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127 Cards in this Set

  • Front
  • Back
Clinical Characteristics of Parkinson's Disease
"involuntary tremulous movement, with lessened muscular power, in parts not in action and even when supported; ith a propensity to bend the trunk forwards and to pass from a walking to a running pace, the senses and the intellects uninjured"
-rhythmic tremor at rest
-rigidity with "cog-wheel" characteristic
-akinesia
-also causes depression
Pathology of Parkinson's
-Death of DA neurons in the Substantia nigra
-loss of DA in the Caudate
-loss of inhibition in the caudate
-overactive output (globus pallidus) to the thalamus
-thalamus overinhibits the motor cortex
-complex basal ganglia-cortical loops
Epidemelogy of Parkinsons
-Fifth or sixth decade of life
-85% idiopathic
-prevalence: 3 per 1000
-culmulative life-time risk: 1 in 40
-approximately 1 million patients
-no cure
Etiology of Parkinson's
Genetic Factors: 1999-examined 17,000 twins
>50 years old: no genetic effect
<50 years old: 10% genetic defect (13 known genes)

-Diet: Less vitamins, antioxidants=> higher incidence
-Smoking=less incidence
-environment=increase incidence in rural areas due to DA neuron toxins
Rotenone
-Rotenone is an odorless chemical that is used as a broad-spectrum insecticide, piscicide, and pesticide
-In 2000 it was reported that injecting rotenone into rats causes symptoms of Parkinson's disease to develop. Rotenone was continuously applied over a period of five weeks, mixed with DMSO and PEG to enhance tissue penetration, and injected into the jugular vein
-The study does not directly suggest that rotenone exposure is responsible for Parkinson's disease in humans but is consistent with the belief that chronic exposure to environmental toxins increases the likelihood of the disease.
Glial MAO-B
MAO-B breaks down dopamine secreted by the dopaminergic neurons
Paraquat
-one of the most widely used herbicides in the world. Paraquat, a viologen, is quick-acting and non-selective, killing green plant tissue on contact. It is also toxic to human beings when swallowed.
-Paraquat-induced toxicity in rats has also been linked to Parkinson's-like pathological degenerative mechanisms.
-A study by the Buck Institute showed a connection between exposure to paraquat and iron in infancy and mid-life Parkinson's in laboratory mice
Paraquat + Maneb
Impairs Movement and depletes dopamine
Difference Between a Normal Brain and a Parkinson's Brain
-No inhibition or excitation via the substantia nigra, leading to a) increased inhibition from D2 neurons, decreased inhibition from STN, increased output from the GPe, and increased inhibition to the Thalamus, leading to less output to the motor cortex.
-
Stages of Parkinson's Disease
100-20% Dopamine Control=Compensation (no symptoms)
20-10% Dopamine Control=Mild Symptoms
10-0% Dopamine Control=Marked Symptoms

Adaptive Capacity=100-20%
Decompensation=20-0%
Levodopa Therapy
-Main treatment with L-DOPA (precursor for dopamine)
-Sinemet is L-DOPA + carbidopa
carbidopa
-peripheral decarboxylase inhibitor
-prevents L-DOPA catabolism
-allows for slow release L-DOPA
Main Problems with Levadopa therapy
-on/off fluctuations
-dyskinesias
-eventually doesn't work
-peripheral side effects (NE and E)
-anticholinergics help as well
Drugs used to Treat Parkinson's Disease
Anticholinergics: (antihistamines, antidepressants, miscellaneous)

-Dopaminergic=Dopamine precursor(with decarboxylase inhibitor), dopamine agonists

-MAOB inhibitor
Parkinson's Outlook
-Chronic DA treatment can result in Schizophrenic symptoms
-Several surgical treatments for Parkinson's
When are surgical treatments for Parkinson's used?
-Used after therapeutic window closes
-stem cell transplantation
-pallidotomy and thalamotomy
-stimulators
Opiate Derived From
-alkaloids found in the opium poppy (Papaver somniferum)
Opioids Derived from
-compounds with opiate like actions, including, but not confined to opiates (eg. synthetic, endogenous opioids)
Types of Opioids
-Naturally Occurring
-Semi-synthetic
-Synthetic
Naturally Occurring
-Opium
-Sap from Opium poppy
Two Major Active Alkaloids of Opium
Morphine
Codeine
Paregoric
-Camphorated tincture of opum
-tincture of paregoric
Opium Tincture
-deodorized opium tincture
-deodorized tincture of opium
-tincture of opium
-laudanum
-opium
-DTO (deodorized tincture of opium)
Morphene
-Morpheus (god of dreams)
-son of hypnos
-~10% of opium by weight
Codeine
-methlymorphine
-~0.5% of opium
Semi-synthetic opium
-Heroin
-hydromorphone
-hydrocodone
-oxycodone
Heroin
-diacetylmorphine
-addition of two acetyl groups to morphine
-~10x more potent than morphine
-pharmacological effect usually thought to be identical to morphine
-in brain: heroin>morphine
Hydrocodone
Hycodan, Vicodin
Hydromorphone
Dilaudid
Oxycodone
Percodan, Oxycontin
Synthetic Opiates
-Phenylpiperidines
-Methadone & Congeners
-Benzomorphans
Phenlpiperidines
-Fentanyl "china white"
-Carfentanil (Wildnil)
-Meperidine (Demerol) (MPPP)
Methadone and Congeners
-Methadone (Dolophine)
-Propoxyphene (Darvon)
Benzomorphans
Pentazocine (Talwin)
Analgesic Potency
(Mild to moderate pain)
Codeine, propoxyphene (Darvon)
Analgesic Potency
(Moderately Severe Pain)
Meperdine (Demerol)
Analgesic Potency
(Severe Pain)
Heroin, Hydromorphone (Dilaudid)
Opioid Antagonists
-naloxone (Narcan)
-Naltrexone
-Suboxone (buprenorphine + naloxone)
Endogenous Opioids
-enkephalins, endorphins, and dynorphins
-morphene and codeine
History of Use of Opium
-ingredients in all sorts of medicinal preparations
History of use of Morphine
-"soldier's disease"
Major Effects of Opium
-Analgesia-relief of pain in absence of impairment in other sensory modalities

-Euphoria-Pleasure=produce sense of well being, reduce anxiety, positive feelings
Other Effects of Opium
-Nausea and vomiting
-respiratory depression
-miosis (opposite of mydriasis)
-gastrointestinal effects)
-cough suppression
-motor effects
Effects of repeated administration of opium
Tolerance, Withdrawal, and sensitization
Sensitization
-Psychomotor Stimulant Effects
-rewarding effects (conditioned place preference)
Mechanisms of Action of Opium
-Primary action on opioid receptors located in CNS +/or periphery
Different effects on Opioid receptor due to action at
-different receptor subtypes
-receptors at different locations
Endogenous Opioids Translation
Peptide Transmitter Production of :
1) Peptide (precursor)
2) Storage Vesicles
3) Converting Enzymes
Endogenous Opioids Post-Translational Processing
Supply by:
Axonal Transport and storage
Opioid Peptide Gene Families
-Proopiomelanocortin (POMC)
-Proenkephalin
-Prodynorphin ('proenkephalin B')
Precursor Gene Family of Proopiomelanocortin (POMC)
-B-Endorphin
-ACTH, Melanocortin SH
Proenkephalin->enkephalins
-met-enkephalin & 2 extended met-enk
-leu-enkephalin
Prodynorphine-forms of leu-enkephalin
-dynorphins, A and B
-Neoendorphins, meu and beta
Differential Distribution of Opiates
-Endorphins: -discrete, hypothalamic-endocrine related

-enkephalins and dynorphins: wide distribution, local circuit, and short axon projections
Opioid Receptor Types
-Mu
-Delta
-kappa
Opioid Receptor: Mu; Preferred Ligand
Morphine and Endorphins
Opioid Receptor: Delta; Preferred Ligand
Enkephalins
Opioid Receptor: Kappa; Preferred Ligand
Ketocyclazocine and dynorphins
Cellular Actions of Opioid Receptors
-G-protein coupled receptors
-inhibitory

-Negatively coupled receptor
-ADC=>ATP=>cAMP=>protein kinase A
Analgesia
Spinal Actions:
-dorsal horn of spinal cord
-primary pain afferents
-inhibit incoming pain signals:opioid receptors
Supraspinal Actions: Brain Area circuit and descending pathways
Brain Areas:
Diencephalon, Midbrain, Rostroventral Medial Medulla, Spinal cord
Supraspinal Actions = Stimulation
Stimulation=>analgesia and inhibit cells in dorsal horn
Supraspinal Actions= Lesion
Lesion=>block analgesia to systemic or local morphine
Supraspinal actions
-mu sites seem most important
-specific blockade of mu1 shifts dose-response curve for morphine analgesia up to 12 fold to the right
Heroine vs. Morphine Analgesia
-difference pharmacokinetic?
-recent evidence for different receptors
-MOR-1 knockouts
-Morphine, not heroin analgesia abolished in knockout mice
Reinforcing Effects of Opioids
-all classical opioid drugs of abuse have a preference for mu sites (eg. morphine, heroin, methadone, fentanyl)

-delta compounds may contribute but little known

-kappa compounds are not self-administered
-psychomimetic and aversive in humans
Opioid/DA Interaction
-intra-vta opioid support SA and CPP
-DA antagonist or 6-OHDA lesion impair SA
-DA antagonist into VTA or ACC impair SA
Mechanism of mu compounds
-increase DA cell firing
-increase DA release in ACC
-accompanied by locomotor activation
Model for reinforcing effects
Site of action: VTA-accumbens DA system, "disinhibition"
K compounds
-decreas DA cell firing
-decrease DA release
-decrease locomotion
Respiratory Depression and Mu2 effects
-specific mu1 antagonist (naloxonazine) shift analgesia dose-response curve for morphine to right
-not shift dose-response curve for:
-elevation of pCo2
-depression of pO2
-respiratory neurons in medulla in region of n. solitary tract
Gastrointestinal effects at mu and k sites
-in stomach, small and large intestine
-decreased mobility
-common bioassay>ability to inhibit intestinal contractions
MOR Knockouts
-morphine has affinity for all opioid receptor subtypes (much stronger for mu)
-evidence for site of action from pharmacological experiments with drugs that may act at multiple sites
MOR knockouts vs. DOR or KOR knockouts
All effects abolished in MOR knockouts and maintained in DOR KOR knockouts
Nicotine
-Alkaloid in Tobacco: 5% by weight

-Tobacco smoke is a very complex mixture
-carbon monoxide
-thousands of particulates
-nicotine major psychoactive agent
-cigarette: ~9mg; 1 mg absorbed
routes of administration of nicotine
-inhalation (smoking)
-via lungs (25% reaches brain within 7-sec)

-Oral (chewing, moist snuff, gum)
-via oral membranes
-nasal (snuff
-via membranes of nasal cavities
Absorption of Nicotine
-most routes extremely effective
-rapid repeated administration unique to cigarettes
-one pack per day=7300 cigarettes per year
Metabolism and excretion of nicotine
-kidney and liver
-short half-life (~2hrs)
-milk
Peripheral Effects of Nicotine
Sympathetic
-increase heart rate
-increase blood pressure
-secretion of NE and E from adrenals
-vasoconstriction
Parasympathetic
-increase stomach acid
-increase intestinal motility
Toxicity of Pesticides in half in a cigar
60 mg
CNS effects of Nicotine
-psychomotor performance
-reinforcement
Mechanism of Action of Nicotine
-nicotinic acetylcholine receptor
Acetylcholine
First transmitter identified: PNS
Synthesis of Acetylcholine
-choline
-acetyl coenzyme A
-choline acetyltransferase
Nicotine
-Alkaloid in Tobacco: 5% by weight

-Tobacco smoke is a very complex mixture
-carbon monoxide
-thousands of particulates
-nicotine major psychoactive agent
-cigarette: ~9mg; 1 mg absorbed
routes of administration of nicotine
-inhalation (smoking)
-via lungs (25% reaches brain within 7-sec)

-Oral (chewing, moist snuff, gum)
-via oral membranes
-nasal (snuff
-via membranes of nasal cavities
Absorption of Nicotine
-most routes extremely effective
-rapid repeated administration unique to cigarettes
-one pack per day=7300 cigarettes per year
Metabolism and excretion of nicotine
-kidney and liver
-short half-life (~2hrs)
-milk
Peripheral Effects of Nicotine
Sympathetic
-increase heart rate
-increase blood pressure
-secretion of NE and E from adrenals
-vasoconstriction
Parasympathetic
-increase stomach acid
-increase intestinal motility
Toxicity of Pesticides in half in a cigar
60 mg
CNS effects of Nicotine
-psychomotor performance
-reinforcement
Mechanism of Action of Nicotine
-nicotinic acetylcholine receptor
Acetylcholine
First transmitter identified: PNS
Synthesis of Acetylcholine
-choline
-acetyl coenzyme A
-choline acetyltransferase
Positive Symptoms of Schizophrenia
-Hallucinations: sensory experiences without external stimulation; commonly auditory
-delusions-fixed irrational beliefs that are contrary to reality; can't be explained by a person's culture; commonly persecutory in nature; sometimes delusions of grandeur
Negative Symptoms of Schizophrenia
-Avolition-lack of energy and inability to persist in routine activities
-Alogia (poverty of speech)-reduction in the amount or content of speech
-Anhedonia-inability to experience pleasure
-asociality-severe impairment in social relationships
-flat affect or incongruent affect-lack of or inappropriate emotional expression; blunted
Cognitive Symptoms of Schizophrenia
-Executive Processes-memory, attention
-Disorganized speech-misuse of words, incoherence, blocking
-Lack of insight-inability to recognize their own illness
DSM-IV Criteria to Diagnose Schizophrenia
-At least 2 of the following for 1 month: delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, negative symptoms
-marked functional impairment
-continuous signs for 6 months
-not due to drugs or other medical conditions (eg amphetamine psychosis)
Three Subtypes of Schizophrenia
Paranoid type:
-Preoccupied with delusions and hallucinations
-no disorganized speech, catatonia, or flat affect
Disorganized Type:
-disorganized speech and behavior, often inappropriate
Catatonic Type:
-Clinical Picture with at least two:
-motoric immobility, catalepsy, stupor (waxy inflexibility)
-excessive motor activity that is apparently purposeless
-extreme negativism or mutism
-peculiarities of movement (eg voluntary assumption of bizarre postures), stereotypes, odd mannerisms, or grimacing
-echolalia or echopraxia
How long do you have to have the symptoms of schizophrenia to be considered to have the disease?
6 months
Epidemiology of Schizophrenia
Incidence in about 1 in 100 (1% of adults)
Heritability of Schizophrenia
-Most likely in Identical Twins, Children where both parents are schizophrenic
Etiology of Schizophrenia
-Combination of Factors
-Genetic,
-Developmental
-Environmental
-Lots of Possible combinations
-The more "risk" you have from one factor, the less you need from other factors
Etiology-Genetic Risk
-Lots of possible combinations
-the more susceptibility genes you have, the smaller the second "hit" you need
Etiology: Developmental of Schizophrenia
-Mild "insults" occuring during gestation, infancy, or early childhood
-may be as late as adolescence
Etiology: Environment of Schizophrenia
-If mother was depressed during pregnancy, more likely to get a step graph of schizophrenia
-blood flow in brain is off
-increase in DA transmission exacerbates Schizophrenia
-decrease in DA neurotransmision is therapeutic
Therapies for Schizophrenia
-Majority of the treatment is with antipsychotic medications
-beginning of widespread use of antipsychotic agents was in 1955, which led to a decrease inn institutionalization
Neuroleptic or Antipsychotic
-literally means thin neural transmission
-in practice, both terms refer to drugs used to treat schizophrenia only
-wide variety of off-label application
-incorrectly known as "major tranquilizers"
Schizophrenia Causes in the brain
-caused by overactive dopamine?
-just block DA
-only helps positive symptoms
-not whole picture: glutamate and 5HT
Ways of decreasing DA neurotransmission
-inhibition of synthesis of L-DOPA
-interference with vesicular storage
-block of DA receptors and autoreceptors (antipsychotics)
DA antagonist Drugs
-Chlorpromazine, or thorazine
-marketed by SmithKlineFrench in 1950
-first antipsychotic
-derivative of phenothiazine (anti-emetic)
-very sedating at first but tolerance builds
-a "major traquilizer also used as a pre-anaesthetic
-some anti-cholinergic activity
-messy drug with actions at several receptor sites
-tardive dyskinesia
Secondary DA Antagonist Drugs
-Haloperidol (haldol)
-long time in the body, only 60% excreted in the first week
-prototypical DA antagonist "conventional antipsychotic"
-fluphenazine (Permitil and Prolixin)
-less sedating
-all can caused tardive dyskinesia
Side effects of Tardive Dyskensia
-Parkinsonism
-Dystonia=abnormal face and body movements
-Akathisia=restlessness
-Tardive dyskinesia=long term, exacerbated by drug holiday regime, more common in females, chronic (not easily reversible), worsened in response to reducing drug
-many other undesirable side effects (eg constipation, metabolic syndrome, sedation, lactation, and retrograde ejaculation)
Novel Antipsychotics
-Dibenzodiazapine derivatives
-Treat positive and negative symptoms with limited success
-some have less or less severe motor side effects
-some have more potential for other medical problems
-expensive
Newer Drugs to treat Schizophrenia
-Clozapine (clozaril)
-very few motor side effects
-treats positive and negative symptoms
-half life of 12 hours
-limited to treatment resistant patients
-anticholinergic, adrenolytic, antihistaminic, and antiserotonergic activity
-causes agranulocytosis: blood monitoring required
-increased risk of seizures
Less well known newer drugs to treat Schizophrenia
-risperidone (risperdal)
-blocks DA and 5-HT receptors
-dose-related mild Parkinsonian side effects
-some cases of cardiac hypotension
-approved for autism to quell violence, and used widely in children with "emotional disturbance"
-Olanzapine (Zyprexa)
-binds to a lot of DA and 5-HT receptors
-lower tardive dyskinesia risk
-lower seizure risk
-can be given once every 2 weeks as a depot
Quetiapine (seroquel)
-blocks DA, 5-HT, and NE receptors
-high sedation
-low tardive dyskinesia risk
-lower seizure risk
Ziprasidone (geodon)
-blocks DA, 5-HT, NE and Histamine receptors
-high metabolic syndrome risk
-black box warning for QTc interval increase
Apriprazole (Abilify)
-marketed for bipolar mania
Paliperidone (INVEGA)
-active metabolite of risperidone
Thorazine
-derivative of phenothiazine (anti-emetic)
-very sedating at first but tolerance builds
-some anticholinergic activity
-actively metabolized (half-life of 30 hrs)
Antipsychotics
-several options
-most have very similar mechanisms of action
-often a "trial and error" to find the best match
-Manage side effect profiles depending on the patient
Which one causes more Tardive Dyskinesia
-Haloperidol
Novel vs. Conventional Schizophrenia Treatments
Novel:
-5-HT
-Low EPS/TD potential
-efficacy across multiple domains
-minimal/no prolactin elevation
-mesolimbic specific (A10)
Conventional
-D2 blockade
-high EPS/TD
-Efficacy limited to positive symptoms
-Prolactin elevation
-affect all DA pathways (A9 and A10)
Main points of antipsychotic side effects
-Motor effects (mostly with conventional antipsychotics)
-sedation
-weight gain
-off target effects in other organ systems
Behavioral Methods to find new Schizophrenia drugs
-startle methods
-behavioral model of sensorimotor gating deficits in schizophrenia: prepulse inhibition of acoustic startle
-prepulse deficits=reduced inhibition
Antipsychotics and PPI
All antipsychotics on the market prevent PPI deficits produced by DA agonists
-ability to block PPI deficits correlates with clinical potency