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156 Cards in this Set

  • Front
  • Back
Endogenous opioid Peptides system
The system in the human body, that senses and attenuates pain. Also the system putatively responsible for the "runners high" and the "placebo effect"
The pain sensation pathway
complex constellation of unpleasant sensory, emotional and cognitive experiences provoked by real or perceived tissue damage and manifested by certain autonomic, psychological and behavioral reactions
Nociception
Receptor-mediated awareness of potentially damaging stimulus (thermal, chemical, mechanical)
- not necessarily experienced as pain
- this is the SENSORY component
Pain
Perception of the unpleasant sensation
- involves affective processing of sensory input (i.e. expectations, memories, etc)
-involves the sensory + emotional components
-this emotional coponent makes pain unique from other sensing
3 types of pain
Protective
Hypersensitivity
Malfunctioning
Withdrawal (protective) pain
-noxious stimuli (heat, cold, intense mechanical force, chemical irritants) detected by peripheral neuron
-travel though spinal cord and tells you to quit doing what you are doing that is causing the pain
Hypersensitivity Pain
-Inflammatory Pain (peripheral inflamation positive symptoms)
-Inflammation or Tissue damage already there (surgical wound etc) don't touch it anymore because we don't need to damge it anymore needs to heal
Malfunctioning Pain
-nerves are firing which makes you feel pain even though it doesn't exist
-pathological, dysfunctional neurons
3 Essential steps to the pain detection
1. Transduction- the induction of the pain message
2. Transmission- The movement of the pain message through the CNS
3. Modulation and Perception- Response to the Pain
Nociceptor
-a primary afferent neuron that demonstrates selective sensitivity to noxious stimuli
-polymodal= respond to a wide range of stimuli
Noxious
-a tissue damaging stimuli
Mechanical: pinching, cutting, stretching
Thermal: heat, cold
chemical: Mediators released upon tissue damage (bradykinin, histamine, serotonin, prostaglandins, luekotrienes)
Polymodal: respond to al lof the above stimuli (almost always associated with slow tonic pain)
Tranduction Nociceptor Facts
Nociception: the detection of damage by nociceptors
-not spontanously active
-level of stimulation must exceed threshold
-activates action potential
-may become sensitzed
- most other receptors become desensitized
-due to repeated or prolonged stimulation, especially by chemical mediators
-causes hyperalgesia and could cause allodyni
Hyperalgesia
increased sensitivity to pain burn yourself in same spot again hurts worse
Allodynia
pain sensation where it normally shouldn't be sunburn touch yourself hurts later
Nociceptors attached to
A delta and C peripheral nerve fibers
Opium
-dried milky juice from capsules of Papaver soniferum- a brown mass which can be ground to a powder
-contains 23 alkaloids
-good grade opium has 9-14% morphine, and .5-2% codeine
-pain relief of opium was discovered long before the endogenous system that act as surrogates to endogenous opiate system
Uses for opioids
- decrease pain: analgesia w/oloss of consciousness, hallmark of opiods-patient continues to experience pain, but is comfortable, i.e. patient experiences euphoria, mental clouding, and drowsiness
-decreased cough
How opioids work
-opiod peptides and drugs produced their effects by actions at opiod receptors (mu, kappa and delta) all of which have subtypes
-endogenous opioids and opioid drugs share many of the same pharmacological properties by acting as agonists at the same receptors
-exogenous opioids that act on mu receptors can induce release of endogenous opioids that act on kappa and delta receptors
Mu receptor
-opiod receptor
-analgesia is surpaspinal/spinal
-intense respiratory depression
-constipation
-euphoria sedation
-intense positive reinforcement
-endogenous ligands: endorphins>enkephalins, >dynorphins
Delta Receptor
-opioid receptor
-analgesia spina/suprapinal
- +/- respiratory depression
-no constipation
-behavioral effects: euphoria
-no positive reinforcement
-endogenous ligands: enkephalins>endorphins>dynorphins
Kappa Receptors
-analgesia is spinal/supraspinal
-some respiratory depression
-constipation
-behavioral effects: dysphoria and sedation
-some positive reinforcement
- endogenous ligands: dynorphins>>endorphins and enkaphalins
Effects of Opioids: Central Nervous System
-Analgesia: decreased sensitivity to painful stimuli
-altered perception of both intensity of stimulus and associated unpleasantness (emotion and sensing as oppose to aspirin)
-euphoria : sense of well-being, decrease and anxiety and distress but may also induce restlessness and malaise (dysphoria)
-Sedation: drowsiness without amnesia: unclear thinking, in high enough doses can cause loss of consciousness
-Cough suppression: depression of cough reflex (brainstem), can lead to buildup of fluid and collapsed lung
-miosis : pinpoint pupils
-nausea and vomiting
Respiratory Depression
-most difficult to manage for chronic pain treatment
-inhibits brainstem respiratory mechanisms
-measured as depress response to CO2 challenge
-important to remember in individuals with chronic breathing disorders (asthma, COPD etc)
Effects of Opioids: Peripheral effects
-cardiovascular: no major effects outside of bradycardia (merperdine is exception) May cause hypotension particularly in cases of blood loss
-GI tract: constipation because opioid receptors are present in high concentration in the GI. Leads to rythmic contraction deceases, propulsive peristaltic waves are diminished in the large intestine
*Partial agonists can cause complete impaction of bowels
-Pruritus: may cause sweating and itching, flushing and warming of skin
Tolerance of Opioids
-frequent use of opiates leads to a loss of effectiveness=tolerance
-tolerance requires larger doses to be given
-thought to be due to a persistent activation of mu receptors which inhibits their internalization and recycling, therefore they can NOT be continually activated and inhibit release of neurotransmitters
-Persistent administration can lead to hyperalgesia - an increase in the sensation of pain
Dependence
-physical dependence (defined as having a withdrawal syndrome when discontinued) also develops
-few become addicted but relapse is common among addicts
Withdrawal Symptoms
-runny nose,tearing,chills,goosebumps,rapid breathing, hyperthermia ,dilated pupils, muscular aches, vomiting diarrrhea, anxiety, and hostility
-withdrawal peaks at ~2 days and is over in ~5 days
Opioid Analgesics:Clinical Uses
-frequently used as a premedicant before surgery because of sedative properties
-commonly used in cardiovascular surgery where cardiovascular depression must be minimized-but respiratory assistance must be provided
-severe pain, cough suppressant, labor pain (epidural), pain of kidney stones and gallstones, relief of dyspnea (shortness of breath) and painful myocardial ischemia from pulmoary edema
-pain associated with cancer and other terminal illnesses
-diarrhea
-oral partial agonists are frequently administered follow extraction for a few days of use
Pharmacokinetics
-well absorbed (subQ, IM, oral)
-substantial first pass effect orally
-certain opioids (codeine, oxycodone) have reduced first pass metabolism
-concentrate in highly perfused tissues -brain, liver, lung, kidneys, spleen. Drug amounts in muscle are much lower
-converted to polar metabolites and excreted by the kidneys
Cautions to Therapy
-using pure agonists and weak partial agonists there is a risk of diminishing analgesia and inducing withdrawal state.
-Head Injuries -respiratory depression can lead to cerebral vasodilation and in pts with increased intracranial pressure this could be lethal to brain function
-pregnancy- fetus may become physically dependent and manifest withdrawal symptoms
-in pts with impaired pulmonary function may lead to acute respiratory failure
Drug interactions
-sedative/hypnotics: increased CNS depression, particularly respiratory repression
-anti-psychotic tranquilizers: increased sedation, variable effects on respiratory depression, accentuation of cardiovascular effects
-monoamine oxidase inhibitors : high incidence of hyperpyrexic coma, hypertension
Subclasses of Opioid Analgesic Drugs
-strong agonists
-mild to moderate agonists
-opioids with mixed actions
-antitussives
-opioid antagonists
Strong Agonists: Key points
-strong mu receptor, variable for gamma and kappa receptors
-produce analgesia, anxiety relief, sedation and slowed GI transit
-used for severe pain, pulmonary edema, heroin rehab
-subject to first pass effect and duration 1-4 hours (methadone 4-6)
-sides effects include respiratory depression, severe constipation, addiction liability and convulsion
Stong Agonists Classes
-phenanthrenes
-phenlyheptylamines
-phenlpiperdines
-morphinans (levorphanol is similar to morphine)
Phenanthrenes
-morphine, hydromorphine, oxymorphine, heroin
-slowly and erratically absorbed, making dosing difficult
-considerable first-pass effect -absorbed at high amount
-crosses BBB slowly
-half life is ~2hours
-prompt analgesic effects when M is given I.V.
Heroin
-crosses BBB more rapidly than morphine
-binds poorly to mu receptors
-requires metabolic activation within the body
-converted within brain to 6 MAM and morphine
-can drug test within 3-5 hours to find the 6-MAM in the urine
Phenylhaptylamines
-methadone
-effective orally, IV, subQ, spinal, rectal, bioavailablity greater than morphine
-potent mu opioid recptor agonist
-also blocks NMDA (glutamate, excitatory) receptors and monamine reuptake transporters (dopamine, Norepinephrine, serotonin) and thus may be effective when other opioids have failed.
-major use is in the treatment of opioid abuse because it causes no euphoria
-stored long term in tissues to allow for sustained release
Phenylpiperdines
-fentanyl-most widely used, among this group are sufentanil, alfentanil, remifentanil
-mu agonist, 100 times more potent that morphine
-popular in anesthesia, given IV rapid recovery
-peak analgesia in ~5min; CV effects are minimal
-gives same morphine like unwanted effects
-choice of agent is dependent on desired effects: Sufentanil is more potent that fentanyl while alfentanil is more rapid with shorter duration and remifentanyl has a very short half-life
Phenylpiperidines
-Merperidine (demerol)
Meperidine (Demerol)
-identical to M in analgesia and other effects
-preferred during labor (does not require glucuronidation for elimination)
-shows same disposition in newborn as in mother
-unlike other opioids, merperidine causes restlessness rather than sedation
-can cause tachycardia
-includes anticholinergic effects (dry mouth etc)
Meperdine-overdose syndrome
-includes restlessness, hallucinations, convulsions
-metabolite, nor-meperdine, is though to be responsible for the syndrome
Meperdine - MAOI syndrome
-can be lethal
-excitement, convulsions, hyperthermia > coma> death
-given these side effects, demerol use as a first-line analgesic is increasingly rare
Mild to moderate Opioid agonists
-essentially similar to strong agonists with lesser effects of analgesia and sedation
-used for mild to moderate pain and cough
-toxicity is similar to strong agonists
Mild to moderate Opioid agonist types
-phenanthrenes:codeine, oxycodone, dihydrocodeine, hyrocodone
-phenylheptylamines: propoxyphene (darvon)
-phenylpiperidines: diphenoxylate (dimotal), difenoxin, loperamide (immodium)
Phenanthrenes
-codeine, oxycodone, dihydrocodeine, hydrocodone
-somewhat less effective than morphine as analgesics
-prescribed following molar extraction to manage pain
-usually used in combination with aspirin acetaminophen (tylenol) ibuprofen etc
-Hydrocodone APAP (vicodin) hydrocodone+acetaminphen
Hydrocodone APAP
-vicodin
-can be habit forming
-has a serum half life of 3.8 hrs
-metabolized to hyromorphone by CYP2D6
-should not be mixed with alcohol (hepatotoxicity) codeine, amphetamines, barbituates
-Adverse events include dizziness, itching, nausea, drowsiness, constipation, vomiting, euphoria
-percoset = oxycodone + acetaminophen
-vicodin is a frequent drug of abuse
Phenylheptylamines
-propoxyphene (Darvon)
-chemically related to methadone, .3-.5 lower analgesic power than codeine
-inhibits cardiac Na+ channels> cardiac arrhythmias
-packages carries a black box warning due to low efficacy and adverse events
-drug of choice for suicide in right to die societies
Phenylpiperdines: diphenoxylate, difenoxin, loperamide
-diphenoxylate and difenoxin used for diarrhea, not analgesia
-poor solubility limits parenteral injection
-loperamide (imodium) also used for diarrhea: cant reach the brain, so no analgesic action or potential for abuse; available over the counter (schedule V dosing-available without a prescription)
Mixed Opioid Agonists
-partial receptor agonist and receptor antagonist function
-moderate pain/rehabilitation
-long duration of action 4-8 hours
-compounds must possess the property to show antagonism at mu opioid receptors and agonisms at the delta and kappa opioid receptors
Mixed Opioid Agonist Types
-Phenanthrenes: nalbuphine (nubain), buprenorphine (subutex)
-benzomorphans: pentazocin (talwin)
-morphinans: butorphanol (stadol)
Phenanthrene: Nalbuphine
-strong kappa receptor agonist and mu receptor antagonist
-limited respiratory depression as with morphine, however, it is resistant to reversal by receptor antagonists
Buprenorphine (subutex)
-phenathrene
-partial mu receptor agonist and kappa receptor antagonist
-25-50x more potent than morphine
-long duration due to slow dissociation with mu receptors which is resistant to antagonists
-used in place of for detox of heroin users
Morphinans:Butorphanol (stadol)
-analgesia similar to nalbuphine and buprenorphine but more sedation
-kappa agonists and partial agonist/antagonist for mu receptor
Benzomorphans
-pentazocine (fortral, talwin)
-a partial agonist/weak antagonist at mu opioid receptors
-produces CNS effects similar to morphine
-analgesia due to kappa activity
-may precipitate withdrawal syndrome in mu opioid dependent subjects
-produces pyschotomimetic effects (parenteral doses >60mg)
Antitussives
-opioid analgesics are among the most effective for the control of cough
-effect is found at doses much lower than that required for analgesic action -receptors appear to be diff. than opioid
-physiological mechanism of cough isnt well known but antitussives appear to work both centrally and peripherally
-dextromorphan (free of additive properties and produces less constipation) and codeine(lower doses than analgesia)
Antagonists
-naloxone and naltrexone
-used to control opioid overdose and abuse
-used in cases of life-threatening respiratory and CNS depression
-also used for less life-threatening side effects of epidural: itching, nausea and vomiting while still providing analgesia
-used in oral form (relistor, methylnaltexone bromide) to treat constipation in late stage advances illness-likely by inhibiting mu receptors in the gut
Naloxone and Naltexone
-potent antagonists with a high affinity for the mu opioid receptors
-reverse the action of mu receptor agonists
-lower affintity for delta and kappa receptors but can also reverse opioid action at these receptors
-inert when given alone to a naive patient
-dramatically reverse opioid effects
-naloxone used for the treatment of opioid overdose, short duration of action 1-2 hours
-naltrexone used as maintenance drug fro addicts as it blocks all the effects of heroin
Alpha delta nerve fibers
-myelinated 2-5mm in diameter
-carry signals at 5-40 M/sec
-sharp pain and provide prrecise location
Type I: HTM (high-threshold mechanical), high heat threshold, lower for mechanical
Type II: lower heat, high mechanical
-pricking- skin cut, needle prick-sharp and stinging
C nerve fibers
-unmyelinated, .4-1.2mm in diameter.
-carry signals at .5-2 M/sec- achey dull pain
-highly heterogenous
-inflammation on burned skin. Not localized, burning and annoying.
Free nerve endings (unmyelinated terminals) detect damage released from cells:
-globulin-serum protein
-arichidonic acid (PGE2)
-histamine
-NGF
-Substance P and calcitonin gene-related peptide
-ATP, ion changes K, heat
These stimuli (and many others) are released by damaged tisue and stimulate nociceptors
TRPV1
-Transient Receptor Potential Vallinoid Type 1
-Capsaicin Receptor
-because this receptor can be activated by a wide range of agonists it is a taret for a new clas of compounds which could have off target effects too)
Pain transmission Step
-dorsal horn
-action potentials: one = low pain, many = high pain
-lead to the release of glutamate and neuropeptides which stimulates the dorsal horn neuron
Alpha delta nerve fibers
-myelinated 2-5mm in diameter
-carry signals at 5-40 M/sec
-sharp pain and provide prrecise location
Type I: HTM (high-threshold mechanical), high heat threshold, lower for mechanical
Type II: lower heat, high mechanical
-pricking- skin cut, needle prick-sharp and stinging
C nerve fibers
-unmyelinated, .4-1.2mm in diameter.
-carry signals at .5-2 M/sec- achey dull pain
-highly heterogenous
-inflammation on burned skin. Not localized, burning and annoying.
Free nerve endings (unmyelinated terminals) detect damage released from cells:
-globulin-serum protein
-arichidonic acid (PGE2)
-histamine
-NGF
-Substance P and calcitonin gene-related peptide
-ATP, ion changes K, heat
These stimuli (and many others) are released by damaged tisue and stimulate nociceptors
TRPV1
-Transient Receptor Potential Vallinoid Type 1
-Capsaicin Receptor
-because this receptor can be activated by a wide range of agonists it is a taret for a new clas of compounds which could have off target effects too)
Pain transmission Step
-dorsal horn
-action potentials: one = low pain, many = high pain
-lead to the release of glutamate and neuropeptides which stimulates the dorsal horn neuron
Endogenous Pain opiate system:
-counters pain: helps flight when in a fight
-credited for the well-known analgesic "placebo effect"
-acupuncture thought to activate endogenous pain modulation pathway
One component of ths system ins the endogenous Opioid Peptides that act on the opioid receptors on primary and secondary afferent neurons
-3 general families
-the natural ligands for the opioid receptors
-the opioid anagesics act as surrogates (cocaine etc)
-Three families:
Enkephalins, endorphins and dynorphins
Three families and precursors
-Proenkephalin --> leu and met enkephalins
- Prodynorphin --> dynorphins
-Pro-opiomelanocortin (POMC) --> endorphins
EOPs
-EOPs are NOT produced directly by biosynthesis
-each family of EOP is derived by peptidase cleavage of a peptide precursor protein, which is processed within neurons of the CNS
Endophins
-produced by the pituitary gland and hypothalamus during srenuous exercise, excitement and pain. Cand produce analgesia and a sense of well-being. Found throughout the body in addition to the CNS
Enkephalins
-penta peptides that regulate nociception
Enkephalins
-penta peptides that regulate nociception
Dynorphins
-produced in the brain- are implicated in a number of processes depending on their source- painresponse, appetite suppression, weight control, inhibition of oxytocin secretion, circapding rhythm.
Enkephalins
-penta peptides that regulate nociception
Dynorphins
-produced in the brain- are implicated in a number of processes depending on their source- painresponse, appetite suppression, weight control, inhibition of oxytocin secretion, circapding rhythm.
Dynorphins
-produced in the brain- are implicated in a number of processes depending on their source- painresponse, appetite suppression, weight control, inhibition of oxytocin secretion, circapding rhythm.
EOPs bind to opiate receptors
-EOPs attenuate pain by binding to opioid receptors.
-They are full agonists for these receptors
-family includes mu, delta and kapa opioid receptors
Mu receptor functions and EOP affinity
-Supraspinal and spinal analgessia; sedation; inhibition of respiration; slowed GI transit; modulation of hormone and neurotransmitter release
-endorphins >enkephalins >dynorphins
Delta receptor functions and EOP affinity
-supraspinal and spinal analgesia; modulation of hormone and neurotransmitter release
-enkephalins >endorphins and dynorphins
Kappa receptor functions and EOP affinity
-supraspinal and spinal analgesia; psychotomimetic effects; slowed GI transit
-dynorphins >> endorphins and enkephalins
Opioid Receptor Family
-all are GPCRs of the Gi/o type
-highly concentrated in the dorsal horn of the spinal cord but found also in numerous locations in the brain
-opioids exhibit analgesic effects, euphoriant effects, respiratory depression, and physical dependence
-N/OFQ or ORL1 is anotehr analogous system where ORL1 is the GPCR and Nociception is the endogenous ligand. Poorly understood, but thought to be involved in pain modulation uncoupled from respiratory depression.
Mechanism of Inhibiting pain in the Dorsal Horn
-Opioid Receptors have 2 well-established G-protein based actions on neurons
1. Presynaptic nerve terminal-inhibits Ca influx
-inhibit release of neurotransmitters (substance P and glutamate, noreepi, serotonin)
2. postsynaptic neuron activates K+ efflux
-hyperpolarizes nurons to maintain resting potential
ONLY the MOR(mu opioid receptor) is on the Post-synaptic neuron
The Gate Control Theory of Pain Modulation
-pain stimulates C fibers to release Substance P, increasing the firing rate of 2nd order neurons in in the dorsal horn
-Simultaneous stimulation of AB fibers activates the interneurons to release enkephalin
-the inhibition of 2nd order nerons by enkephalin closes the gate
EOPs modulate pain response
-in the descending pain modulatory system (supraspinal)
-at the synapse between the primary and secondary neurons (in the dorsal horn) (spinal)
Supraspinal: Descending pain modulation pathway
-brain to spinal cord: opioids activate the descending pathways
-neurons in the forebrain send excitatory projections to the midbrain PAG which excites neurons in the RVM (raphe nucleus)
-the EOP that modulates this response in unknown but inhibitors of enkephalin degradation induces analgesia
Mechanisms of Inhibition of Descending Pain Pathway
-pain inhibitory neuron is activated by opioids and the release of GABA is inhibited
-this reduction in GABA (inhibitory neurotransmitter) enhances descending inhibition to the dorsal horn
Epilepsy affects 1% of the population
2/3rds have the disease controled by drugs leaving 500,000 in US with uncontrolled disease
Chronic Disorder (epilepsy) characterized by unpredictable and recurrent seizures originating in the cerebral cortex
Seizure- finite episodes of brain dysfunction resulting from an abnormal discharge of neurons
Cause is typically unknown but can result from neurologic disease such as infection, neoplasm and injury.
Hereditary Factors: small groups of individuals have been found to harbor a single gene defect in the GABAa receptor or in voltage-gated ion channels
Seizures originate in ...
the cerebral cortex
Anti-epileptic drug effects
can impact tooth and jaw structure and induce gingival hyperplasia
Origin Epileptic discharge
-an epileptic attack is thought to arise from abnormal firing of a small collection (focus, "patch") of abnormal neurons
-The few clustered abnormal neurons making up a focus can elicit normal neurons, adjacent or remote along the abnormal tract to fire in the same abnormal manner
Mechanisms of Seizures
-epilepsies are disorders of neuronal excitability
-defective synapses are involved
-primary brain synaptic neurotransmitters (NT) are g-aminobutyric (GABA), glutamate, and aspartate
-GABA is the principal NT of inhibitory neurons
-glutamate and aspartate are the principal NTs of excitatory neurons
Abnormal Firing of neurons
-an epileptic seizure is an imbalance between the excitatory and inhibitory currents in the brain
Abnormal firing in the brain in epilepsy is characterized by two distinct hallmarks
1. Hyperexcitability
2. Hypersynchrony
Hyperexcitability
-Abnormal responsiveness of a neuron to an excitatory input with multiple discharges instead of one or two
Hypersynchrony
-recruitment of large number of neighboring neurons into an abnormal firing mode
Classification of Seizures
-many different forms of epileptic seizures
-symptoms seen in any form of epilepsy reflects the area of brain involved in abnormal discharge
Broadly seizures are classified into:
Partial Seizures
1. Simple partial
2. complex partial
3. partial seizures secondarily generalize
Generalized Seizures
1. Generalized tonic-colonic (grand-mal)
2. absence (petit-mal)
3. tonic seizures
4. atomic seizures
5. clonic and mycolonic seizures
Simple Partial Seizure
-local manifestations (one limb/muscle group);
-60-90 seconds of jerking or lights flashin
-15-20 min of weakness
-no loss of consciousness individual can recount the event
-Motor-involves motor strip abnormal movements
-somatosensory - hearing and smell
-autonomic symptomes-temporal lobe -tachycardia, flushing
-psychological-frontal or temporal lobe-agitation
complex Partial seizure
-local onset, but the discharge becomes more widespread
-impairment of consciousness; staring or falling amnesia;
-"automatisms" lip smacking, swallowing, fumbling, scratching
-usually lasts 30-120 seconds followed by gradual recovery where patient may feel ill
partial seizure secondarily generalized
-partial seizure is following by a secondary more generalized (grand mal) seizure where they lose consciousness
-1-2 minutes
Generalized Seizures
-Seizures originating from a focus located in deep central structures of brain are classified as (primary) generalized seizures
-absence (petit mal),
tonic-clonic (grand mal),
myoclonic, atonic
Absence (petit mal)
-abrupt, brief loss of consciousness (10-45 seconds)
-mild jerking of eyelids and extremities, automatisms, may begin in childhood and may occur up to hundreds of times a day
Tonic-clonic (grand mal)
-dramatic
-sudden onset of major convulsions
-"tonic" spasm of musculature, then "clonic" jerking
-begins with rigidity that is followed by 15-30 seconds of tremor then massive jerking over 60-120 seconds
Clonic
rhythmic jerking due to non-complete muscle contraction, pt <3 yrs
tonic
-pt <3yrs, truncal and facial muscles stiffen, traumatic injury due to falls, lead to confusion
Myoclonic
-rapid involuntary shock-like muscle contraction causing a jerk - also occur in healthy people as they fall asleep or hiccups (hypnic jerks)
Atonic
-sudden loss of muscle strength, collapse, change in consciousness
Status epilepticus
-comes in many forms
-patient shows "continuous" seizures (one seizure continues to follow the other)
-convulsive status epilepticus is a medical emergency and life-threatening
Principles of Antiepileptic Pharmacotherapy
-inhibit the seizure focus
-inhibit spread of the discharge through the CNS
Antiepileptic pharmacotherapy supress neuronal firing by
a. inhibiting voltage-activated ion channels
b. enhance funciton of GABA - inhibitory neurotransmitter
Antiseizure Drugs
-fial to control seizures in some patients
-numerous undesirable effects
-treatment individualized-depends on seizure type
-complete seizure control in half of paitents; improvement in another 25%
Direct GABA modulators (anti-epileptic)
-phenobarbital
-valium
-tigabine
-gabapentin
Sodium Channel blockers (anti-epileptic)
-phenytoin
-valproate
Barbituates
-phenobarbital
-enhances GABA mediated current by prolonging the openings of Cl- channels
-used for partial and generalized tonic-clonic seizures (tried for all seizure types)
-first
-sedation is major side effect
-tolerance to sedation develops
-widely used antiepileptic
Tigabine
-inhibitor of GABA uptake by inhibitng the tansporter isoform GAT-1, therefore prolonging inhibitor action of synpatically release GABA
-partial seizure- as adjuvant and monotherapy
-side effects: nervousness, dizziness, tremor, ataxia, somnolence (state of near sleep)
-oxidized by CYP3A with a half life of 5-8 hours
Gabapentin
-GABA analogue that does not directly act on GABA receptors, but modifies GABA release
-also decreases Ca entry and inhibits glutamate release by binding directly to the Ca++ channels
-used for partial and tonic-clonic seizures
-side effects including somnolence, dizziness, tremor, ataxia and headache
-neither drug is metabolized and is excreted in its native form. These drugs don't have significant drug-drug interactions, but have short 1/2 lives (5-7) hours
Slowing recovery of voltage-activated Na+ channels
-during neuronal firing, Na+ channels open to allow Na+ influx, but pass through an inactive state before participating in the next firing
-slowing recovery from this inactive state can suppress the high frequency repetitive neuronal firing characteristic of epilepsies
Drugs that slow recovery of NA+ channels
-Phenytoin
Phenytoin
-oldest anti-seizure drug
-blocks sustained high-frequency repeptivie firing of action potentials
-serum levels variable among patients and dose is saturable
Phenytoin clinical use
-effective for both partial and generalized tonic-clonic seizures
-effective against primary and secondary attacks
-not effective for absence seizures
-foshphenytoin used i.v. is the choice of tx for staus epilepticus
Phenytoin toxicities
-eye effects -nystgmus (rapid eye movements), diplopia (double vision)
-hirsutism (excessive hair)
-gingival hyperplasia
Valproate
-appears to inhibit both Na+ and Ca2+ channels
-also increases GABA levels-inhibits degradation
-effective against absence, partial and generalized tonic-clonic seizures a variety of applications
-preffered drug for patients with both absence seizures and tonic-clonic seizures
-GI Problems, sedation, ataxia, tremor. hepatic enzymes elevate- fulminant hepatitis (1:10,000)
Movement Disorders
-Neurological disease that can effect the speed, quality and ability to move.
-May lead to an increase in involuntary, movement or a decrease in voluntary movement.
Parkinsonism definition
-tremor, rigidity, bradykinesia
Tremor definition
-shaking
Huntington's Chorea
-rapid movements
Ballismus
-violent involuntary movements
Athetosis
-slow, writhing movements
Dystonia
-sustained torsion, abnormal posture
Tics
-aka Tourettes
-involuntary, compulsive and repetitive movements
Drug-induced Dyskinesias
-diminished voluntary movement
Restless Legs Syndrome
-urge to move
Wilson's Disease
-accumulation of copper leads to tremor and ataxia
Parkinsonism
-affects 1 in 100 ppl over the age of 60 and rising with life expectancy increases
-avg age of onset is 60, rare under 50(usually genetic defects) and increases with incidence at 70 and 80
-most cases are idiopathic, however a mutation in a few genes (SNCA, LRRK2, UCHL1) are the underlying cause of autosomal dominant Parkinson's
-secondary cases result from drug toxicities, pollutant toxicities, head trauma, viral infections
-progressive disease leading to increased disability and cognitive failure
-characterized by a combination of bradykinesia (hallmark of diagnosis), tremor, rigitiy, and postural instability
Bradykinesia
-hallmark of parkinson's disease
-slowed initiation of voluntary movement and progressive reduction in speed and amplitude of repetitive actions
Parkinson's and Dental Health
-daily dental regimens can be difficult due to inability to control movement
-Tremor, rigidity, abnormal posture may make dental exams difficult-these should be timed properly based on medication.
Regulation of movement
-occurs in basal ganglia and cerebellum regulate movement
-initiates in the cerebral cortex
-collection of nuclei that modify movement on a min to min basis, they form circuits and signal back to cerebral cortex via thalamus
-damage to cerebellum-ataxia (thought to be involved in coordinated-difficulty talking, sequencing events and repetitive actions
-basal ganglia-inhibits ability to stop and start movements (skilled tasks like playing piano or using scissors)
Damage to Substantia nigra
-induces parkinsons
Striatum
-important for planning and modulation
Parkinson Cause
-result's from death of dopamine producing neurons in the substantia nigra
Dopaminergic pathways
-neurons that synthesize and secret dopamine
-pathway= powerline of neurons interconnecting two rgions in the brain
-pathways:mesolimbic (reward), mesocortical motivation/Emotional response, nigrostriatal (movement production), tuberoinfudilar(prolactin production)
-nigrostiatal dopaminergic pathway is the pathway disrupted in Parkinson's
-neurons that connect substantia nigra to the striatum are the ones that die in parkinsons
NNigrostriatal dopaminergic neurons
-normally inhibit striatal cholinergic interneurons to promote proper movement
-in striatum there are stiatal cholinergic interneurons that produce Ach, this stimulates neuron networks to produce GABA and reduce excitation of the motor cortex
-regulated by dopaminergic neurons that exted from the substantia nigra, these neurons produce dopamine that binds to inhibitory D2 receptors on the striatal cholinergic interneurons, this inhibits ACh and inhibition of GABA production and enhancement of excitation.
-dopamine excites motor cortex
-movement is the result of oscillation between inhibitory and excitatory states
Death of Dopaminergic neurons
-dopamine loss leads to release of acetyl cholines by striatal cholinerginc interneurons and thus an increase in GABAinergic (inhibitory processes)
-no dopamine, then returned to state where striatal cholinergic interneurons produce ACh which stimulates GABA (constantly in off-state of movement> movement is inhibited and difficult to initiate movement
-Net effect=loss of balance between excitatory and inhibitory processes into the motor cortex
Causes of Neuron death in Parkinson
-MPTP is known to specifically kill cells in substantia nigra
Lewy Bodies
-found in the remaining neurons in PD pts, thought to be the result of stress on the neurons that induce death,
-not known if result of stress or killing the cell
Microglial Cells
-inflammatory cells that can induce neuronal death through the release of cytokines
Therapy for Parkinson's
-restore the dopamine levels (dopamine cant cross BBB, L-Dopa does cross the BBB but causes GI effects)
-MAO inhibitors
-dopamine receptor agonist
-
Levodopa Pharmacokinetics
-much of L-DOPA is decarboxylated to dopamine before crossing BBB
-carbidopa is a peripheral dopa decarboxylase inhibitor, this combination reduces GI effects
-L-DOPA + Carbidopa =SINEMET
Levodopa Clinical Use
-Most effective in first 3-4 yrs of use, responsiveness is reduced and adverse events enhanced. Could be due to loss of striatal neurons or dopamine receptors.
-must be taken before meals to improve absorption
-effective at reducing bradykinesia
-plasma concentrations peak 1-2 after an oral dose and the half life is 1-3 hours (implications here for peak period for dental visits)
-thought that striatal neurons die off because of loss of dopamine receptors
Side effects of L-Dopa Therapy
-GI effects(anorexia, nausea, vominting)
-Response fluctuations (random off-periods of akinesia altereratin with periods of improved mobilty )
-Behavioral effects (depression, agitation, confusion)
-Cardiovascular effects (cardiac arrhythmias due to increased NE formation peripherally
-dyskinesias (complex motor phenomenon that results in involuntary movement and priming that causes these movements to persist each time drug is administered
COMT
-Catechol-O-methyltransferase pathway
-metabolizes the levadopa and dopamine -inhibits both pathways
Selectiv COMT inhibitors
-Tolcapone &Entacopone
-diminish L-DOPA peripheral metabolism and prolong L-dopa effect
-may reduce on/off fluctuations
-Tolcapone has been associated with liver disease and requires signed consent and hepatic enzyme monitoring, not true to Entacapone