Intro to Neuropharmacology Flashcards
1
Q
BBB’s Capillaries
A
- Blood brain barrier
- Brain capillaries have closed intercellular clefts are closed and form tight junctions
- Fenestra are absent
- Astrocytes surround about 85% of capillaries
2
Q
BBB + Drug
A
- Reduced diffusion of water-soluble/ionized molecules
- Drugs MUST be nonionized/lipid-soluble to pass into CNS
- Water-soluble drugs have to be moved by specific transport processes
- P-gp transporters can exclude certain compounds from the brain
3
Q
High Permeability Brain Areas
A
- Area Postrema - adjacent to CTZ, allows toxic substances in blood to stimulate vomiting (Apomorphine)
- Medium Eminence - hypothalamic releasing factors transported to pituitary gland
- Pineal gland - releases hormones into the blood
4
Q
CTZ
A
Chemoreceptor Trigger Zone
5
Q
BBB + Pharmacological Uses
A
- Loratadine - antihistaminic that blocks H1 receptors in periphery, DOESN’T cross BBB, antagonism caused brain produced sedation (diphenhydramine)
- Carbidopa - dopa decarboxylase inhibitor, doesn’t enter brain, prevents levodopa conversion to dopamine in periphery
- Naloxegol - Pegylated derivative of naloxone which doesn’t cross BBB and can reverse constipation produced by opiate agonists
6
Q
Spinal Cord
A
- Transmits messages cia afferent and efferent nerves from the periphery => CNS
- Site of some muscle relaxants and opioids
- Autonomic NS and somatic NS
7
Q
Brain Stem
A
- Medula, pons, midbrain, and cerebellum
- 12 cranial nerves originate here
- Mediate sensory/motor function and deal with special senses
8
Q
Cerebellum
A
- Coordinates motor movement via inputs from vestibular system/cortices
- Clinical syndromes that occurs here mainly associated with awkwardness of intentional movements
9
Q
Cerebellum Syndromes
A
- Ataxia - poor motor coordination/balance/speech, eye movement problems, can be produced by antiepileptic drugs
- Asthenia - muscles tire more easily than normal
- Tremor - intention tremor (evident during purposeful movements)
10
Q
Reticular Formation
A
- RAS, medulla of midbrain
- HIGHLY interconnected to other neurons
- Regulates alertness, sleep, BP, heart rate, and respiration
- Contains nuclei for monoamine neurons (NE, Epi, 5HT)
- Locus Ceruleus/Nucleus Tractus Solitarius => NE/Epi
- Raphe => 5HT
11
Q
Thalamus
A
- Main function: relay motor and sensory signals to cortex
- Important for consciousness, sleep, and sensory interpretation
12
Q
Midbrain
A
- Relay for auditory and cisual systems
- Dopamine neurons in substania nigra (motor control, Parkinsons)
- Ventral tegmental Area (emotion/cognitive fxn, SCZ)
13
Q
Extrapyramidal Motor System
A
- Basal ganglia - caudate nucleus, putamen, and globus pallidus
- Dopaminergic innervation from the substantia nigra
- Disruption causes movement problems like Parkinson’s
14
Q
Basal Ganglia Disorders
A
- Parkinsons - rigid, slownessm resting tremor. Increase dopamine function in BG to treat
- Chorea - Brief, abrupt, irregular. Treat by decreasing dopamine or enhancing GABA
- Athetosis - slow writhing, snake-like. Treat by decrease DA
- Tardive Dyskinesia - repetitive, involuntary, purposeless movements (long-term antipsychotic treatments). Treat by decreasing DA
15
Q
Hypothalamus
A
- Integrating region for ANS
- Regulates body temperature, water balance, hunger, and hormone levels
16
Q
Limbic System
A
- Prefrontal cortex, cingulate ortex, and entorhinal cortex
- Cimplex emotions, motivational functions, and short term memory
- Associated with SCZ, mania, depression, anxiety
17
Q
Cerebral Cortex
A
- Higher mental fxn, cognitive/emotion
- Information processing by modality
- Somatosensory, special senses, sleep, association
18
Q
Postsynaptic Receptors
A
- Receptor number depends on [agonist]
- Chronic excess of agonist = down regulation of receptors (desensitization)
- Chronic deficiency of agonist or antagonist blocking receptors => increase/up-regulation in number of receptors (supersensitivity)
19
Q
Transporters Background
A
- Exist on presynaptic terminals
- Control the reuptake of neurotransmitters
- Transporter antagonists bind directly to transporter and prevent reuptake (leaves more in synapse)
20
Q
Genetic Transporter Families
A
- NET - NE transporter
- SERT - 5HT transporter
- DAT - Dopamine transporter
- GABA transporter - GAT (1-3)
21
Q
Transporter Characteristics
A
- DAT/NET may transport both ways
- Cocaine blcoks all 3 monoamine transporters
- TCA only block SERT and NET
- SSRI - blocks SERT (fluoxetine, paroxetine)
- SNRI - blocks SERT/NET (venlafaxine)
22
Q
Neurotransmitters
A
-Released from one neuron to induce activity in another neuron or tissue
23
Q
Neuromodulator
A
- Substance released from one neuron
- Little effect by itself but alters the response to other neurotransmitters (benzos)
24
Q
ACh
A
- Acetylcholine
- CNS action from muscarinic => nicotinic receptors in CNS
- Associated with several neuropathic syndromes
25
ACh Associated Syndromes
1. Alzheimer's - severe impairment of cognitive function, treat with choline and anticholinersterases
2. Parkinsons - extrapyramidal motor impairment, cholinergic/dopaminergic imbalance. Anticholinergics may help
3. Huntington's - degeneration of cholinergic interneurons, cholinergic/dopaminergic imbalance. Antipsychotics may help by blocking dopamine
4. Central side effects - induced by many drugs, cause atropine-like effects
26
Catecholamines
- NE
- Epi
- DA
27
NE
- RAS, locus ceruleus, and lateral tegmental system
- Alpha and Beta receptors
- Alpha2 - autoreceptors that decrease NE neurons from brain stem
- Site of action of Clonidine (agonist) - regulates BP, suppresses SNS activity (withdrawal, anxiety, ADHD)
28
Epi
- Located in lower brain stem
| - Role in regulating blood pressure
29
DA
- Predominate catecholamine in CNS
- Nigrostriatal, mesolimbic, mesocortical, tuberinfundibular system
- DA inhibits prolactin secretion
- Bromocriptine (dopamine agonist) - treats hyperprolactinemia
30
DA Receptors
- D1 and D5 structurally similar
- D2, D3, and D4 structurally similar
- D2 plays the predominent role in Parkinson's and response to antipsychotic drugs
- Extrapyramidal symptoms (drug SE), more likely with 1st gen. antipsychotic drugs
31
5-HT
- An indolamine
- Tryptophan hydroxylase - rate-limiting enzyme, not saturated so diet can influence production
- Fenfluramine - indirect 5-HT agonist (removed for toxicity)
32
5-HIAA
-Principle metabolite, 2 isoforms of MAO
-MAO-A: metabolizes
5-HT, NE, DA, tyramine. Blocked by tranulcypromine (Parnate) which inhibits A and B
-MAO-B: metabolizes DA, blocked selectively by selegiline for Parkinsons
33
SSRI
- Antidepressant with fewer SE than TCA
- EX: Fluoxetine
- Used from depression, bulimia, anorexia, and panic disorder
34
5HT1 Receptors
- G-protein linked and decrease adenylyl cyclase
- 5HT1A postsynaptic receptors that may be responsible for "serotonin syndrome" (overdose of 5-HT uptake inhibitor)
- Produces myoclonus, tremor, ataxis, akathisia, diaphoresis, delirium, life threatening hyperthermia
35
5HT1A Autoreceptors
- Buspirone (Buspar): selective partial agonist
- Used to treat anxiety
- Less sedative properties than other antianxiety drugs
36
5HT1B
- Mediates vasoconstriction on cerebral vascular
| - Sumatriptan (Imitrex) is selective agonist useful in treating migraines
37
5HT2 Receptors
- G-protein linked/phospholipase C
- 5HT2A - receptors mediate forebrain cortical excitations (Risperidone, selective antagonist)
- 5HT2C - regulate appetite (Lorcaserin, selective agonist to decrease appetite)
38
5HT3 Receptors
- Ligand-gated ion channel
- Dense in area postrema where they influence emesis
- Selective antagonist is Zofran
39
5HT + Physiological Roles
- Sleep
- Anxiety (Buspirone)
- Cognition (Risperidone)
- Temperature regulation
- Appetite
- Mood
40
GABA
- Gamma aminobutyric acid
| - Inhibitory transmitter, primary inhibitory neurotransmitter in CNS
41
GABA-A
- GABA-A, accounts for pharmacological actions of benzos and barbs
- Ligand-gated Cl- channel, causes hyperpolarization
42
GABA-B
- G-protein coupled receptor
- Baclofen - agonist, muscle relaxant and antispastic drug
- NOT modulated by benzos and barbs
- Presynaptic GABA-B decrease calcium conductance and transitter release
- Postsynaptic GABA-B mediate IPSP by opening K+ channels
43
Glutamate + Asparate + NMDA Receptor
1. Excitatory amino acids - high concentrations in the brain/increase neuronal activity synthesized from glutamine
2. Ligand-gated ion channel (Ca++/Na+)
3. Glutamate receptor site - opened by glutamate causing Ca++/Na+ enter neuron and depolarization/excitation to occur
4. Synthesized from gltuamine
44
Memantine
- Namenda
- Competitive antagonist at glutamate receptor
- Alzheimer's drug therapy
45
Felbamate
- Felbatol
- Glycine antagonist
- Glycine potentiates the binding of glutamate
- Antiepileptic drug therapy
46
PCP/Ketamine
- Dissociative anesthetic with receptor sites inside the glutamate channel
- Noncompetitive and indirectly antagonize glutamate
47
General Characteristics of CNS Drugs
1. Physiological State
2. Physical Dependence
3. Psychological Dependence
4. Tolerance
48
Physiological State
- Many CNS drugs stimulate or depress the brain
- Stimulant/depressant effects are usually additive with other drugs in their class
- Receptor antagonist represents a true antagonism/"antidote" (opioid => Naloxone, benzo => Flumazenil)
- Physiological antagonism is more common and is rarely complete (caffeine against ethanol sedation
49
Physical Dependence
- Removal of drug from a dependent person
- Results in withdrawl or abstinence syndrome
- Cross-dependent to other drugs in same pharmacological class
50
Psychological Dependence
- Individual feels that the effects of a drug are necessary to maintain an optimal state of well-being
- Doesn't necessarily imply pathology, but becomes pathological when the use of drug impairs functioning
- May occur without physical dependence or tolerance => basis of compulsive drug use and addiction
51
Tolerance
-Repeated administration, same dose has lesser effects
6 types of tolerance:
- Pharmacokinetic
- Pharmacodynamic
- Cross Tolerance
- Behavioral/learned
- Acute
- Innate
52
Pharmacokinetic Tolerance
- Less drugs gets tot he site of action
| - Increase in hepatic enzymes => increased metabolism => metabolic tolerance
53
Pharmacodynamic Tolerance
- Same amount gets to drug site but response is reduced
| - Changes in receptors or mechanisms
54
Cross Tolerance
- Tolerance to most/all drugs within a class
- May be partial or incomplete
- "opioid rotation"
55
Behavioral/Learned Tolerance
- Same amount of drugs gets to site
| - Individual compensates
56
Acute Tolerance
- Rapid developing tolerance
| - Can occur within a few hours after exposure to CNS drugs
57
Innate Tolerance
- Genetically determined
| - Less affected by certain drugs on an individual basis
