Lec 17 & 18 (Anxiety/Epilepsy & Dopamine/Serotonin)

Question 1

Class I ACD Mechanisms (5)

[GABA-A transmission]

Answer 1

1. positive allosteric modulator, increase affinity of GABA for its receptor
   - act to increase inhibition of nervous system
2. irreversible (or reversible) inactivation of GABA-T(transaminase)
   - inhibits GABA breakdown/catalysis
3. increase GABA synthesis
4. blocks GABA repute
   - prolongs signaling
5. protect GABA-A receptor from desensitization

Question 2

Class II ACD Mechanism (1)

[Na+ channel]

Answer 2

1. act to slow rate of Na+ channel recovery from refractory period/ inhibition of action potential
   - limits ability of neuron to fire at high frequencies, decreased neuron excitability

Question 3

Class III ACD Mechanisms (1)

[Ca2+ channels]

Answer 3

1. T-type Ca2+ channels play a role in burst firing of action potentials in the thalamus
   - ACDs that inhibit these channels

Question 4

Anticonvulsant Drugs - Side Effects + Risks

Answer 4

hepatotoxicity - can induce p450's 
double vision 
ataxia (loss of coordination) 
sedation (with BZDs) 
aplastic anemia (lack of blood cell production)

drug interactions, narrow therapeutic window
lack of compliance (due to side effects)
dangers with use of generics

Question 5

original drug for anxiety disorder treatment

Answer 5

alcohol

Question 6

effects of benzodiazepines (inc dose)

Answer 6

mild sedation 
-anxiolytic action 
strong sedation 
-impaired cognition, retrograde amnesia, used for surgery
hypnosis 
-sleep 
stupor

Question 7

mechanism of action - BZDs

Answer 7

positive allosteric modulation of GABA-A receptor

• bind to a separate site
• increase affinity of GABA for its receptor, a LGIC for Cl- (inhibitory)
• influx of Cl- into the cell hyperpolarizes and leads to decreased ability to reach threshold/fire AP

Question 8

BZD administration

Answer 8

• oral (p.o) safer than i.v. (rapid CNS distribution, risk of overdose)
• lipophilic, high bioavailability, rapid onset of CNS effects
• active and inactive metabolites of varying half-lives

Question 9

BZD elimination

Answer 9

-primarily cleared via biotransformation, CYP450 and/or glucuronide conjugation

Question 10

BZD precautions

Answer 10

• can have additive actions with other CNS depressants, especially alcohol
• individuals with hepatic dysfunction
• individuals taking drugs that are CYP450 inhibitors

Question 11

BZD withdrawal

Answer 11

rapid discontinuation can lead to seizures or anxiety-like symptoms. want to gradually discontinue

Question 12

BZD overdose

Answer 12

can give flumezanil, a direct antagonist of GABA-receptor

-blocks BZD binding site

Question 13

Risk of Baribituates

Answer 13

• low therapeutic index/safety margin
• high abuse liability, risk of respiratory depression
• acts at multiple receptors, not selective
• induces p450 enzymes
• no antidote

Question 14

BZD sensitivity at GABA-Rec

Answer 14

gamma subunit

Question 15

allosteric modulators of GABA-rec

Answer 15

barbiturates 
propofol 
(at high concentrations propofol and barbiturates act as direct agonists) 
alcohol 
benzodiazepines

Question 16

GABA-A Rec Subtype: alpha-5

Answer 16

mediates cognitive enhancing effects

Question 17

GABA-A Rec Subtype: alpha-2/3

Answer 17

mediated anxiolytic and anticonvulsant efects

Question 18

GABA-A Rec Subtype: alpha-1

Answer 18

amnesic/sedative (sleep inducing), muscle relaxant

Question 19

Parkinson’s: Physical Characteristics

Answer 19

Tremor: resting - depressed with voluntary movement, unilateral
Rigidity
Akinesia: lack of movement, slowness (bradykinesia)
Postural Instability

Question 20

Parkinson’s: Neuropathological Features

Answer 20

neurodegenerative disorder

-degeneration of the dopaminergic neurons in the niagrostriatal pathway, which controls and coordinates movement

Question 21

Dopamine Synthesis
(enzymes and intermediates)

Answer 21

tyrosin –> L-dopa (tyrosine hydroxylase)
L-dopa –> dopamine (dopa decarboxylase)
dopamine degredation
-MAO and COMT

Question 22

Parkinson’s: Pharmacotherapy (3)

Answer 22

1. increased rate of dopamine synthesis
   - addition of L-dopa, precursor
   - Carbidopa: inhibits peripheral dopa decarboxylase, increases amount of L-dopa entering brain
2. increase L-dopa duration/decrease DA degredation
   - carbidopa inhibits dopa-decarboxylase
   - enzymes to inhibit MAO-B or COMT
3. mimic dopamine
   - administration of D2-receptor. decrease amount of L-dopa needed to increase dopamine signaling

Question 23

Parkinson’s: Non-Pharamcological Strategy

Answer 23

deep brain stimulation

-electrically inhibits subthalamic nucleus, decreases excessive inhibition to thalamus

Question 24

Substantia Niagra

Answer 24

area of basal ganglia with dopaminergic neurons

-degradation with Parkinson’s, loss of dopamine cells

Question 25

Parkinson's: Pharmacotherapy Side Effects

Answer 25

nausea, arrhythmias, orthostatic hypotension, on-off phenomenon, dyskinesias, psychosis

Question 26

Classes of Antidepressants (4) | mechanism of action, side effects

Answer 26

1. SSRI's - sexual dysfunction, nausea, weight 2. Atypical: NE/DA/5-HT reuptake inhibitors, 5-HT2A/alpha2 receptor antagonists - nausea, weight gain, sexual dysfunction 3. MAO Inhibitors: decrease monamine degradation - hypotension, weight gain, anticholinergic, tyramine storm, manic effects 4. Lithium: primarily for bipolar to prevent mood swings. substitutes for Na+ on neurons and alters receptor-mediated signaling - narrow TI, nausea, tremor, kidney dysfunction, overdose can lead to coma/death

Question 27

Schizophrenia: Symptoms

Answer 27

- Positive: delusion, hallucination, disorganized speech, catatonia - Negative: decreased affect, poor speech (alogia), decreased movement (avolition), lack of pleasure (anhedonia)

Question 28

Schizophrenic: biological effects, dopamine hypothesis

Answer 28

- significant genetic component - atrophy of regions (increased neuron density), enlarged ventricles - thought due to overactive dopaminergic neurons. see drug induced psychosis. explains therapeutic actions, but not etiology.

Question 29

Classes of Antipsychotics

Answer 29

- Typical (ie haloperidol): inhibit D2-receptors - Atypical (i.e. clozapine): inhibit 5-HT2, D4 and- D2 receptors - Side effects: sudden cardiac death, tardive dyskinesia, metabolic syndrome, agranulocytosis (with clozapine, no WBCs)