205 NS - Disease & Pharmacology Flashcards
What is the importance of the hippocampus on memory?
Consolidation of short-term memory to long-term memory
Which part of the brain is responsible for explicit long-term memory?
Hippocampus
Which part of the brain is responsible for skills & habits?
Striatum
Which part of the brain is responsible for emotional responses?
Amygdala
Which part of the brain is responsible for skeletal musculature?
Cerebellum
Why does long-term memory require protein synthesis?
To stabilize learning-induced synaptic changes in the brain
Anterograde amnesia
Difficulty in acquiring new material & difficulty remembering events since onset of illness/injury
What is the 4AT test?
A screening instrument designed for rapid and sensitive initial assessment of cognitive impairment and delirium
What is oxidative stress?
Excessive production of reactive oxygen species (ROS), which may form free radicals that are highly reactive and unstable → oxidize other molecules → can result in severe damage & death
What are the therapeutic approaches for stroke?
Thrombolytics, neuroprotective agents, preventative
What is the only approved drug for stroke currently?
Alteplase (thrombolytics)
What is the MOA of Alteplase?
Cause breakdown of the clot by inducing fibrinolysis
activation of plasminogen (inactive) → plasmin (active)
What drugs are used in the prevention of stroke?
Blood-thinning agents (Aspirin) & drugs to lower LDL cholesterol (Statins)
Types of drugs to treat Alzheimer’s disease & 1 example of each.
Cholinesterase inhibitors - donepezil, rivstigmine, galantamine
NMDA-Receptor Antagonist - memantine
What are the hallmarks of Alzheimer’s disease?
Accumulation of beta-amyloid plaques between nerve cells (neurons)
What are the hallmarks of Parkinson’s disease?
Histology - the presence of Lewy bodies
Motor - hypokinesia, masked face, lead pipe rigidity, cog-wheel rigidity, resting tremor, shuffling gait
Types of drugs to treat Parkinson’s disease & 1 example of each.
Levodopa - in combination with carbidopa & entacapone
Dopamine agonist - pramipexole
MAO-B inhibitors - selegiline
Muscarinic ACh receptor antagonist - orphenadrine
What is the mode of inheritance of Huntington’s disease?
Autosomal dominant
What are the hallmarks of Huntington’s disease?
Histology - Aggregation of huntingtin protein rich in glutamate repeats
Motor - chorea (dance like movement)
What is the neurobiology of Huntington’s disease?
- Striatum degenerates → Globus pallidus (GP) less inhibition
- GP release more neurotransmitters to the subthalamic nucleus (STN) → higher STN inhibition
- Less excitatory neurotransmitter release to Substantia nigra pars reticulata (PR)
- PR less excited → reduces inhibitory neurotransmission to the thalamus
- Thalamus receives less inhibition from PR → disinhibited → increase transmission from the thalamus to motor cortex → over-stimulation
Types of drugs to treat Huntington’s disease & 1 example of each.
Dopaminergic antagonist - tetrabenazine, chlorpromazine, haloperidol
What are the Z-drugs and what are they for?
GABA-A receptor agonists
Zolpidem
Zopiclone
Zaleplon
For insomnia
Types of drugs to treat insomnia
Sleep disorders & treatment
Benzodiazepines - GABA-A receptor agonists Z-drugs - zolpidem, zopiclone, zaleplon Orexin antagonist - suvorexant Melatonin agonist - remelteon Anticonvulsant - gabapentin
Drugs to treat narcolepsy - excessive daytime sleepiness
Sleep disorders & treatment
Modafinil
Methylphenidate
Drugs to treat ADHD
Sleep disorders & treatment
Atomoxetine
Adderall - amphetamine
Retrograde amnesia
Difficulty in remembering info prior to the onset of illness/injury
How’s the EEG of partial seizures?
Each has one electrical, usually random & not sync
How’s the EEG of generalized seizures?
Synchronized activity in all
What is status epilepticus?
Continuous or repetitive seizures lasting ≥ 30 mins
What are epileptic effectors?
Ion channels & ligand-gated receptors - determine seizure threshold
What are epileptic mediators?
Cytokines & prostaglandins - inflammatory mediators, can be therapeutic targets
The function of GABA-A receptor
Control the majority of inhibitory signaling in the CNS - controls excessive excitatory effect, puts a cap on it
What is the effect of vigabatrin & tiagabin on IPSP?
Prolongs IPSP (↑ half-life of GABA) - ↑ duration
What is the effect of barbituates & benzodiazepines on IPSP?
↑ the affinity of GABA for GABA-A receptor - ↑ amplitude
What is Generalized Anxiety Disorder (GAD)?
An ongoing state of excessive anxiety lacking any clear reason or focus
What are the treatments for Generalized Anxiety Disorder (GAD)?
Cognitive behavioral therapy (CBT)
SSRIs/SNRIs
Pregabalin
Benzodiazepines (short-term)
What are the treatments for Panic Disorder?
Cognitive behavioral therapy (CBT)
SSRIs/SNRIs
Tricyclic antidepressants
Benzodiazepines (short-term)
What are the treatments for phobias?
Behavioral therapy
SSRIs/SNRIs
What are the treatments for Obsessive Compulsive Disorder?
Cognitive behavioral therapy (CBT)
SSRIs
TCA - Clomipramine
How long are benzodiazepines used for?
< 2 weeks
What is used for long-term treatment for anxiety disorders?
SSRIs & buspirone
MOA of Benzodiazepines
Binds to GABA-A receptors to enhance the action of GABA
MOA of SSRIs/SNRIs
Inhibits reuptake of serotonin leading to increased serotonin in the synaptic cleft
Inhibitors of monoamine uptake (4)
Selective serotonin (5-HT) reuptake inhibitors (SSRIs)
Classic tricyclic antidepressants (TCAs)
Newer, mixed 5-HT & noradrenaline reuptake inhibitors
Noradrenaline reuptake inhibitors
Drug therapy for bipolar disorder
Mood stabilizers - lithium & certain anticonvulsants: valproate, carbamazepine
2nd-gen antipsychotics: aripiprazole, quetiapine, risperidone
Name a 1st-gen & 2nd-gen antipsychotic drug.
1st-gen: Chlorpromazine
2nd-gen: Clozapine
What are the 4 characteristic symptoms of the neuroleptic malignant syndrome in order?
Altered mental status
Motor abnormalities
Hyperthermia
Autonomic hyperactivity
What may cause neuroleptic malignant syndrome?
Antipsychotics - haloperidol, olanzapine
Antiemetics - metoclopramide
Withdrawal of antiparkinson drugs
What’s the management of neuroleptic malignant syndrome?
Rapid cooling
Benzodiazepines
Dantrolene
Bromocriptine/amantadine
Where do primary brain tumors originate from?
In the brain either in brain parenchyma or extraneural structures
Where do secondary brain tumors (brain metastases) originate from?
Originate in tissues outside the brain & spread to the brain
Are primary or secondary brain tumors more common?
Secondary brain tumors (brain metastases) are ~10x more common
Drugs approved for brain tumors. (6)
Bevacizumab Carmustine Everolimus Lomustine Naxitamab-gqgk Temozolomide
“All-or-none” principle
Action potential, not graded
Constant amplitude
Action potential mechanism
- Hypopolarization
- Depolarization
- Overshoot
- Repolarization
- Hyperpolarization.
Refractory period
Period during an action potential when no further excitation can occur
Which domain of the voltage-gated sodium channel contains the voltage sensor?
4th TM domain
- when sense change in voltage, it moves up changing the conformation → channels open
Conformational states of voltage-gated sodium channel
Deactivated → open → inactivated → repolarization
Deactivated state of voltage-gated sodium channel
Channels are deactivated
M-gate is closed, doesn’t let Na+ through
Activated state of voltage-gated sodium channel
Current passes through and changes voltage difference across membrane
Channel activates → m-gate open
Inactivated state of voltage-gated sodium channel
Neuron depolarizes
H-gate swings shut and blocks Na+ from entering cell
Passive signals (Graded potential)
Diminish as they spread from their site of initiation
Strategies to increase current spread along axon
Increase axon diameter
Reduce membrane current leak - adding insulating material
3 morphological type of synapses
Axodendritic (very common)
Axosomatic (common)
Axoaxonic (uncommon)
Depolarising influences
Positive charges moving in
Negative charges moving out
Hyperpolarising influences
Positive charges moving out
Negative charges moving in
Ionotropic receptors vs Metabotropic receptors
Ionotropic - direct gating
Metabotropic receptors - indirect gating
Local anesthetics
Analgesia close to source of pain
Central analgesia
Analgesia through central/spinal sites w/o loss of consciousness
General anesthesia
Loss of consciousness ± analgesia
Opium alkaloids
Morphine
Metabolism of opiod analgesics
Phase 1 metabolism: CYP pathway
Phase 2 conjugation
- can be both
Why do drugs have to be metabolized?
So they can:
- Be excreted
- Reach their target site
β-arrestin recruitment is involved in:
Internalization & recycling of opioid receptors
Recruit further signaling molecules to modify neuronal function
Opioid receptor signaling
- Opioid agonist G-protein activation
- Receptor phosphorylation
3a. Arrestin recruitment
3b. Internalization - MAPK signaling
- Recycling
Endogenous opioids
Endorphins
Enkephalins
Analgesic tolerance
A gradual decrease in analgesic efficacy over time
Requirement of escalation in opioid dose to maintain analgesia
Where are opioid receptors found?
On presynaptic terminal of primary afferent nociceptors & 2° neurons
RAVE hypothesis
Endocytosis resensitizes receptors - Receptor Activation Versus Endocytosis
Strong recycling → no tolerance
No recycling → tolerance
Paracetemol (acetaminophen)
analgesics
Analgesic & antipyretic
Aspirin
analgesics
Anti-platelet
Anti-inflammtory
Should not be used in age <16 y.o.
NSAIDs
analgesics
Ibuprofen
Reduce inflammation, analgesics, antipyretic
Opioid analgesics
analgesics
Morphine - full agonist at μ-opiod receptor
Codeine - partial μ-receptor agonist
First-line treatment of neuralgic pain treatment
analgesics
Anticonsulvants - gabapentin, pregabalin
Migraine treatments
analgesics
Triptans (Serotonin 5HT1 Receptor Agonists) - Sumatriptan
COX-2
Enzyme responsible for inflammation and pain
Meningitis
Infection & inflammation of the meninges
Pyogenic - bacterial
Aseptic - viral
Pyogenic meningitis pathology?
Thick layer of exudate
Neutrophils
How do pathogens reach meninges?
Haematogenous spread Adjacent infections Neurosurgery Trauma Remote foci of infection
Cause of acute bacterial meningitis
Streptococcus pneumoniae
Causes of viral meningitis
Enteroviruses - coxsackie virus
HSV-2
Risk factors of bacterial meningitis
Decreased cell-mediated immunity
Neurosurgery/head trauma
Fracture of cribiform plate
What’s the most common viral cause of chronic meningitis?
HIV
Distinguishing feature of Neisseria meningitis
Petechial rash can rapidly become purpuric
3 main considerations of empirical antimicrobials for bacterial meninges
- Must cross BBB
- Bactericidal
- Active against most common pathogens
Encephalitis
Inflammation of brain
Causes of encephalitis
Viruses
Treatment for HSV & Varicella-Zoster virus
Acyclovir
Treatment for cytomegalovirus
Ganciclovir
Encephalopathy
Altered brain function w/o inflammation, mostly non-infectious
腦病
Brain abscess
Intracerebral infection, collection of pus
Do virus cause brain abscesses?
No
Subdural empyema
Collection of pus between dura & arachnoid matter layer of meninges
Epidural empyema
Between dura matter and skull/vertebral column
Key diff between empyema & other brain infections
No need to cross BBB to cause disease
Acute flaccid myelitis
Infection of the spinal cord
Brain barriers to infection
Physical protection - skull/vertebrae, meninges, CSF
Brain-CSF barrier
BBB
Olfactory portal
Mechanism of bacterial invasion of blood-brain & blood-CSF barriers
Transcellular penetration
Paracellular entry
“Trojan horse” mechanism
What protects the brain from infection?
Nasal cavity harbor normal bacterial flora
Cells secrete mucins
Mucocilliary process
Secretion of antimicrobial substances
Tight junctions between epithelial cells
DC extend processes into nasal cavity to help macrophages clear foreign antigens
Treatment of trigeminal neuralgia
analgesics
Carbamazepine
MOA of antipsychotics
Inhibit dopamine D2 receptors
