Definitions

• Neuroleptic: A term that refers to the effects of antipsychotic drugs on a patient, especially on his or her cognition and behavior.

• Neuroleptic drugs may produce a state of apathy, lack of initiative and limited range of emotion.

• In psychotic patients, neuroleptic drugs cause a reduction in confusion and agitation and tend to normalize psychomotor activity.The term comes from the Greek "lepsis" meaning a taking hold.

Agonists and Antagonists

• http://www.uri.edu/pharmacy/animation/animation.html#aa

Definitions

• Extrapyramidal side effects: Physical symptoms, including tremor, slurred speech, akathesia (inability to sit still), dystonia (repetitive muscle contractions), anxiety, distress, paranoia, bradyphrenia (slowed thought), and drug-induced parkinsonianism that are primarily associated with improper dosing of or unusual reactions to neuroleptic (anti-psychotic) medications.

Treatment of Schizophrenia

• ‘Neuroleptic’ drugs are potent antagonists at the D2 receptor

• Excess release of dopamine in the mesolimbic pathway has been linked to psychotic experiences.

• These drugs are often associated with extrapyrimidal neurological effects

Examples of Neuroleptic Drugs

N

Chlorpromazine(Thorazine)

Initially developed as an anesthetic

S

Cl NMe 2

F

O

NOH

Cl

Haloperidol(Haldol)

Long acting drug that can be given by injection (every 4 weeks) to non-compliant patients.

Traditional Neuroleptic Drugs

Trifluoperazine Fluanxol

Atypical Antipsychotic Drugs

• Generally have fewer extrapyramidal effects

• Generally regarded as more selective for D2 receptors in the proper region of the brain

Examples of Atypical Antipsychotic Drugs

Clozapine(Clozaril)

Resperidone (Risperdal)

Olanzapine (Zyprexa)

Quetiapine (Seroquel)

Atypical Antipsychotic Drugs

Recreational Drugs:Reward pathways in the CNS

• The most important reward pathway in brain is the mesolimbic dopamine system.

• This circuit (VTA-NAc) is a key detector of a rewarding stimulus. Under normal conditions, the circuit controls an individual’s responses to natural rewards, such as food, sex, and social interactions, and is therefore an important determinant of motivation and incentive drive.

Ventral Tegmental

Area• The ventral tegmentum or the ventral tegmental area

(VTA) (tegmentum, Latin for covering) is part of the midbrain, lying close to the substantia nigra.

• The ventral tegmentum is considered to be part of the pleasure system, or reward circuit, one of the major sources of incentive and behavioral motivation. Activities that produce pleasure tend to activate the ventral tegmentum, and psychostimulant drugs (such as cocaine) directly target this area. Hence, it is widely implicated in neurobiological theories of addiction.

• It is also shown to process various types of emotion and security motivation, where it may also play a role in avoidance and fear-conditioning.

Nucleus Accumbens

• The nucleus accumbens, part of the limbic system, plays a role in sexual arousal and the "high" derived from certain recreational drugs.

• These responses are heavily modulated by dopaminergic projections from the limbic system.

• In simplistic terms, activation of the pathway tells the individual to repeat what it just did to get that reward. It also tells the memory centers in the brain to pay particular attention to all features of that rewarding experience, so it can be repeated in the future.

• Not surprisingly, it is a very old pathway from an evolutionary point of view. The use of dopamine neurons to mediate behavioral responses to natural rewards is seen in worms and flies, which evolved 1-2 billion years ago.

• http://www3.utsouthwestern.edu/molpsych/paths_b02.htm

Cocaine

Cocaine

• Cocaine is a dopamine reuptake inhibitor, a noradrenaline reuptake inhibitor and a serotonin reuptake inhibitor.

• Cocaine is addictive due to its effect on the mesolimbic reward system

• Cocaine is still used as a topical anesthetic, particularly in surgeries of the nose and throat.

Cocaine

Norepinephrine Reuptake Inhibitors as Antidepressants

• Norepinephrine reuptake inhibitors (NRIs), also known as noradrenaline reuptake inhibitors (NARIs), are compounds that elevate the extracellular level of the neurotransmitter norepinephrine in the central nervous system by inhibiting its reuptake from the synaptic cleft into the presynaptic neuronal terminal.

• The drugs inhibit the class of neurotransmitter transporters known as norepinephrine transporters. They have virtually no action at other monoamine transporters.

Depression• http://www.healthcentral.com/depression/intro

duction-5003-109.html

• http://www.healthcentral.com/depression/introduction-5003-109.html

• http://www.healthscout.com/animation/68/10/main.html

• http://www.insidecymbalta.com/patient_resources/neuro_animation.jsp

Norepinephrin Reuptake Inhibitors for Depression

• Atomoxetine is classified as a norepinephrine reuptake inhibitor, and is approved for use in children, adolescents, and adults.

• Atomoxetine is the first non-stimulant drug approved for the treatment of attention-deficit hyperactivity disorder (ADHD). It is sold in the form of the hydrochloride salt of atomoxetine. It is manufactured and marketed under the brand name Strattera by Eli Lilly and Company as a generic Attentin by Torrent Pharmaceuticals. There is currently no generic available within the United States due to patent restrictions.

O

NH

Atomoxetine(Strattera, Eli Lilly & Co.)

CH3

H3C

NHCH3

OH

Epinephrine

HO

HO

Atomoxetine

• Strattera was originally intended to be a new antidepressant drug; however, in clinical trials, no such benefits could be proven. Since norepinephrine is believed to play a role in ADHD, Strattera was tested and subsequently approved as an ADHD treatment.

O

NH

Atomoxetine(Strattera, Eli Lilly & Co.)

CH3

H3C

NHCH3

OH

Epinephrine

HO

HO

• Reboxetine is an antidepressant drug used in the treatment of clinical depression, panic disorder and ADD/ADHD. Its mesylate (i.e. methanesulfonate) salt is sold under tradenames including Edronax, Norebox, Prolift, Solvex or Vestra.

• Unlike most antidepressants on the market, reboxetine is a noradrenaline reuptake inhibitor (NARI); it does not inhibit the reuptake of serotonin, therefore it can be safely combined with an SSRI.

HO

HO

NHMe

OH

Epinephrine(Adrenaline)

O

Reboxetine

NH

O

O

• Viloxazine (Emovit, Vivalan, Vivarint, Vicilan) is a bicyclic antidepressant morpholine derivative that inhibits the reuptake of norepinephrine.

• In 1976, Lippman and Pugsley reported that viloxazine, like imipramine, inhibited norepinephrine reuptake in the hearts of rats and mice; unlike imipramine, (or desipramine or amitriptyline, for that matter) it did not block reuptake of norepinephrine in neither the medullae nor the hypothalami of rats.

HO

HO

NHMe

OH

Epinephrine(Adrenaline)

O

Viloxazine

O

O

HN

Further ‘tinkering’ with the structure of the antipsychotic drugs led to a drug

which was useful in treating depression

N

Chlorpromazine(anti-psychotic)

S

Cl NMe 2

N

Imipramine(anti-depressant)

NMe 2

Historical• Imipramine was, in the late 1950s, the first tricyclic

antidepressant to be developed (by Ciba-Geigy). Initially, it was tried against psychotic disorders (e.g. schizophrenia), but proved insufficient.

• During the clinical studies its antidepressant qualities, unsurpassed until the advent of SSRIs, became evident. Subsequently it was extensively used as standard antidepressant and later served as a prototypical drug for the development of the later released tricyclics.

• It is not as commonly used today but sometimes used to treat major depression as a second-line treatment.

N

Chlorpromazine(anti-psychotic)

S

Cl NMe 2

N

Imipramine(anti-depressant)

NMe 2

“Tricyclic” Antidepressants

• The ‘tricyclic’ antidepressants share the common structural feature of fused 6-7-6 membered rings, as shown below.

A

Nitrogen or carbonSingle or double bond

Tricyclic Antidepressants

A

Nitrogen or carbon

N

Me

MeAmitriptyline(Elavil, etc.)

N

N

Me

Me

Cl

Clomipramine(Novartis)

N

N

Me

HDesipramine

N

N

Me

MeImipramineN

Me

MeNortryptyline

Single or double bond

Tricyclic Antidepresants

Tricyclic antidepressants

• Tricyclic antidepressants are a class of antidepressant drugs first used in the 1950s. They are named after the drugs' molecular structure, which contains three rings of atoms (compare tetracyclic antidepressant). The term 'tricyclic antidepressant' is sometimes abbreviated to TCA.

Tricyclic Antidepressants

• The exact mechanism of action is not well understood, however it is generally thought that tricylic antidepressants work by inhibiting the re-uptake of the neurotransmitters norepinephrine, dopamine, or serotonin by nerve cells.

• Tricyclics may also possess an affinity for muscarinic and histamine H1 receptors to varying degrees. Although the pharmacologic effect occurs immediately, often the patient's symptoms do not respond for 2 to 4 weeks.

Tricyclic Antidepressants

• Tricyclic antidepressants are used in numerous applications; mainly indicated for the treatment of clinical depression, pain, nocturnal enuresis, and ADHD,

• but they have also been used successfully for headache, bulimia nervosa, interstitial cystitis, irritable bowel syndrome, narcolepsy, persistent hiccups, pathological crying or laughing, smoking cessation, as an adjunct in schizophrenia, and in ciguatera poisoning.

Selective Serotonin Reuptake Inhibitors (SSRI’s)

Fluoxetine (Prozac)Paroxetine

(Seroxat, Paxil, Aropax)

Duloxetine (Cymbalta, Yentreve) Sertraline hydrochloride

(Zoloft, Lustral)

SSRI’s

SSRI’s

Definitions• Narcolepsy is a neurological condition most characterized by Excessive

Daytime Sleepiness (EDS). A narcoleptic will most likely experience disturbed nocturnal sleep, confused with insomnia, and disorder of REM or rapid eye movement sleep. A person with narcolepsy is likely to become drowsy or to fall asleep, often at inappropriate times and places.

• There appears to be a strong link between narcoleptic individuals and certain genetic conditions.

• One factor that may predispose an individual to narcolepsy involves an area of Chromosome 6 known as the HLA (human leukocyte antigen) complex. Certain variations in the HLA complex are thought to increase the risk of an auto-immune response to protein producing neurons in the brain. The protein produced, called hypocretin or orexin, is responsible for controlling appetite and sleep patterns.

• Individuals with narcolepsy often have reduced numbers of these protein-producing neurons in their brains.