug for ADHD Reuptake blockade of both NE and DA

Corticosteroids----

anti-inflammatory and analgesic properties

Barbiturates

any of a class of sedative and sleep-inducing drugs derived from barbituric acid.

Which of the following correctly describes bipolar I and bipolar II disorder?

bipolar 1- Full manic cycles with possibility of depression. bipolar 2-Hypomania (mania but less severe) combined with full depression over an extended period of time

classes of steroids

corticosteroids sex steroids neurosteroids

Bipolar Diagnosis symptoms for: depressive manic switch

depressive-Sadness, insomnia, worthlessness, loss of energy manic-Behavioral and physiological hyperactivity "Switch" or "Flip"- Fear that antidepressants trigger manic episode:

Parkinson's Disease mechanism

dopamine oxidation mediates mito and lyso dysfunction Found that accumulation of oxidized dopamine causes build-up of α-synuclein, and the combination of the two caused the dysfunction that leads to dopamine cell death and Parkinson's.

Mood Stabilizer

drugs that diminish mood swings, usually more effective on manic behaviors. Mechanisms not known, some might act on GABA system, some on glutamate.

True or false: Parkinson's disease is the most common neurodegenerative disease, followed by Alzheimer's disease as the second most common.

false

fear vs anxiety

fear Limited duration Clearly identifiable stimulus (stimulus specific) anxiety Emotion that lasts for extended periods of time Not associated with a single eliciting stimulus (no adrenaline rush)

___ is a cognitive response and ___ is a cognitive disorder

fear- response anxiety-disorder

Motivation to use corticosteroids

for anti-inflammatory and analgesic properties can potentially lead to dependency and addiction-like behavior such as that has been seen with prednisone.

Motivation to use anabolic steroids

for body performance and body image can lead to overuse increasing the risk for effects such as cessation of bone growth and increased androgenic effects.

Anabolic steroids can function through two molecular mechanisms:

genomic action or cell-membrane.

medication for cortisol reaction

hydrocortisone

Parkinson's

idiopathic neurodegenerative symptoms: Bradykinesia Muscle Rigidity Resting Tremor Posture & Balance

Which classic mood stabilizer is typically used in the treatment of Bipolar disorder? Lithium Barbiturates Potassium Benzodiazepines

lithium

mood stabilizers

lithium carbamazepine Valproate

Neurosteroids -

modify neuronal activity Progesterone and its metabolite 3α,5α-THPROG Allopregnanolone now prescribed to treat post-partum depression (see Depression lecture) Act via GABA-A receptors,

new treatments of Alzheimers block

neurodegeneration

Pathophysiology of Bipolar

poorly understood Working model: drugs that stabilize mood do so by altering intracellular 2nd and 3rd messengers to stabilize neuronal membranes and receptors.

if you were to treat a patient with L-dopa, what kind of pharmacological treatment would this be?

prodrug

Bipolar Disorder has some characteristics of both _____

schizophrenia and Major Depressive Disorder, but is distinct from both

In which general area of the U.S is the death due to Alzheimer's disease the highest? Southwest Southeast Northwest Northeast

southeast

cortisol

stress hormone

presence of ___ is thought to be more closely linked to the development of AD symptoms

tau

True or false: Benzodiazepines are in fact not antidepressants, they intensify depression in the same way that alcohol does.

true

True or false: Dementia, which is a cognitive impairment with the inability to form new memories, is the major symptom experienced by Alzheimer patients.

true

True or false: One daily dose of Concerta results in the same plasma concentration as three daily doses of methylphenidate.

true

Do the symptoms of Alzheimer's Disease show a correlation with the parts of the brain most affected by cell loss?

yes

Anabolic Effects

↑ Muscle Growth ↑ Bone Strength ↑ Red Blood Cell # Enhance Neural Conduction (i.e. nerves fire faster)