HNN Topic 12 - Movement, Parkinson's, CNS Pharmacology Flashcards
What is dopamine synthesised from?
Amino acid - tyrosine
What is the effect of psychomotor stimulants?
Cause wakefulness and euphoria
Give examples of psychomimetic drugs
- LSD
- Mescaline
- Ketamine
- Phenycyclidine
- THC
Describe the structure of dopamine
- Catecholamine (monoamine)
- Catechol ring and amine side group
List the types of dopamine receptors
- D-1 like receptors
- D-2 like receptors
What is the effect of antischizophrenia drugs?
Effective in relieving some of the symptoms of schizophrenic illness
What are monoamines?
Neurotransmitters derived from amino acids
Describe the storage and exocytosis of dopamine
- Stored in vescicles
- Released in response to calcium influx caused by action potential
How is depressive illness categorised?
Affective disorder - disorder of mood rather than thought/cognition
What is the role of the basal ganglia in controlling voluntary movement?
- Initiation of movement - putting plan into action
- Planning complex voluntary movements
What are the common side effects experienced on Levodopa?
- On/off episodes - freezing
- Dyskinesia
- Impulsive/compulsive behaviour
- Withdrawal syndrome - depression, anxiety, pain
- Nausea and vomiting - doperidone prescribed to prevent
Describe the function of the cerebellum in voluntary movement
- Coordination and smooth execution of movements
- Motor learning
List the dopaminergic pathways
- Nigrostriatal
- Mesolimbic
- Mesocortical
- Tuberoinfundibular
Where are noradrenergic neurons and terminals found?
- Neurons
- In pons in medualla (locus cerulus and reticular formation)
- Sympathetic ganglia - all spinal levels
- Terminals
- Glands, smooth muscles (sympathetic)
- Forebrain, cerebellum, brainstem, spinal cord
What is the function of the mesocortical pathway?
- Mediates cognitive and emotional behaviour
- Dopamine helps in improved working memory and attention
What is the goal of pharmacotherapies used to treat schizophrenia?
Reduce dopaminergic signalling at D2 receptors (mesolimbic/cortical pathway)
Describe D-2 like receptor types and their action
- D2, 3, 4 receptors
- Inhibit cAMP
- Coupled to inhibitory G-proteins
Why is the therapeutic onset of antidepressant drugs potentially problematic?
- Therapeutic onset = 2-4 weeks
- Problem in acutely suicidal patients
- Effects of ketamine (quick onset) being trialled for treating acute depression
Describe the mesolimbic pathway
Originates in ventral tegmental area, projects to amygdala, pyriform cortex, lateral septal nuclei and nucleus accumbens
What is the effect of general anaesthetic agents?
- Used to produce surgical anaesthesia
- Act on GABA receptors - main inhibitory neurotransmitter of brain
List types of drugs which act on the CNS
- General anaesthetic agents
- Anxiolytics and sedatives
- Antischizophrenia (antipsychotic) drugs
- Antidepressant drugs
- Analgesic drugs
- Psychomotor stimulants
- Pschomimetic drugs
- Cognition enhancers
- Other disease specific drugs
Explain the clinical relevance of the tuberoinfundibular pathway
Antipsychotic drugs may disinhibit prolactin release and cause galactorrhoea
Describe the symptoms of schizophrenia
- Positive symptoms (additional to normal experience)
- Hallucinations (usually auditory)
- Dellusions of persecution/grandeur
- Disorder of logical thought
- Negative symptoms
- Depression - unresponsive to typical antidepressants
- Anhedonia
- Avolition - lack of drive
- Slow thought/speech/actions
- Lack of recognition of illness
- Cognitive deficits - difficulties in learning and planning, impaired attention
How is physiotherapy helpful in managing Parkinson’s disease?
Prevent falls, maintain/gain independence, reduce pain
List the common non-motor symptoms of Parkinson’s disease
- Anhedonia - inability to experience pleasure
- Sleep problems
- Memory problems and cognitive deterioration
- Loss of smell and taste
- GI symptoms - constipation
- Urinary control disturbances - incontinence
- Depression and anxiety
- Hallucinations
List the types of movement
- Ballistic movements
- Persuit/visual feedback movements
Describe the mechanism of action and effectiveness of Levodopa
- Converted to dopamine by dopamine carboxylase - replaces endogenous dopamine
- Usually effective at first, after 5 years only 20% still respond - loss of dopaminergic cells to convert to dopamine
What are the main inputs and outputs of the cerebellum in voluntary movements?
- Input - mainly from sensory cortex
- Output - to primary motor cortex (via thalamus)
What is the general function of serotonin?
- Determines overall level of arousal
- Part of descending pain control system
Describe classification of drugs based on their mechanism of action
- Agonist - activates receptor producing functional response
- Antagonist - binds to receptor without activating it, blocks action of agonists
- Partial agonist - partially activates a receptor, producing a smaller functional response in the cell
- Some don’t act on receptors e.g. enzyme inhibitor - donepezil
Describe the pathological changes which occur in Parkinson’s disease
- Causes distinctive neuropathological brain changes
- Formation of Lewy bodies - abnormal proteinaceous spherical bodies
- Spindle or thread-like branching Lewy neurites in the somata of the involved nerve cells
What is the role of the primary somatosensory cortex in voluntary movement?
- Feedback to control/adjust movements - proprioception
Give examples of disease specific drugs
- Anti-epilepsy e.g. gabapentin
- Anti-Parkinson’s e.g. L-DOPA
- Anti-Bipolar disorder drugs e.g. lithium
- To treat addiction/dependence
Describe the epidemiology of schizophrenia
- Common psychiatric disorder - 1% of population
- V few make long-term recovery, 10% commit suicide
How does the control of movements change as they are practiced?
Most movements are learned - complex movements initially require a lot of conscious thought, with practice they become more involuntary (subconscious)
What is the effect of cognition enhancers?
- Improve memory and cognition
- Mild cognition enhancing effect in early stages of Alzheimer’s - doesn’t prevent degredation of neurones causing the disease
- Inhibit breakdown of acetyl choline in synapses - promote cholinergic function
How is dietary therapy helpful in management of Parkinson’s disease?
Adapt diet to prevent constipation
Describe the tuberoinfundibular pathway
Originates in arcuate nucleus of hypothalamus, projects to pituitary gland (median eminence)
Describe the mechanism of action and side effect of MAOIs
- Reduce breakdown of dopamine
- Given w/ Levodopa - worsens side effects (involuntary movements and sickness)
- Side effects - headaches, indigestion, depression, flu-like symptoms
Describe the nigrostriatal pathway and its function
- Originates in substantia nigra (pars compacta), projects to dorsal striatum (caudate nucleus + putamen)
- Control of motor function and learning new motor skills
Why are some areas of the brain outside the BBB?
Postrema - responsible for vomit reflex lies outside the BBB in order to detect toxins in the blood
What is the function of the tuberoinfundibular pathway?
- Dopamine inhibits prolactin release from the anterior pituitary
- Stimulates growth hormone release
Give examples of antischizophrenia drugs
- Typical e.g. chloromazine, haloperidol
- Atypical e.g. clozapine, olanzapine
List the monoamine neurotransmitters
- Dopamine
- Serotonin
- Noradrenaline
Where is dopamine produced?
Several areas of the brain - substantia nigra (pars compacta) and ventral tegmental area
What is the function of the mesolimbic pathway?
- Emotions and reward system - mediates pleasure in the brain
- Released during pleasurable situations + stimulates one to seek out pleasurable activity/occuputation
- All drugs of abuse stimulate this pathway
What is the role of the primary motor cortex in voluntary movement?
- Origin of descending pathways - output to muscles
- Somatotopic map shows distribution of areas of cortex which control specific muscles
List the side effects of antischizophrenia drugs
- Parkinson’s like akinesia - D2 antagonism
- Unpleasantness - D2 antagonism
- Prolactin hypersecretion (galactorrhoea) - D2 antagonism
- Posterior hypotension - alpha 2 adrenoceptor antagonism
- Sedation - histamine R antagonism
- Dry mouth - muscarinic R antagonism
- Weight gain - HI/5HT2C R antagonism
What is the motor effects of damage to the cerebellum?
Cerebellar ataxia - poor coordination
Which kind of receptors does dopamine act on?
G-protein coupled receptors
Describe the synthesis of dopamine
- Tyrosine in blood taken up into brain by low affinity amino acid transport system
- Transported from extracelluar fluid of brain to dopaminergic neurons by high + low affinity amino acid transporters
- Tyrosine converted to L-DOPA (dopamine precursor) by tyrosine hydrogenase (TH) - rate limiting step
- L-DOPA converted to dopamine by 1-amino acid decarboxylase (dopa decarboxylase) in the cytoplasm
List the predominant motor symptoms of Parkinson’s disease
- Resting tremor e.g. pill-rolling
- Bradykinesia/akinesia - progressive slowing/absence of voluntary movements
- Postural instability - shuffling gait, falls
- Rigidity - stooped posture, lack of arm movement when walking, axial and limb rigidity (cogwheeling/lead pipe)
Also - oral motor disorders (quiet, hurried speech and dribbling) and scrawled writing
Describe the mesocortical pathway
Originates in the ventral tegmental area, projects to the frontal cortex and septohippocampal regions
Define Parkinson’s disease
Progressive multisystem neurodegenerative disease affecting people mainly in the later years of life
What is the function of the blood brain barrier?
- Maintain constant environment
- Protect brain from foreign substances
- Protect brain from peripheral transmitters
What are the problems with using D2 antagonists to treat schizophrenia?
- D2 blockage immediate but therapeutic effect takes weeks
- Some patients do not respond
- Drugs effective against positive symptoms but not negative/cognitive symptoms
Explain the clinical relevance of the mesocortical pathway
Antipsychotic drugs worsen negative symptoms of schizophrenia by blocking dopamine receptors in mesocortical pathway
What is the effect of psychomimetic drugs?
Hallucinogens - drugs that cause disturbances of perception and behaviour
List the causes of Parkinson’s disease
- Aging
- Genetic factors - synuclein, Parkin and other genes
- Environmental factors - toxins (e.g. MPTP), herbicides, pesticides
List the potential routes of administration of drugs which act on the CNS
- Enteral - lipophilic drugs (absorbed by GI tract)
- Parenteral - IM, SC
- Invasive routes (intrathecal)
List the treatment/management options for Parkinson’s disease
- Occupational therapy
- Physiotherapy
- Speech and language therapy
- Dietary therapy
- Pharmacotherapies
List diseases affecting movement caused by damage to the basal ganglia
- Parkinson’s disease - difficulty initiating movement
- Huntington’s disease - random involuntary movements
What are the main inputs and outputs of the basal ganglia in controlling voluntary movement?
- Input - mainly prefrontal cortex
- Output -
- Pre-motor area (via thalamus)
- Supplementary motor area
Describe the types of D-1 like receptors and their action
- D1, D5
- Cause activation of cAMP
- Coupled to stimulatory G-proteins
What are anxiolytics/sedatives used to treat?
Anxiety, epilepsy, anaesthesia, panic disorder, alcohol withdrawal, muscle relaxation
What is the role of the supplementary and premotor areas?
- Planning of movement
- SMA = upper body, PMA = lower body
What are the benefits of invasive routes of administration of CNS drugs, give examples of drugs which would be administered in this way?
V quick action
E.g.:
- Meningitis antibiotics
- Opiate analgesics
- Regional anaesthesia (epidural)
What is the general function of noradrenaline?
Maintaining attention and vigilance
Give examples of psychomotor stimulants
- Cocaine
- Amphetemines e.g. Vyvanse for ADHD
- Methylphenidate (Ritalin)
- Caffeine
Give examples of analgesic drugs
- Opiates e.g. morphine
- Baclofen
- NSAIDs - ibuprofen, aspirin
Give examples of cognition enhancers
Galantamine, donepezil
List the types of Parkinson’s pharmacotherapies
- Drugs that replace dopamine e.g. Levodopa
- D2/3 agonists e.g. Bromocriptine
- Monoamine oxidase inhibitors e.g. Selegiline
Where are D-1 like receptors found?
Throughout the brain, blood vessels and smooth muscle
What is the chemoreceptor trigger zone?
Postrema of brainstem - outside BBB, vomiting reflex
How is dopamine inactivated?
- Reuptake into presynaptic terminal by dopamine transporter
- Metabolism - monoamine oxidase or catechol-O-methyl transferase
Describe persuit/visual feedback movements
- Motor command continually updated according to sensory feedback
- Accurate (modified while in progress) but slow
Where are monoamine containing neurons found?
Mainly in the brainstem
What is the role of the prefrontal cortex in voluntary movement?
Decision to make movement - analyses environment
How can it be proven that the effectiveness of antischizophrenia drugs is due to their action on D2 receptors?
- Not selective - efficacy is due to action on D2 receptors as drugs with high affinity for D2 receptors require a lower dose for clinical efficacy than other similar drugs
Describe the structure of the BBB
- Astrocytes, pericytes, microglia
- Basement membrane
- Endothelial cells - tight junctions between
- Blood - lymphocytes, monocytes, neutrophils
Describe the mechanism of action and side effects of D2/3 agonists
- Mimics action of dopamine
- Side effects
- Drowsiness, fainting, nausea, constipation
- Impulsive/compulsive behaviour
- Hypotension
- Headaches
- Psychological problems e.g. hallucinations
What is the effect of antidepressant drugs?
- Alleviate the symptoms of depressive illness
- Bind to selective serotonin reuptake receptor - block reuptake of serotonin, prolonging its action
List the areas of the cortex involved in planning/instruction of voluntary movement
- M1 - primary motor cortex (area 4)
- S1 - primary somatosensory cortex
- Supplementary + pre-motor areas (area 6)
- Prefrontal cortex
- Area 5
- Area 7
Describe the symptoms of Huntington’s disease
- Choreas - involuntary movements
- Difficulty speaking and swallowing
- Progressive cognitive decline
List other sensory areas involved in voluntary movement
- Visual to visual cortex
- Vestibular - feedback from organs of balance to subcortical areas
How is speech and language therapy helpful in managing Parkinson’s disease?
- Maintain communication ability
- Help with problems with eating/drinking - swallowing, dribbling etc.
What is the aim of pharmacotherapies used to treat Parkinson’s disease?
Enhance dopaminergic signallnig in nigrostriatal pathway
Describe the progression of the pathological changes which occur in Parkinson’s disease
- Lewy bodies confined to medulla, pontine tegmentum and olfactory bulb in early pre-symptomatic stages - loss of sense of smell
- Progression - substantia nigra etc. affected = clinical symptoms
What causes Huntington’s disease?
Inherited triple repeat base disorder
Describe ballistic movements
- Based on a pre-programmed set of instructions
- Rapid but innaccurate - no time for compensation
How are general anaesthetic agents administered?
- Inhalation (short action) or intravenous (rapid acting)
- Often IV induction then maintenance with inhalation
Give examples of antidepressant drugs?
- Monoamine oxidase inhibitors e.g. phenelzine
- Tricyclic antidepressants e.g. imipramine
- SSRIs e.g. fluoxetine
Why is drug entry to the CNS restricted?
Blood brain barrier
What is the effect of analgesic drugs?
- Painkillers - used clinically for blocking nociceptive pain
Describe the synthesis of monoamines
- Dopamine and noradrenaline derived from tyrosine
- Serotonin derived from tryptophan
Give examples of anxiolytics/sedatives
- Barbiturates e.g. phenobarbital
- Benzodiazepines e.g. diazepam
Explain the clinical relevance of the mesolimbic pathway
Antipsychotic drugs decrease positive symptoms of schizophrenia by blocking dopamine receptors in the mesolimbic pathway
How is entry of drugs to the CNS aided?
- Prodrugs e.g. L-DOPA
- Carrier molecules
- Transient BBB disruption e.g. mannitol
When do motor symptoms of Parkinson’s appear?
After 95% of nigrostriatal dopaminergic neurons are lost
Where are serotonergic neurons and terminals found?
- Neurons - most levels of brainstem, concentrated in raphe nucleus
- Terminals - widespread in forebrain, cerebellum, brainstem and spinal cord
What is the effect of anxiolytics and sedatives?
- Cause sleep and reduce anxiety
- Act on GABA A receptor
How are most movements performed?
- Mixture of ballistic and persuit
- Mixture of voluntary and involuntary
- Most are learned
