Drugs for Schizophrenia and Degenerative Disorders

what is dopamine?

both an excitatory and inhibitory neurotransmitter?

what is the nigrostriatal tract?

the substantial nigra to the striatum

what is the mesolimbic tract?

the VTA to the limbic system

what is the mesocortical tract?

VTA to the prefrontal cortex

what is the tuberoinfundibular tract?

the hypothalamus to the pituitary

what are the 2 major types of dopamine receptors?

D-1 and D-2 receptors

what is dopamine involved in?

motor control, award and motivation

what is increase in dopaminergic activity associated with?

psychosis (ex. schizophrenia)

what is a decrease in dopaminergic activity associated with?

neurodegenerative disorder (ex. Parkison's disease)

what is the criteria for schizophrenia diagnosis (DSM-5)

thought disorder characterized. by 2 or more of the following, each present for a significant portion of time during the 1-month period
At least one of these must be (1), (2), or (3);
- delusions
- hallucinations
- disorganized speech
- grossly disorganized or catatonic behaviour
- negative symptoms
the persons level of functioning in one or major major areas
disturbance is not attributable to the physiological effects of substance

positive symptoms of schizophrenia?

- halluncinations
- delusions
- illusions
- paranoia
- agitation, anxiety
- disorganized thoughts
- agression

negative symptoms of schizophrenia?

- apathy
- withdrawal
- lack of ability to preform ADL's
- diminished or missing affect
- poor judgement
- lack of awareness or insight
- little or no functional speech

cognitive symptoms of schizophrenia?

- deficits in long-term memory
- inability to focus attention
- diminished working memory
- difficulty following instructions
- difficulty following a thread of conversation
- difficultly in identifying the steps needed to complete a task and placing them in the proper sequence

what is schizophrenia associated with?

increased activity at the dopamine D-2 receptors

what can dopamine agonists induce?

psychosis

what are antipsychotic drugs?

most are dopamine D2 receptor antagonists

what do some antipsychotic drugs include?

exhibit serontonergic activity (agonist 5HT1a and antagonist 5HT2a activity)

what does serotonergic agonism help to manage in schizophrenia?

negative symptoms

what do typical antipsychotics do?

antagonize dopamine on the D2 receptors in the mesolimic and mesocortical tracts

what is the common typical antipsychotic?

haloperidol; non-phenothiazine antipsychotic drug

what do typical antipsychotics treat?

positive symptoms of schizophrenia

do typical antipsychotics have an effect on negative symptoms?

nope

what are extra pyramidal effects of typical antipsychotics?

acute dystonia, pseudo-parkinsonism, akathisia, tardive dyskinesia

what are the extrapyramidal effects of typical antipsychotics associated with?

antagonists action on D2 receptors in the nigrostriatal tract

what are chorpromazine and other phenothiazine drugs associated with (compared to non-phenothiazine drug such as haloperidol)?

greater anticholinergic effects, hypotension, and increased sedation

what is risk of EPS and weight gain high in?

all typical/ conventional antipsychotic drugs

what are elderly patients with dementia related psychosis at increased risk for when taking antipsychotic drugs?

death

is it appropriate to use phenothiazine drugs for delirium?

NO! it is abusive

what are do atypical antipsychotics?

- antagonist activity on D2 receptors, post synaptic 5HT2a receptors, and a-2 adrenergic receptors
- agonist activity at 5HT1a presynaptic receptors

what do atypical antipsychotics treat?

both positive and negative symptoms!

why do atypical antipsychotics evoke fewer EPS?

they bind less tightly to D2

what are atypical antipsychotics associated with?

obesity and its risks

what are 3rd generation antipsychotic drugs?

dopamine system stabilizers

how do dopamine system stabilizers work?

- they are partial agonists at dopamine D2 and D3 receptors
- partial agonist at 5HT1a receptors (presynaptic)
- antagonist at 5HT2A receptors (post synaptic)

what symptoms do dopamine system stabilizers improve?

both positive and negative, may also have some benefits on cognition

benefits of dopamine system stabilizers (4)?

- minimal risk of EPS
- low incidence of serious side effects compared to other antipsychotic drug therapy
- little to no weight gain
- absence of anticholinergic effects

what are the side effects of dopamine system stabilizers (6)?

- drowsiness
- insomnia
- agitation
- changes in BP
- anxiety
- headache

in addition ot reduktion in positive symptoms and EPS, what can drugs binding to the dopamine D2 receptor do?

produce antiemetic effects

what can side effects that drugs that bind the muscarinic and adrenergic receptors cause (6)?

- blurred vison
- dry mouth
- constipation
- urinary retention
- orthostatic hypotension
- light-headedness

what side effect can drugs that bind to histamine receptors cause?

sedation

what is Parkison's disease?

a neurodegenerative disorder affecting individuals over the age of 50; characterized by loss of dopaminergic neurons in the nigrostriatal pathway

what are the symptoms of parkinson's?

tremor, muscular rigidity, bradykinesia, and postural instability

what does loss of dopaminergic neurons in the nigrostriatal tract cause?

imbalance between the DA and Act in the basal ganglia

what happens when the inhibitory effect of dopamine is lost?

excitatory effect of acetylcholine on movement is unopposed

what can improve the symptoms of PD?

DA agonists and Ach antagonists

what are other symptoms associated with PD?

anxiety, depression, and sleep disturbances

what are the dopaminergic drugs used in PD?

levodopa and carbidopa, dopamine agonists, MAOIs and COMT inhibitors

what are the cholinergic drugs used in PD?

muscarinic cholinergic antagonists

what does drug therapy for PD often include?

combination of drugs

what is levodopa (L-dopa)?

a precursor to dopamine, converted to dopamine by the enzyme dopamine decarboxylase

what is needed for L-dopa to work?

dopamine neurons must be present

what is the problem with taking L-dopa alone?

a significant fraction will be converted to dopamine before reaching the CNS; this increase in peripheral dopamine results in nausea, vomiting, cardias arrhythmia and orthostatic hypotension

what is the function of carbidopa?

prevents the conversion of L-dopa into DA, but does not penetrate the blood brain barrier; reduces L-dopa dose 70%

what does benzotropine do?

preferentially binds to muscarinic cholinergic receptors in the CNS

what are some side effects of benzotropine?

dry mouth, blurred vision, tachycardia, urinary retention and constipation

is benzotropine as effective as L-dopa?

nope

when is bezotropine used?

in the early time course of PD, or for those who cannot tolerate L-dopa therapy

what is Alzheimers disease?

a progressive neurodegenerative disorder affecting individuals over the age of 65

what is dementia characterized by?

progressive memory loss, confusion, inability to think or communicate effectively

what are the causes of alzheimers?

genetics, brain atrophy attributed to environmental and immunological and nutritional factors

what happens to the brain in Alzheimers?

structural damage (amyloid plaques and neurofibrillary tangles, and chronic inflammation)

what are the cognitive symptoms associated with Alzheimers?

impaired memory, confusion, inability to recognize family and friends, aggressive behaviour, depression, psychoses and anxiety

what is the goal of Alzheimers therapy?

to improve ADLs, behaviour and cognition

what is donezepril (aricept)

ach angosst; used in the early stages of the disease when Ach neurons are still present and functioning in the cerebral cortex

what does donepezil do?

prevents breakdown of acetylcholine

where else may donepezil exert effects?

has parasympathomimetic effects (especially on the GI system)

what other drugs may be used to treat Alzheimers?

antipsychotic, antidepressant and antianxiety drugs