Unit 2_Pharm

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CNS Medications:

CNS Medications Sedative – Hypnotics Antidepressants Antipsychotics Antiseizure Anti-Parkinson’s

Blood Brain Barrier:

Blood Brain Barrier Tight junctions in endothelial cells Capillaries lack fenestrations and gaps Drugs must be able to cross to work in CNS

General Mechanisms of CNS Drugs:

General Mechanisms of CNS Drugs Presynaptic action potentials Neurotransmitter synthesis Neurotransmitter storage Neurotransmitter release Neurotransmitter clearance Neurotransmitter degradation Postsynaptic receptors Membrane effects

Neurotransmitters:

Neurotransmitters Removal of signal: Uptake 1- reuptake by presynaptic membranes- Monoamine oxidase (MAO) Uptake 2- uptake by postsynaptic membranes – catechol -O-methyl transferase (COMT) Degradation in the synaptic cleft Diffusion away from the synaptic cleft

Major Neurotransmitters Targeted:

Major Neurotransmitters Targeted Acetylcholine Monoamines DA NE Serotonin Amino Acids GABA Glutamate Opiates

CNS Neurotransmitters:

CNS Neurotransmitters Acetylcholine- cerebral cortex, thalamus, brainstem, spinal cord, amygdala 1. Arousal (wakefulness)- increased cortical activity 2. REM sleep- decreased muscle tone and altered EEG- brainstem 3. Learning and memory- forebrain Acts on Nicotinic and Muscarinic receptors - multiple subtypes

Acetylcholine Synthesis and Degradation:

Acetylcholine Synthesis and Degradation

CNS Neurotransmitters:

CNS Neurotransmitters 2. MONOAMINES Dopamine (DA) Norepinephrine (NE) Serotonin (5-HT)

A. Dopamine:

A. Dopamine D1 family of receptors (D1,D5) - stimulate Gs D2 family of receptors (D2-D4) - stimulate Gi Cortex (all) Limbic (all, especially D3) basal ganglia (D1,D2) Pituitary (D2)

Dopamine Synthesis and Degradation:

Dopamine Synthesis and Degradation COMT

Dopamine Actions:

Dopamine Actions Behavior, mental health, movement Reward, memory, learning Implicated in disease: Low levels - depression, stress induced anxiety, Parkinson’s, ADHD High levels - mania, addictions, psychosis

B. Norepinephrine:

B. Norepinephrine Pathways originate in Locus coeruleus of pons Hypothalamus - increases CRH 3.Increased input to amygdala (PTSD?) Implicated in: Depression Anxiety ADHD Pain suppression Cardiovascular

B. Norepinephrine Synthesis and Degradation:

B. Norepinephrine Synthesis and Degradation Tyrosine hydroxylase Amino acid decarboxylase Dopamine beta hydroxylase A

C. Serotonin:

C. Serotonin Originate in Brainstem (reticular) Inhibitory? Implicated in: Sleep Inhibition of aggression Mood Inhibition of compulsive sexual behavior

3. Amino Acid Neurotransmitters:

3. Amino Acid Neurotransmitters Inhibitory Glycine - interneurons in spine, brainstem GABA-basal ganglia, spinal cord, cerebellum, cortex Excitatory Glutamate- throughout brain and spine Aspartate - throughout brain and spine

GABA- gamma amino butyric acid:

GABA- gamma amino butyric acid Ubiquitous Interneurons GABA A - Linked to Cl - Channels on post synaptic membranes GABA B – L inked to K+ channels on presynaptic (and postsynaptic) membranes

Glutamate:

Glutamate Most common Excitatory Opens Na+ ion channels NMDA , AMPA receptor-cortex, hippocampus, amygdala , basal ganglia

Sedative-Hypnotics:

Sedative-Hypnotics Benzodiazepines -mostly known for treating anxiety - several specifically for sleep- - can produce tolerance and dependence - Mechanism of action - inhibit neurons in reticular formation - bind GABA CL- channel - Side effects: drowsy, muscle weakness “hangover ”- stored in fat, slow release

Sedative-Hypnotics:

Sedative-Hypnotics 2. Non-Benzodiazepines A. Barbiturates- Phenobarbital ( Solfoton ) - small TI (10) - tolerance, dependency Mechanism of action: - bind GABA A (reticular formation, limbic) - at low doses sensitize GABA receptor - at high doses, act as GABA agonists------ in higher brain centers (anesthesia) Side effects: - “hangover”, muscle weakness,

Sedative-Hypnotics:

Sedative-Hypnotics 2. Non-Benzodiazepines B. Newer medications 1. Zolpidem ( Ambien ) Appear to bind only the Alpha 1 subunit of GABA A Fewer side effects Dependency not a problem?

Sedative-Hypnotics:

Sedative-Hypnotics 2. Non-Benzodiazepines C. Antihistamines Diphenydramine (Benadryl) First Generation drugs enter CNS H1 antagonists (inverse agonists) Anticholinergic side effects Sedation, hypnosis side effect

Psychological Disorders:

Psychological Disorders 1 . Depression and Anxiety: Depression symptoms: - persistant sad, anxious, “empty” - wt loss/gain - insomnia, oversleeping - difficulty concentrating - restlessness, irritability - decreased energy and loss of pleasure - thoughts of death or suicide 5 or more for 2 weeks…..

Drugs to Treat Depression and Anxiety:

Drugs to Treat Depression and Anxiety Mechanisms of Depression: Decreased NE Decreased Serotonin Decreased GABA Increased corticosteroids Decreased DA Animation of Synapse by Harvard emedtv.com/depression-introduction-video

Psych Medications:

Psych Medications Amine Hypothesis- NE, DA, 5-HT

ECT findings….:

ECT findings…. Initial increase in DA Secondary increase in NE 8-10 ECT increase 5-HT

Antidepressant Drugs:

Antidepressant Drugs 1.Tricyclics- Amitriptyline ( Elavil ) Side effects: sedation, anticholinergic , OH, seizures 2. MAO Inhibitors – Phenelzine ( Nardil ) Side effects: restlesness , agitation, anticholinergic

Antidepressant Drugs:

Antidepressant Drugs 3. SSRI- Paroxetine (Paxil ), Sertraline (Zoloft), etc) Side effects: same as tricyclics , but less severe 4. SNRI- Duloxetine ( Cymbalta ) Tremor, anticholinergic , nightmares 5. Dopamine stimulants : Bupropion ( Wellbutrin ) Side effects: tremor, seizure, psychosis

Drugs to Treat Depression:

Drugs to Treat Depression

Anxiety :

Anxiety Fear or apprehension of certain situations Generalized, panic disorder, OCD, posttraumatic stress syndrome

Psychological Disorders:

Psychological Disorders Generalized Anxiety symptoms: Emotional - fear, worry, apprehension Physical - Dyspnea , heart palpitations, chest pain - nausea, stomach ache - etc

Psychological Disorders:

Psychological Disorders Anxiety Causes? Generalized Anxiety Stress response (hypothalamus)- CRF and desensitization Amygdala hypothalamus adrenal ( cortisol ) brain stem (locus ceruleus ) amygdala hypothalamus Vicious cycle. Depletes NE from locus ceruleus . - May trigger depression - Serotonin, GABA also involved

Psychological Disorders:

Psychological Disorders Anxiety (Panic attacks): Physical Symptoms: - same as general anxiety - plus: - trembling, shaking - fear of losing control - hot or cold flashes Emotional Symptoms - desire to escape - avoidance - jumpiness, nervousness - etc

Psychological Disorders:

Psychological Disorders Anxiety Causes? 2. Panic Attacks- Fearful memory (hippocampus) - traffic jam, crowded airplane, bridges Sensory input amygdala hypothalamus adrenal Cortisol , Epinephrine physical symptoms

Antianxiety Drugs:

Antianxiety Drugs 1. Benzodiazepines - Alprazolam ( Xanax )- common - Clonazapam ( Klonopin ) - Diazepam (Valium, etc) - Lorazepam ( Ativan )- nursing homes! Side effects: Sedation, muscle weakness, dependence

Antianxiety Drugs:

Antianxiety Drugs 2. Azapirones - Buspirone ( Buspar ) 5HT agonist Side effects: less sedation, tolerance, dependance 3. SSRI 4. B- antagonist 5. A2- agonist

Antipsychotic Medications (Neuroleptics):

Antipsychotic Medications (Neuroleptics) Psychosis = Group of mental disorders Thought disturbances Impaired perception of reality Schizophrenia most common Familial linkage Dopamine Theory of Psychosis

CNS Disorders - Psych:

CNS Disorders - Psych Psychosis due to excess Dopamine in limbic system Drugs are Dopamine antagonists High Potency Drugs – Haloperidol ( Haldol ) , Loxapine ( Loxitine ). etc Side effects: strongly extrapyramidal , some anticholinergic , sedation, orthostatic hypotension Low Potency Drugs – Chlorpromazine ( Thorazine ) , Thioridizine ( Mellaril , etc) Side effects: strongly anticholinergic , some extrapyramidal , sedation, orthostatic hypotension Atypical Agents- Clozapine ( Clozaril ), Resperidone ( Risperdal ) , Quetiapine ( Seroquel ), etc Selective for dopamine receptors in limbic system Side effects: less frequency and intensity of above Extrapyramidal = dystonia , akathesia , parkinson symptoms, dyskinesias

Bipolar Disorder:

Bipolar Disorder Causes unclear – DA??? Mania = increased neurotransmitter Depression = decreased neurotransmitter TX= stabilize neurons (mostly anti-mania)

Drugs to Treat Bipolar Disorder:

Drugs to Treat Bipolar Disorder Lithium - mechanism unclear - small cation - may mimic Na+ - uncoupling 2nd messengers - enzyme inhibition (protein kinase C) - decrease release NE, DA - increase release of GABA, ACh, 5-HT Side effects: Tremor (fine in low dose, course in high) Muscle weakness, respiratory depression Confusion, lack of concentration, nystagmus

Drugs to Treat Bipolar Disorder:

Drugs to Treat Bipolar Disorder 2. Selective Dopamine Antagonists - Resperidone ( Risperdal ) , etc Inhibit actions of DA Side effects: anticholinergic (less) Parkinsonism (less) Tardive dyskenesia (less) Sedation (less)

Drugs to Treat Bipolar Disorder:

Drugs to Treat Bipolar Disorder 3. Antiseizure Medications- Carbamazepine ( Tegretol ) - blocks Na+ channels Gabapentin ( Neurontin ) - GABA release? Side effects Sedation Fatigue Ataxia

Antiseizure Medications :

Antiseizure Medications

GABA medications:

GABA medications 3 . Valproic Acid ( Depakote ) Side Effects: Dizziness, Drowsiness 4 . Gabapentin ( Neurontin )- 2 nd generation Side Effects: Sedation, muscle weakness, dizziness, confusion

Seizures::

Seizures: Abnormal increase in electrical discharges in the brain - fever - head injuries - low blood sugar - poisoning - drugs - neurological abnormalities

Seizures::

Seizures: Changes in: Body movements (convulsions) Sensory perception Emotions Awareness

Seizures:

Seizures Divided by hemisphere involvment Divided by specific symptoms Seizures of all types usually self-limiting

Slide48:

Complex Partial Seizures (right temporal lobe ) Click on Video Image to view video Absence Click on Video Image to view video Myoclonic Click on Video Image to view video Atonic Click on Video Image to view video

Seizures and Their Treatment:

Seizures and Their Treatment So why treat if seizures are typically self limiting? Injury from falls EKG changes can occur-cardiac arrest Further damage to brain Social Three basic drug mechanisms: 1. GABA 2. Slowing of Na+ channel cycling 3. Antagonizing glutamate

GABA medications:

GABA medications Barbiturates - Phenobarbital ( Solfoton , etc) Side Effects: (tolerance, dependence) Sedation, muscle weakness 2. Benzodiazepines - Clonazepam ( Klonopin ) Side Effects: (tolerance, dependence) Sedation, muscle weakness

Drugs that Slow Recovery of Sodium Channels :

Drugs that Slow Recovery of Sodium Channels 1. Hydantoins - Phenytoin ( Dylantin ) often first choice for partial, tonic- clonic Side Effects: Sedation, dizziness, hirsutism 2 . Iminostilbenes - Carbamazepine ( Tegretol ) Treats all but absence seizure Side Effects: Dizziness, drowsiness, water retention (ADH), CHF, arrhythmia

Slowed Sodium Recovery cont…:

Slowed Sodium Recovery cont… 3. Succinimides - Ethosuximide ( Zarontin ) Side Effects: Sedation, dizziness, hirsutism 4. Lamotrigine ( Lamictal ) – second generation Side Effects: Dizziness, Ataxia

NMDA Inhibitors:

NMDA Inhibitors Second Generation Drugs- initially used as “add-ons” Felbamate-(Felbatol ) Side effects: aplastic anemia, hepatotoxicity Topirimate ( Topomax ) – also inhibits Na + and Increases GABA Side effects: drowsiness, dizziness

Seizures and Their Treatment:

Seizures and Their Treatment Status Epilepticus Series of seizures without recovery period Causes: Sudden withdrawal of anti-seizure medication cerebral infarct Drug withdrawal Tx- IV meds Benzodiazepines Phenytoin If continues, phenobarbital

Movement Disorders: Parkinson’s Disease:

Movement Disorders: Parkinson’s Disease Parkinsons is a progressive disease caused by loss of dopamine neurons from the substantia nigra.

Pathology of Parkinson Disease:

Pathology of Parkinson Disease Neurons from substantia nigra degenerate Results in loss of DA in putamen and caudate nucleus (corpus striatum) Upsets balance of Ach and GABA - other NT involved

Direct Pathway in Parkinson’s:

Direct Pathway in Parkinson’s

Indirect Pathway in Parkinson’s:

Indirect Pathway in Parkinson’s

Etiology of Parkinson Disease:

Etiology of Parkinson Disease Genetic Autosomal dominant Abnormal protein (alpha- synuclein)accumulation May damage mitochondria and cell membrane Oxygen free radicals- steal electrons from pr-

Etiology of Parkinson Disease:

Etiology of Parkinson Disease Environmental - toxins - ex: synthetic meperidine - 20-30 y/o - contaminated with MPTP

CNS Disorders -Movement:

CNS Disorders -Movement Parkinson’s characterized by a number of motor abnormalities, including (in the following order): resting tremor rigidity bradykinesia shuffling gait and imbalance

CNS Disorders -Movement:

CNS Disorders -Movement Treatment : Dopamine Precursors Levodopa - converted to DA by AADC - also converted in periphery - only ~ 1-3% reaches brain

CNS Disorders -Movement:

CNS Disorders -Movement I. Dopamine Precursors 2. Sinemet (combination of l-dopa and carbidopa ) Side effects: - arrhythmias, GI dysfunction (peripheral) - dyskinesia , psychotic like behavior (central) Considerations: - absorption- on-off effect ( dyskinesia vs akinesia ) - loss of effectiveness - timing of therapy sessions

Movement Disorders:

Movement Disorders II. Dopamine Agonists – - selective drugs offer fewer side effects: Pramipexole ( Mirapex ), Ropinirole ( ReQuip ) SE: Nausea, vomiting, confusion, hallucination III. Anticholinergics – Trihexyphenidyl ( Artane ), etc. - help reduce resting tremor and rigidity - adjuvant to l-Dopa drugs SE: confusion, hallucinations, etc.

Movement Disorders:

Movement Disorders IV. MAO-B inhibitors– Selegiline ( Eldepryl ) - blocks the degradation of dopamine - may help slow progression SE: CV effects with certain foods (containing tyramine ), dizziness, sedation V. COMT Inhibitors - Tolcapone ( Tasmar ), etc - usually adjuvant to L- Dopa drugs (more L- Dopa reaches brain) SE: dyskinesias , nausea, dizziness

Movement Disorders:

Movement Disorders VI. Amantadine ( Symmetrel ) - antiviral agent - adjuvant to L- Dopa drugs - reduces dyskinesias - blocks NMDA receptors - reduces action of glutamate SE: OH, depression, confusion, hallucinations

Course of Tx:

Course of Tx When to start sinemet ? Some suggest DA agonists first - may slow progression 3. Add others as needed? No real consensus

Non-Pharmacologic TX:

Non-Pharmacologic TX Stem Cells Deep brain stimulators - globus pallidus - reduce tremor - subthalamic nucleus- all symptoms

Movement Disorders:

Movement Disorders II. Normal Pressure Hydrocephalus(NPH ) 2 forms: 1. Overproduction of CSF – associated with head trauma 2. Blockage in flow of CSF - tumors Symptoms (in order of occurrence) 1. changes in gait and balance 2. urinary frequency and incontinence 3. cognitive disorders Diagnosis: MRI, gait analysis before and after CSF withdrawal Treatment: cerebral shunt – not everyone candidate

NPH:

NPH Know the signs and symptoms Be able to distinguish between NPH and Parkinson’s Call the physician to ask for confirmation ( have they had an MRI?)

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