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15 Cards in this Set

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Baclofen
very useful for treating the spasticity
b. Review
i. GABA is the major inhibitory NT of the CNS.
ii. GABAA receptors are chloride ion channels
iii. GABAB receptors are G-protein receptors located on the pre-synaptic side. They decrease the release of excitatory NTs when stimulated.
iv. Glutamate is the major excitatory NT in the CNS
Muscarinic Antagonists
a. Dicyclomine (Bentyl)
b. Flavoxate (Urispas) – used for urological disorders
c. Oxybutynin (Ditropan) – used for urological disorders
d. Oxyphencyclimine (Daricon)
e. Trihexylphenidyl (Artane)
f. Muscarinic antagonists cause anti-SLUDE (Salivation, Lacrimation, Urination, Defecation, and Emesis). You give muscarinic receptor antagonists to prevent patients from having any of the previously mentioned social taboos due to ALS
HD
A. HD is an autosomal dominant disorder that is characterized by incoordination, cognitive decline, and a progressively psychotic state.
B. One of the primary brain areas affected is the neostriatum. The average age of onset is 35-45 (ranges from 2-80). The defective HD gene causes a CAG- trinucleotide repeat which results in the formation of an abnormal Huntingtin protein.
C. Treatment
1. Treatment is very similar to ALS and is palliative
2. We need to include anti-psychotics when treating HD i.e. benzodiazepines (Xanax, valium)
PD
A. General facts
1. Parkinson’s is a progressive, chronic, degenerative disorder involving brain regions that control such activities as posture, balance, and locomotion.
2. PD affects over 1 million Americans, usually over the age of 40
3. The term “Parkinson’s disease” is usually used when the cause is unknown. Some of the known causes that are not age-related are brain disease or injury (such as tumors, trauma or encephalitis), and exposure to environmental toxins such as carbon monoxide or manganese
4. Specifically, the appearance of the disease reflects an imbalance between the inhibitory effects of the NT dopamine (DA) and the opposing stimulatory effects of acetylcholine (ACh) in the extra-pyramidal and basal ganglia. The lack of DA allows the actions of ACh to predominate in these brain areas
a. The symptoms are caused by the insufficient formation and action of dopamine, primarily in the basal ganglia
b. If we raise our arm, we are primarily using inhibition, because although we are contracting one muscle we are inhibiting the contraction of countless other counter-acting muscles.
c. The loss of inhibitory dopamine causes the over-excitation of our muscles and the “pillrolling” tremor
d. The rigidity of Parkinson’s develops later in the disease as all the neurons are firing simultaneously causing a lock-down effect.
PD
1. Rigidity
2. Tremor (noticeable first in the fine motor skills)
3. Bradykinesia
4. Altered gait
5. These symptoms do not appear until we lose 70% of our dopamine projections
Selegiline
1. MAO type B inhibitors – Monoamine oxidase is the enzyme responsible for the breakdown of monoamines (ingested monoamines, serotonin, and dopamine.) There are two types: MAO-A is found in the Alimentary tract and the rest of the body. MAO-B is found in the Blood and Brain. Where we are concerned it is located in the pre-synaptic cleft
a. Selegiline (deprenyl) – Selegiline blocks the action of MAO-B and causes more dopamine to be available
i. The metabolites of selegiline are amphetamines and methamphetamines which are CNS stimulants (A good thing)
ii. Only works early in the disease process before the pre-synaptic terminal degrades
Muscarinic Antagonists
-If we do not have dopamine to counteract the ACh, we can cause tonic inhibition of ACh
a. Trihexlphenidyl (Artane) - Inhibits ACh activity in key excitatory pathways; can be used for treating early, mild parkinsonism, or more often as an adjunct with dopaminergic drugs
b. Bentropine – centrally acting anti-muscarinic
Dopamine Replacement
a. Levodopa – can be given orally and crosses the BBB, but 90% is destroyed in the gut (By which enzyme? III.C.1) or converted to dopamine in the periphery (which is then unable to cross the BBB)
i. This causes problems because dopamine has effects outside the CNS such as cardiac tachycardias,
b. Carbidopa or benserazide – inhibits DOPA decarboxylase, the enzyme which converts levodopa to DA. Carbidopa does not cross the BBB
c. Carbidopa/levodopa (Sinemet® or Atamet) - given together, a greater amount of DA leaves the gut and is therefore available for transport to the brain.
d. Almost every patient with Parkinson’s is on Sinemet
DA Receptor Agonists
a. There are 5 DA receptors, we will only focus on D1 (which is mostly on the presynaptic side) and D2 (which is on the postsynaptic side and is the focus of this class of drugs). The better the D2 agonist, the better the drug action
b. D2 agonists work in the late stages of Parkinson’s when the number of dopamine producing neurons has decreased
c. Bromocriptine (Parlodel) – an ergot derivative that is a full agonist at D2 receptors and a partial agonist at D1 receptors
d. Pergolide (Permax) – another ergot derivative that is a D2 and a D1 agonist
e. Pramipexole (Mirapex) – highly selective D2 agonist
f. Ropinirole (Requip) – highly selective D2 agonist
Amantadine
i. Causes DA stored in vesicles to be released
ii. Not affective in advanced stages when stored pools of DA are low
iii. NT Note: If the name sounds vaguely familiar it’s because this drug is also an antiviral we were supposed to learn last block. It’s used prophylactically against influenza A. See Pharm B28 I.B.
COMT Inhibitors
a. Catechol-O-Methyltransferase is an enzyme that is responsible for degrading dopamine
b. Entacapone (Comtan)
c. Tolcapone (Tasmar)
d. Both these drugs have black box warnings from the FDA. They cause hepatotoxicity and are not prescribed
OTHER PD Drugs
a. Diphenhydramine - antihistamine (H1 antag.) that also seems to block reuptake of DA
b. Ethopropazine - phenothiazine with marked anticholinergic properties (very atypical of this class of drugs)
c. Procyclidine - atropine-like activity that is particularly useful for alleviating rigidity and excessive salivation (sialorrhea)
PD Drug Side Effects
1. Nausea and vomiting (most common) – Dopamine has receptors in the Chemoreceptive Trigger Zone (CTZ).
2. Anorexia – caused by the nausea and vomiting
3. Blood abnormalities NT Note: More in future lectures
4. Endocrine problems – Dopamine inhibits the release of prolactin
5. Cardiovascular problems
a. Tachycardia (DA directly stimulates the heart)
b. Orthostatic hypotension
6. Neuroleptic Malignant Syndrome – if dopamine (levodopa) is withdrawn abruptly. It’s a life threatening situation NT Note: More details next lecture
Long Term PD Drug Problems
1. Dyskinesias
2. On-off phenomenon
a. Patients experience a switch between “on” times when they have good symptomatic control immediately followed by “off” times when symptoms are under poor control.
b. Initially it is caused by improper drug dosing, however in later stages it is due to unknown reasons
3. End of dose failure
a. Shortening of effectiveness of each dosage
b. Hypothetical: When you take a drug that is supposed to last for 6 hours yet after 5 hours the symptoms reappear and the patient has a need to re-administer even though it is contraindicated
4. Secondary levodopa failure (effectiveness drops off after 2-5 years)
PD Drug Interactions
1. MAOI taken with drugs that affect dopamine neurotransmission – can lead to acute hypertensive episodes and a stroke
2. High levels of vitamin B6, increases gastrointestinal dopa decarboxylase activity