Pharm 2.2 Flashcards
What receptors make up the D1 receptor family and what do they do?
D1 and D5
D1 is in Striatum and Neocortex
D5 is in Hippocampus and Hypothalamus
Both elevate cAMP and PIP2 hydrolysis -> elevate intracellular Ca and PKC activation
What is the Dopamine hypothesis of Schizophrenia?
DA receptor is at the center of schizophrenia
Over production of receptor a possibility
Hypothesis based on observation that DA antagonists diminish syptoms and agonists induce / exacerbate.
All effective pharmacologic therapies block DA receptors
What receptors make up the D2 receptor family and what do they do?
D2,3,4
D2: striatum, substantia nigra, pituitary
D3: olfactory tubercle, n.acumbens, hypothalamus
D4: frontal cortex, medulla, midbrain
decrease cAMP, increase K+ currents, decrease voltage dependent Ca++ currents
Where are most DA receptors in the brain located? What is the role?
Nigrostriatum
80% of receptors
modulates movement and learned habits
What role does DA play in the following areas, how do they relate to schizophrenia, what impact do APDs have? Nigrostriatum Mesolimbic Mesocortical Hypothalamic Area Postrema
Nigrostriatum: regulates movement and learned behaviors (APD side effects -> tardive dyskinesia)
Mesolimbic: motivation, goal-directed thinking, affect, reward (overactive, related to positive symptoms. APDs help)
Mesocortical: cognition (hypofunction -> negative symptoms. APDs don’t really help)
Hypothalamic: hormone reg
Area Postrema: emesis (outside BBB)
what is neuroleptic malignant syndrome and how is it treated
Caused by sensitivity to DA blockade by APDs
-fever + parkinsonism, autonomic instability, rhabdomyolysis (elevated CPK)
Treatment: bromocriptine, dantrolene
Differentiate tardive dyskinesia and parkinsonism as related to APD therapy
tardive dyskinesia is seen w/ chronic APD use and is irreversible
-masked by increasing dose of APD, worsens w/ withdrawal
parkinsonism occurs in the short-term and is easily treated (adjust meds)
Both induced in proportion to affinity for D2 receptor of APD in use.
Why would APDs be used pre-surgically?
Older APDs used for anti-emetic effect (H1 blockade)
What is schizoaffective disorder?
Schizophrenic symptoms plus mood disorder - bipolar, depression
Treat w/ APD plus antidepressant, lithium, valproate
What is the mean time range from diagnosis to death in Parkinson’s Disease?
15 years
What cells are primarily effected in Parkinson’s disease?
Midbrain DA cells, especialy nigrostriatal
-responsible for learning and execution of complex purposeful motor patterns
>80% decrease in cell population needed for symptoms
What is Carbidopa?
Peripheral aromatic amino acid decarboxylase inhibitor
Given to PD patients with Levodopa - improves absorption - reduces peripheral metabolism
In PD patients what are the preferred treatments for:
Depression?
Psychosis?
Dementia?
Depression: SSRI
Psychosis: Clozapine - atypicals preferred
Dementia: Cholinesterase inhibitors
remember that PT and mental exercise is recommended!
What is the current progression of PD treatment?
Delay treatment - manage w/ lifestyle changes as long as poss.
Anticholinergic, MAO-B inhibitor, and/or amantadine -> Direct DA agonist -> Sinemet -> add COMT inhibitor -> use apomorphine as needed for “off” periods -> consider surgical intervention (DBS)
How is essential tremor managed?
Beta blockers (propanolol, metaprolol) or low-dose aniepileptics (primadone, topiramate)
Refractory patients may be treated w/ DBS - >80% complete effectiveness
Features and course of Alzheimer’s Disease
Progressive and fatal disease
Begins w/ short-term memory difficulty -> difficulty with common tools and calculation -> immobilization
Death usually due to complications of immobilization (pneumonia, PE in 6-12 years following diagnosis)
Pathophysiology of Alzheimer’s Disease
Neurodegeneration - atrophy of cerebral cortex
B-amyloid plaque formation - hippocampus and associative cortex
Neurofibrillary tangles - microtubule breakdown due to hyperphosphorylation of tau subunit
More plaques and tangles -> more cognitive impairment
What genetic risk factors are linked to Alzheimer’s disease?
Linked to Amyloid Precursor Protein (APP) and processing proteins presenilins (PS1, PS2): alternate cleavage of APP -> plaque formation
Lipid Transfer Apolipoprotein E4 (APOE-4): 15x increased risk - unknown why
WBC receptor TREM2 - mutations -> increased risk
What evidence has been found that supports the APP AB hypothesis of Alzheimer’s disease?
Icelandic study identified A673T coding mutation in APP that is highly protective against AD, even in presence of ApoE4
mutation -> 40% reduction in amyloidogenic peptide formation
What are characteristics of Lewy Body dementia?
Progressive cognitive decline with dramatically fluctuating cognition.
Patients may experience vivid hallucinations, autonomic disregulation, REM sleep disturbances
What is the risk in off-label use of antipsychotics for treating hallucination, agitation, delusion in Alzheimer’s patients? What about LBD?
2x increased risk of death due to MI, pneumonia, infections with both APD and atypicals.
LBD: very high risk of adverse response to APDs: Parkinsonism, sedation, malignant neuroleptic syndrome*
Semagacestat
gamma secretase inhibitor
gamma secretase cleaves APP
clinical trial halted due to dose-dependent decrease in cognitive function
Plasmin
Degrades plasmin, contributing to thrombolysis / fibrinolysis
What is primary and secondary hemostasis?
Primary: formation of a platelet plug
Secondary: addition of fibrin to platelet plug
