Craviso: Drug Action in the CNS Flashcards
Belongs to a family of membrane transporters that modulate drug distribution; capillary endothelial cells of the BBB have high levels compared to other tissues
P-glycoprotein
What does transport of drugs through membranes by passive diffusion depend on?
the lipid solubility of the drug
The greater the lipid solubility, the (blank) a drug enters the CNS
faster
What are two drugs that have a high lipid solubility, but do not get across the BBB efficiently?
phenobarbital
phenytoin
What are two drugs that have a low lipid solubility, but diffuse across the BBB more readily?
glucose
L-DOPA
List some regions where the BBB is more permeable
area postrema* median eminence pituitary gland pineal gland choroid plexus capillaries
These can cause an increase in BBB permeability
bacterial and viral infections
What is the most promising method for global drug delivery?
vascular route
**each neuron has its own capillary for O2 supply, for the supply of other nutrients, and for removing metabolic waste
How do drugs that influence behavior and improve the functional status of patients w neurological/psych diseases act?
by enhancing or blunting neural excitability, usually by targeting specific transmitter systems
What are some ways that drugs affect the neurons pre-synaptically?
synthesis
storage
release
reuptake/degradation of neurotransmitters
What are some ways that drugs affect neurons post-synaptically?
receptor agonists, antagonists
degradation of neurotransmitters
What is the main goal of antiemetic therapy?
block neurotransmission at the chemoreceptor trigger zone, at afferent inputs to the emetic center and in the emetic center
3 receptors in the chemoreceptor trigger zone?
5HT3
D2
M1
NK1
Antiemetic drug; 5HT3 receptor antagonist; also acts peripherally to block intestinal vagal afferents
ondansetron (Zofran)
granisetron (Kytril)
Antiemetic drug; NK1 receptor antagonist
aprepitant (Emend)
5HT3 receptors are (blank) channels
Na+
Corticosteroid used with antiemetic drugs
dexamethasone
D2 receptor antagonist; may also act peripherally to enhance GI motility; alone or in combo for treating CTI nausea and vomiting; also used for treating unproductive nausea and vomiting
Metoclopramide (Reglan)
Side effects of Metoclopramide?
dystonias
tardive dyskinesia
Oral cannabinoid; thought to act in higher cortical centers; approved for use in patients not responding to other antiemetic agents; can be used for breakthrough or refractory emesis
Dronabinol (Marinol)
**synthetic form of THC
What is smoking marijuana used for medically? Side effects?
pain, inflammation, spasticity;
euphoria, dysphoria, hallucinations, abuse potential
There are two antiemetic drugs used to control non-productive nausea and vomiting. What are they?
Promethazine - D2 receptor antagonist
Doxylamine - H1 receptor antagonist
**both also block mACh receptors
Two H1 receptor antagonists that provide short-term, immediate relief for motion sickness
Dimenhydrinate (Dramamine)
Meclizine (Antivert)
A muscarinic receptor antagonist that is used for long-term, sustained control of motion sickness; skin patch placed behind the ear that produces less side effects than via the oral route
Scopolamine
What are four strategies for antiseizure therapy?
- enhance synthesis of GABA
- block degradation of GABA
- block reuptake of GABA
- enhance postsynaptic GABA-A receptor activity
So, one way to prevent seizures is to upregulate GABA activity. What is one other neurotransmitter that you could alter?
glutamine (downregulate it)
Besides GABA and glutamine, what is another way you could decrease seizures?
block ion conductance through channels (block Ca++ and Na+ influx, or K+ efflux)
Loss of basal forebrain cholinergic neurons that cause a striking deficiency in ACh
Alzheimer’s disease
How to treat Alzheimer’s?
increasing ACh levels using reversible cholinesterase inhibitors
List 3 medications for Alzheimer’s and how they work
Donepezil (Aricept) and Ravistigmine (Excelon) - reversible cholinesterase inhibitors;
Memantine - low affinity open channel blocker of NMDA receptors (inhibits the pathological activation of the receptor)
Progressive loss of dopaminergic neurons in substantia nigra leading to shortage of dopamine in extrapyramidal movement circuit
Parkinson’s disease
Primary treatment for Parkinson’s disease
increase dopamine levels (L-DOPA)
Why do we treat Parkinson’s disease with L-DOPA instead of dopamine?
dopamine doesn’t cross the BBB
Characterized by chorea – irregular, unpredictable involuntary muscle jerks at different parts of the body that impair voluntary activity that is the result of a loss of neurons from structures of the basal ganglia, imbalances both in GABA functions (diminished) and dopamine functions (enhanced)
Huntington’s disease
How to treat Huntington’s disease?
Tetrabenazine - a selective and reversible centrally-acting dopamine depleting drug
D2 receptor antagonists to control abnormal movements and relieve the psychosis that accompanies the disease
a selective and reversible centrally-acting dopamine depleting drug (inhibits VMAT2)
tetrabenazine
**inhibits the transporter that takes dopamine into vesicles for storage and release
Degeneration of spinal, bulbar and cortical motor neurons that leads to muscle weakness, muscle atrophy and fasciculations, spasticity, dysarthria, dysphagia and respiratory compromise
Amyotrophic lateral sclerosis
How to treat ALS?
Riluzole - involves glutamate release, blocks NMDA and kainate glutamate receptors to inhibit voltage-dependent Na+ channels
Two drugs used to treat spasticity?
Baclofen - a GABA-B receptor agonist
Tizanidine - an alpha-2 adrenergic receptor agonist
A GABA-B receptor agonist
Baclofen
An alpha 2 adrenergic receptor agonist
Tizandine
reduced drug effect with repeated use and higher doses required to produce the same effect
tolerance
What are two ways to get drug tolerance?
pharmacokinetic - altered metabolism
physiologic - long-term alterations (at site where drug acts or at other synpases for other neurotransmitters)
tolerance to a drug in one class
e.g., sedative-hypnotics) will lead to tolerance to others in the same class (sedative-hypnotics
cross-tolerance
repeated, compulsive use of a drug that deviates from the social norms of a given culture; disregard of harmful interpersonal or social consequences e.g., ethanol, opiate analgesics, cocaine and other recreational drugs
dependence
drugs within a pharmacological class (e.g., opiate analgesics) support individuals physically dependent on other drugs in the same class - useful property for “detox”
cross-dependence
(All non-research use illegal under federal law) – highest abuse potential
Schedule I
(No telephone prescriptions, no refills)
Schedule II
(Prescription must be rewritten after 6 months or five refills)
Schedule III
(Prescription must be rewritten after 6 months or five refills; differs from Schedule III in penalties for illegal possession)
Schedule IV
(As any other non opioid prescription drug may also be dispensed without prescription unless additional state regulations apply)
Schedule V
Which schedule of drugs do these fall under?
Stimulants Depressants Hallucinogens Narcotics Marijuana
Schedule I
Which schedule of drugs do these fall under?
Opioids
Cocaine, Amphetamine, Amphetamine Complex, etc
Schedule II
3 important considerations when prescribing CNS drugs?
lipophilicity - drug can accumulate in fatty tissue
high degree of plasma protein binding
metabolism via the liver
Concerns when prescribing CNS drugs for the elderly?
diminished hepatic/liver function
paradoxical reactions
polypharmacy
greater susceptibility to side effects
What are some specificity considerations to keep in mind when thinking about CNS drugs?
some CNS drugs don’t have an established mechanism;
classified according to primary mechanism of action but can have a similar therapeutic effect via another mechanism;
classified according to therapeutic use, but can have a variety of uses
