Module 6 - Neurology

• Neurologically active drugs are important in advanced pharmacology for anesthesiology practice.

Anti-Parkinsonian Drugs

• Anti-Parkinsonian drugs are used to treat Parkinson's Disease symptoms like masked face, stooped posture, rigidity, and short-stepped gait.

Movement Disorders

• Movement disorders are a category of neurologic disorders
• Movement disorders are classified as Parkinson's disease or hyperkinetic disorders causing increased movement.
• Hyperkinetic disorders include myoclonus, tremor, dystonia, and tics
• Parkinson's is classified as decreased or slow movement

Movement Disorders Types

• Voluntary movement is affected in movement disorders.
• The corticospinal (pyramidal) tracts deal with voluntary movement.
• The cerebellum is the motor coordination center.

Extrapyramidal System Details

• The extrapyramidal system includes the pons, medulla, and lower motor neurons in tracts.
• It modulates the basal ganglia, cerebellum and directs output through the thalamus to the cerebral cortex which all impact voluntary movement
• The basal ganglia include structures like the subthalamic nucleus, globus pallidus, and substantia nigra.
• Actions and functions include reflexes, locomotion, complex movements, and postural control.
• Neural lesions can cause extrapyramidal movement disorders.

Parkinson's Disease

• Parkinson's Disease (PD) is a slowly progressive, degenerative disorder.
• Notable characteristics include resting tremor, stiffness, rigidity, and gait/postural instability.
• Gait and postural instability are related to slow and decreased movement.
• It is usually idiopathic, but genetic predisposition is possible.
• The mean age of onset is 57 years.
• Juvenile parkinsonism begins in childhood or adolescence, while early-onset can occur from 21-40 years.

Pathophysiology of Parkinson's Disease

• Synuclein, a neuronal and glial cell protein, aggregates and leads to cell death.
• These aggregates accumulate in the nigrostriatal system.
• Degeneration and loss of substantia nigra neurons results in dopamine depletion in the basal ganglia.
• A balance between dopamine and acetylcholine is necessary
• Dopamine inhibits activity in the extrapyramidal system while acetylcholine is excitatory.
• Loss of the inhibitory action and the overproduction of excitatory activity impact proper function.
• Approximately 80% of the brain's dopamine is in the basal ganglia
• dopamine may be as low as 10% of normal in PD.
• Excess excitatory cholinergic activity leads to progressive tremor, muscle rigidity, bradykinesia, and postural disturbances.

Treatment for Parkinson's Disease

• Options include pharmacological and surgical treatments.
• Pharmacological treatments aim to restore dopaminergic function with drugs like Levodopa, Carbidopa, and Dopamine agonists.
• MAO-B inhibitors and Amantadine are also used as pharmacological treatments
• Surgical treatments include stereotactic deep brain stimulation.
• Stereotactic deep brain stimulation targets various areas
• Targets include: thalamas, subthalamic nucleus, and Globus Pallidus
• Lesional surgery is another surgical option.

Anesthetic Considerations

• Autonomic dysfunction, including orthostatic hypotension and poor temperature control, needs to be considered.
• Other considerations: sialorrhea, maintain volume status, pulmonary dysfunction and bradykinesia, and rigidity of respiratory muscles.
• Swallowing impairment and dysphagia are anesthetic considerations.
• Bradykinesia and rigidity of the pharyngeal muscles may be exacerbated by ET intubation.
• There is a risk for aspiration, cognitive impairment, and postop complications

Anesthetic Considerations Details for the Surgeon

• Staged procedures may use MAC, local anesthesia + awake, or GETA (General Endotracheal Anesthesia).
• GABA inhibition in basal ganglia worsens or may abolish microelectrode recordings (MER).
• Medications should be discontinued 15 minutes before MER.
• Dexmedetomidine may abolish MER as well as cause hypotension and paradoxical agitation.
• Propofol depresses neuronal discharge and may induce dyskinesias.
• Fentanyl and remifentanil may worsen rigidity and suppress tremor.
• Benzodiazepines may abolish MER, suppress tremor, and also induce dyskinesias.
• Beta blockers should be avoided if tremors are tested.

Levodopa

• Levodopa as a dopamine precursor, is converted by enzymes to dopamine in the basal ganglia.
• Dopa decarboxylase converts Levodopa.

Levodopa Pharmacokinetics

• 95% of levodopa is rapidly converted to dopamine during the first hepatic pass.
• Dopamine cannot easily cross the blood brain barrier (BBB).
• Results in elevated plasma levels leading to side effects
• Metabolites are converted to dopamine and then homovanillic acid.
• Requires adequate levels of COMT and methionine from diet to metabolize excess catecholamines.

Levodopa/Carbidopa Use

• Medication inhibits decarboxylase in tissues.
• Levodopa is combined with a decarboxylase inhibitor.
• This inhibits levodopa breakdown.
• This maximizes levodopa amount reaching the brain before the bodies converts Levodopa to dopamine
• Allows for lower levodopa doses overall

Levodopa Adverse Effects

• Gastrointestinal adverse effects can occur, such as nausea and vomiting (N/V).
• Nausea and vomiting is due to dopamine stimulation of the CRTZ Chemoreceptor trigger zone
• Avoid dopamine-antagonist antiemetics (eg, promethazine, metoclopramide).
• Carbidopa may reduce nausea and vomiting.
• Endocrine side effects may occur.
• Levodopa inhibits prolactin secretion and increases aldosterone secretion

Levodopa Additional Adverse Effects

• Cardiovascular effects include adrenergic receptor activation from dopamine, epinephrine, and norepinephrine.
• Increased inotropy, orthostatic hypotension (autonomic dysfunction), tachycardia, PVCs/PACs, Afib, VTach, and skin flushing may also occur
• Neuromuscular effects include abnormal involuntary movements, facial tics, grimacing, rocking movements of extremities or trunk, irregular gasps (diaphragmatic dyskinesia), and changes in mobility
• Psychiatric adverse may occur.
• Examples: Hallucinations, paranoia, and impulsive/compulsive behavior

Levodopa Potential Interactions

• Parkinsonism-Hyperpyrexia Syndrome is a life-threatening emergency related to abrupt withdrawal or dose reduction.
• This resembles neuroleptic malignant syndrome NMS
• Parkinsonism-Hyperpyrexia Syndrome can include pyrexia, autonomic instability, and depressed consciousness. Risks
• Risks include DVT/PE, renal failure, and aspiration PNA.
• Treatment includes administration of antiparkinsonian therapy (Levodopa PO or NGT) and supportive measures

Levodopa Drug Interactions

• Antipsychotic drugs can antagonize the effects of dopamine.
• MAOIs can interfere with the inactivation of dopamine.
• Can cause a hyperthermia common effects
• Anticholinergic drugs can improve symptoms through synergism.
• Vitamin B6 can enhance decarboxylase activity (levodopa metabolism).

Dopamine Agonists

• Options include bromocriptine, pramipexole, ropinirole, and rotigotine.
• They mimic dopamine at receptors and are synthetic.
• These drugs do not require transformation or need to transport across the BBB.

Dopamine Agonist Side Effects

• Adverse effects can occur such as hallucinations, dyskinesia, pulmonary fibrosis, vertigo, and nausea.

Amantadine

• Amantadine is an antiviral medication for influenza A prophylaxis that also improves PD symptoms, especially muscle rigidity and bradykinesia.
• Amantadine may increase the release of dopamine DA and delay DA reuptake in the basal ganglia, with possible anticholinergic effects and action as a glutamate antagonist.
• Adverse effects can include peripheral edema, confusion, and psychosis.

Monoamine Oxidase-B (MAO-B) Inhibitors

• MAO-B breaks down dopamine in the CNS.
• Selegine is a highly selective and irreversible inhibitor that doesn't alter peripheral metabolism of norepinephrine.
• Adverse effects can include insomnia, confusion, hallucinations, and paranoia.
• Rasagiline is a MAO-A and MAO-B inhibitor.

COMT Inhibitors Use

• Catechol-O-methyltransferase is partially responsible for the peripheral breakdown of levodopa.
• COMT inhibitors block enzyme activity in the GI tract, slowing the elimination of carbidopa-levodopa.
• Examples: Tolcapone, entacapone.
• Adverse effects can include worsened dyskinesias, nausea, diarrhea, hepatotoxicity (rare), and rhabdomyolysis.

Anticholinergic Drugs

• Examples include Benztropine and trihexyphenidyl.
• These block ACh effects and correct the balance ACh and Dopamine DA.
• Controls tremor and decreases excess salivation, with minimal effect on muscle rigidity and bradykinesia.
• Adverse effects include confusion, hallucinations, sedation, mydriasis, ileus, and urinary retention.

Diphenhydramine

• Diphenhydramine is a histamine receptor antagonist with anticholinergic effects.
• Useful for symptom control and acute Parkinsonian crisis management.
• 50 mg IV may be given perioperatively

Anesthetic Considerations when Preparing for Surgical Procedures

• Anti-parkinsonian drugs should not be held preop; abrupt withdrawal can increase motor symptoms.
• Usually held morning of surgery for deep brain stimulation.
• Avoid phenothiazines and dopamine antagonists for prevention and treatment of nausea and vomiting post-op.

Other Considerations

• CNS activity concerns include altered mental status, confusion, hallucinations, somnolence, insomnia and Involuntary movements.

Parkinson's, Visualized

• MAO-B inhibitors preserve existing dopamine.
• COMT inhibitors preserves levodopa.
• Dopamine agonists mimic dopamine.
• Levodopa replaces dopamine.

Seizure Disorders

• Seizure disorders include various types of epilepsy.
• A seizure is an abnormal, unregulated electrical discharge from the cortical gray matter causing transient Brain function interruption
• Clinical assessment, neuroimaging, laboratory testing, and EEG is critical

Seizures

• Head drop or head twitch, shaking, eye movements, and blinking
• Stiff body and staring off, Possible loss of consciousness, altered awareness focal involuntary movements Convulsions
• Occur in 2% of adults

Types of Epilepsies

• Febrile illness or birth conditions/trauma
• Idiopathic (ages 2-14): Unknown (50%)
• Cerebral trauma, alcohol withdrawal, etc.

Epilepsy Info

• Chronic brain disorder
• Can be genetic
• 2+ non-stress driven seizures
• 24 hrs + apart

Aura

• May precede seizure
• Sensory, autonomic, or psychic sensation or motor activity
• Postictal state post symptoms can include:
  • Deep sleep for several hours
  • Headache
  • Confusion fatigue
  • Muscle soreness generalized sz

Seizure Duration and Neurology

• Most appear neurologically normal between seizures
• AED's can provide sedation

Perioperative Considerations for Seizures

• Major sz during the perioperative period - increases morbidity mortality..
• Known cause? Treat metabolic disturbances, ETOH withdrawal, etc

Admin of AES Drugs

• Fosphenytoin, Levetiracetam, valproic acid AEDs

Factors associated with increased Sz Risk

• ̄Sleep-wake pattern changes with anesthesia
• Electrolyte abnormalities
• Hypoglycemia
• Medication changes
• Age
• Hypoventilation
• PaO2, Paco2, PH, Na, Ca/ K channel problems -Stress - Fatigue etc

Anesthetic Considerations of AESs

• Hypoalbuminemia AEDs are high unbound
• Hepatic P450 increases doses of propofol/thiopentyl, midazolam opioids

Antiseizure Medication Information

• Goal:
• Decrease neuronal excitability or enhance inhibition Alter Na, K, Ca currents across mm -Alter synaptic inhibitory NTs

Overview of AESs

• Treats: Tonic-clonic - Partial seizures, Absence, Broad spectrum

Benzodiazepine Details

• Treats acute seizures - Status - ETOH withdrawal AE is a sedative can cause incoordination or personality change AED's must be slowly tapered off

Phenobarbital Details

• Long acting with many adverse effects such as mental impairment and respiratory depression
• GABA mediated

Gabapentinoid Details

• Structurally related to GABA treats many pain disorders

Levetiracetam Details

• Doesnt need level monitoring

Valproic Acid Details

• Treats all generalized Epilepsies Adverse effect liver and can cause teratogenicity

Phenytoin Details

• Treats Partial Generalized
  • Dose to effect
  • Slow administrations
• Black box warning - risk HOTN, arrhythmias (asystole) 70: 12/4/24: PHENYTOIN (DILANTIN) : • Adverse Effects Peripheral neuropathy Gingival hyperplasia Inhibition of insulin secretion → hyperglycemia (>20 mcg/mL) Hepatotoxicity Skin reactions Increased metabolism of NDMRs Mild blocking effects at NMJ, upregulation of ACh receptors Increased dose requirements σ 71: 12/4/24: CARBAMAZEPINE (TEGRETOL) : • MOA Stabilizes Na channels in inactivated state Neurons less excitable • Adverse effects Liver dysfunction Thrombocytopenia Dizziness, vertigo N/V • Black box warning - fatal dermatologic reactions, σ 72: 12/4/24: LAMOTRIGINE (LAMICTAL) : • MOA Inhibits release of Inhibits (stabilizes) voltage-gated Na channels • Adverse Effects Black box warning - severe, life-threatening rashes (eg, SJS) Dizziness Diplopia, blurred vision HA Sedation Ataxia 73: 12/4/24: ETHOSUXIMIDE (ZARONTIN) : • Drug of choice for absence (petit mal) epilepsy • MOA Block voltage-gated Ca2+ conductance in thalamic neurons • Adverse effects GI intolerance (N/V) Lethargy, dizziness, ataxia Hyponatremia Bone marrow suppression MEMORYMASTER KNOWLEDGE CHECK