Unit 1: Nervous System PDF

UNIT 1: Nervous System PHARMACOLOGY III PHPG 4313  Contents Basic understanding of the definition, pathophysiology, causes, sign and symptoms, management and complication of the following disorders: Seizures Parkinsonism Dementia - Alzheimer's Disease...

UNIT 1: Nervous System PHARMACOLOGY III PHPG 4313  Contents Basic understanding of the definition, pathophysiology, causes, sign and symptoms, management and complication of the following disorders: Seizures Parkinsonism Dementia - Alzheimer's Disease Depression Nociception (Central & Peripheral) &Pyrexia UNIT 1 :NERVOUS SYSTEM The Brain An extremely complex organ made up of billions of connections between neurons. These connections are each highly controlled and regulated. UNIT 1 : NERVOUS SYSTEM  Definition A chronic disease involving periodic sudden bursts of electric activity from the brain resulting in seizures - a periodic attack of disturbed cerebral function. - Abnormal central nervous system electrical activity. Convulsion: Sudden attack of involuntary muscular contractions and relaxations. Epilepsy: A group of recurrent disorders of cerebral function characterized by both seizures and convulsions  What is a Seizure? A seizure is “a brief, temporary disturbance in the electrical activity of the brain” and may affect: Muscle control and movement Speech Vision and/or eye movement Awareness and/or behaviour Seizures can be: Convulsive or non-convulsive Vary in frequency and severity Source: BC Epilepsy Society  Seizures vs. Epilepsy What is the difference? Seizures Epilepsy Often symptoms of another health A chronic (ongoing) series of problem: seizures, and can develop at any diseases age. fever Seizures reoccur frequently and temporary medical, neurological or often without a known cause. neurosurgical illness After the person is treated (illness is resolved) the seizures do not occur again  Epilepsy Neurological disorder that makes people susceptible to seizures Sometimes called a seizure disorder Can develop at any age Seizures are chronic (ongoing and frequent) Seizure can often happen without known cause Many people with epilepsy experience more than one type of seizure.  Why Do Seizures Occur? HEAD INJURY BIRTH INJURY MVAs, Sports accidents Brain injury to fetus during Falls pregnancy & birth Head trauma Perinatal asphyxia Postnatal vascular accidents INTRACEREBRAL INJURIES Tumours CONGENITAL DISORDERS Strokes METABOLIC DISORDERS INFECTION Meningitis HEREDITY FEVER Viral encephalitis Inherit different degrees Measles, Mumps of susceptibility to seizures Diphtheria Unit 1 : Seizures Some warning signs of possible Causes (triggers) seizures may include: Odd feelings, often indescribable Missed dose of medication Unusual smells, tastes, or feelings Sleep deprivation Unusual experiences – "out-of-body" sensations; Illness feeling detached; body looks or feels different; Stress, anxiety, overstimulation situations or people look unexpectedly familiar or strange Hormonal changes Feeling spacey, fuzzy, or confused Alcohol and drugs of abuse Periods of forgetfulness or memory lapses Hyperventilation Daydreaming episodes Flashing lights Jerking movements of an arm, leg, or body Temperature extremes Falling dehydration Tingling, numbness, or feelings of electricity in part of the body Headaches Unexplained confusion, sleepiness, weakness Losing control of urine or stool unexpectedly  Types of Seizures Focal (partial) GENERALIZED Occurs in PART of the Occurs in the WHOLE brain brain Simple Partial Tonic Atonic Complex Partial Tonic-clonic Myoclonic Absence https://www.youtube.com/watch?v=MZBGNVlaa2s  Pathophysiology Characteristic A prime characteristic of epilepsy is recurrent seizures brought on by abnormal electric activity of the brain. Type These attacks may vary from brief and mild episodes known as absence (petit mal) seizures to major tonic clonic (grand mal) seizures with loss of consciousness, convulsion (intervals of violent involuntary muscle contractions), and sensory disturbances. Duration In other cases (psychomotor seizures), there is a 1- to 2-minute period of disorientation. Causes Epilepsy may be the result of a tumor, injury, or neurologic disease, but in most cases the cause in unknown. Diagnosis Electroencephalography (EEG) studies reveal abnormalities in brain activity and can be used in diagnosis and treatment of epilepsy. The disorder is treated with antiepileptic and anticonvulsive drugs to control seizures, and sometimes surgery is of help. If seizures cannot be controlled, the individual with epilepsy may have to avoid certain activities that can lead to harm. Detailed history and physical examination EEG, video EEG Imaging ( CT, MRI, PET)  10-second EEGs: Seizure Evolution Normal Pre-Seizure Seizure Post-Seizure Nerve Cell Communication Neurons communicate between themselves using small molecules called neurotransmitters. Sodium Ions/Channels These neurotransmitters modulate and Potassium Ions/Channels regulate the electrical activity of a given neuron, and tell it when to fire an action potential or when not to. - Glutamate = excitatory (tells the neuron to fire) - GABA = inhibitory (dampens the neuron firing rate) The action potential is an electrical signal that travels down the axon, and is created using Action Potential sodium ions (Na+), and inhibited by potassium ions (K+). Usually these processes work synergistically to produce normal behavior and activity. When dysfunctional, abnormal electrical activity occurs and can produce seizures. SEIZURE  Signs of a Seizure Extended blank stare Uncontrollable jerking body movements "Empty" look in eyes Mouth movements with a dazed look Rapid blinking Frothing at mouth Eyes rolling upward Loss of consciousness Periods of unresponsiveness Loss of body control Inability to pay attention Dazed walking Repetitive (tic-like) movements of body parts, usually head, arms, legs Temporary confusion Source: BC Epilepsy Society Type of Seizure TYPES OF SEIZURES A. Focal Focal seizures involve only a portion of the brain, typically part of one lobe of one hemisphere. The symptoms of each seizure type depend on the site of neuronal discharge and on the extent to which the electrical activity spreads to other neurons in the brain. Focal seizures may progress to become generalized tonic–clonic seizures. 1. Simple partial: These seizures are caused by a group of hyperactive neurons exhibiting abnormal electrical activity and are confined to a single locus in the brain. The electrical discharge does not spread, and the patient does not lose consciousness or awareness. The patient often exhibits abnormal activity of a single limb or muscle group that is controlled by the region of the brain experiencing the disturbance. The patient may also show sensory distortions. This activity may spread. Simple partial seizures may occur at any age 2. Complex partial: These seizures exhibit complex sensory hallucinations and mental distortion. Motor dysfunction may involve chewing movements, diarrhea, and/or urination. Consciousness is altered. Simple partial seizure activity may spread to become complex and then spread to a secondarily generalized convulsion. Complex partial seizures may occur at any age  Partial (focal) Seizures Excessive electrical activity in one cerebral hemisphere. - Affects only part of the body. Simple Partial: Person Complex Partial: may experience a range ○ Loss of awareness at of strange or unusual seizure onset. Person sensations. seems dazed or ○ Motor confused and exhibits ○ Sensory meaningless ○ Autonomic behaviors. ○ Key feature: ○ Typically originate in preservation of frontal or temporal consciousness. lobes (e.g. Temporal lobe epilepsy) TYPES OF SEIZURES B. Generalized Generalized seizures may begin locally and then progress to include abnormal electrical discharges throughout both hemispheres of the brain. Primary generalized seizures may be convulsive or nonconvulsive, and the patient usually has an immediate loss of consciousness. 1. Tonic–clonic: These seizures result in loss of consciousness, followed by tonic (continuous contraction) and clonic (rapid contraction and relaxation) phases. The seizure may be followed by a period of confusion and exhaustion due to the depletion of glucose and energy stores. 2. Absence: These seizures involve a brief, abrupt, and selflimiting loss of consciousness. The onset generally occurs in patients at 3 to 5 years of age and lasts until puberty or beyond. The patient stares and exhibits rapid eye-blinking, which lasts for 3 to 5 seconds. An absence seizure has a very distinct three-per-second spike and wave discharge seen on electroencephalogram. 3. Myoclonic: These seizures consist of short episodes of muscle contractions that may recur for several minutes. They generally occur after wakening and exhibit as brief jerks of the limbs. Myoclonic seizures occur at any age but usually begin around puberty or early adulthood. 4. Clonic: These seizures consist of short episodes of muscle contractions that may closely resemble myoclonic seizures. Consciousness is more impaired with clonic seizures as compared to myoclonic. 5. Tonic: These seizures involve increased tone in the extension muscles and are generally less than 60 seconds long. 6. Atonic: These seizures are also known as drop attacks and are characterized by a sudden loss of muscle tone Generalized Seizures Excessive electrical activity in both cerebral hemispheres. Usually originates in the thalamus or brainstem. Affects the whole body. Loss of consciousness is common. Generalized Seizures Myoclonic: Brief shock-like muscle jerks generalized or restricted to part of one extremity. Atonic: Sudden loss of muscle tone. Tonic Seizures: sudden stiffening of the body, arms, or legs Clonic Seizures: rhythmic jerking movements of the arms and legs without a tonic component Tonic-clonic (grand mal): ○ Tonic phase followed by clonic phase http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/19076.jpg Generalized Seizures Absence (petit mal): Person appears to “blank out” - “Daydreaming” ○ Simple Absence (primarily effects consciousness only) ○ Complex Absence ○ Atypical Absence (Includes physical symptoms like eye blinking or lip movements) Lenox-Glastaut Syndrome. ○ Atypical absence, atonic and myclonic Status Epilepticus: A seizure lasting longer than 30 min, or 3 seizures without a normal period in between ○ May be fatal ○ Emergency intervention required Unit 1 : Seizures manage ment and complic ation of the followin g disorder s:  Antiseizure drug Anti-seizure drugs are classified into five groups, which include: barbiturates benzodiazepines hydantoins phenytoin-like agents succinimides. Phenytoin is the most recognizable and most used drug in the class of hydantoins. The newest drug in this class is fosphenytoin. Phenytoin is used for tonic-clonic and psychomotor seizures. Fosphenytoin is used for control of status epilepticus. Phenytoin-like drugs are useful for a wide range of seizure types, including absence seizures and mixed types of seizures. Antiseizure drug Antiseizure drug is to suppress / prevent abnormal or repetitive firing. There are three mechanisms by which antiseizure drugs act : ○ Stimulating an influx of chloride ions ○ Delaying an influx of sodium ○ Delaying an influx of calcium Antiseizure drug Mechanisms of action of anticonvulsants Inhibition of sodium channels Carbamazepine, lamotrigine, valproate, phenytoin and topiramate act by producing a use‐dependent block of neuronal Na+ channels. Their anticonvulsant action is a result of their ability to prevent high‐frequency repetitive activity. The drugs bind preferentially to inactivated (closed) Na+ channels, stabilizing them in the inactivated state and preventing them from returning to the resting (closed) state, which they must re‐enter before they can again open (see Chapter 5). High‐frequency repetitive depolarization increases the proportion of Na+ channels in the inactivated state and, because these are susceptible to blockade by the antiepileptics, the Na+ current is progressively reduced until it is eventually insufficient to evoke an action potential. Neuronal transmission at normal frequencies is relatively unaffected because a much smaller proportion of the Na+ channels are in the inactivated state. Delaying an influx of sodium Sodium movement is the major factor that determines whether a neuron will undergo an action potential. If these channels are temporarily inactivated, neuronal activity will be suppressed.  Mechanisms of action of anticonvulsants Enhancement of GABA action Vigabatrin is an irreversible inhibitor of GABA‐transaminase, which increases brain GABA levels and central GABA release. Tiagabine inhibits the reuptake of GABA, and by increasing the amount of GABA in the synaptic cleft, increases central inhibition. The benzodiazepines (e.g. clobazam, clonazepam) and phenobarbital also increase central inhibition, by enhancing the action of synaptically released GABA at the GABAA receptor–Cl− channel complex (Chapter 24). Phenobarbital may also reduce the effects of glutamate at excitatory synapses. Valproate also seems to increase GABAergic central inhibition by mechanisms that may involve stimulation of glutamic acid decarboxylase activity and/or inhibition of GABA‐T.  Stimulating an influx of chloride ions Gamma-aminobutyric acid (GABA) is the inhibitory neurotransmitter in the brain. GABA receptor is the receptor that operate the chloride channel. Antiseizure drugs act by mimic the effects of GABA by stimulating the GABA receptor. When the receptor is stimulated, chloride ions move into the cell, thus suppressing the ability of neurons to fire. Barbiturates, benzodiazepines, and several miscellaneous drugs reduce seizure activity by this mechanism. Mechanisms of action of anticonvulsants Inhibition of calcium channels Absence seizures involve oscillatory neuronal activity between the thalamus and cerebral cortex. This oscillation involves (T‐type) Ca2+ channels in the thalamic neurones, which produce low threshold spikes and allow the cells to fire in bursts. Drugs that control absences (ethosuximide, valproate and lamotrigine) reduce this Ca2+ current, dampening the thalamocortical oscillations that are critical in the generation of absence seizures. Delaying an influx of calcium Antiseizure drugs delay the entry of calcium into neurons by blocking calcium channels and this will increase the electrical threshold. If the electrical threshold is increased, the possibility of abnormal firing decreases and seizures are less likely to occur. References Lippincott Illustrated Reviews: Pharmacology Sixth Edition Fundamental Pharmacology for Pharmacy Technicians by Jahangir Moini Medical Pharmacology at a Glance Eighth Edition Michael J. Neal