Pharmacology Exam 3

seizure

• sudden, brief disruption of normal functioning of neurons

• common neurological problem

• caused by toxins, infection, fever, or neurological injury

epilepsy

• disease associated with spontaneously occurring seizures

• affects ~2-4 million in the US and ~50 million worldwide

• appears before 20 years of age, commonly by the first year of life

causes of epilepsy

• genetics, birth hypoxia, brain tumor, abscess, congenital abnormalities, or trauma

diagnosis of epilepsy

• 2 unprovoked seizures less than 24 hours apart

• 1 unprovoked seizure after 2 unprovoked seizures occurring within 10 days

• electroencephalogram (EEG)

types of generalized seizures

• tonic-clonic (grand mal)

• myoclonic

• atonic

• absence (petit mal)

tonic-clonic seizure

• AKA grand mal

• characterized by alternating muscle contraction and relaxation

myoclonic seizure

• characterized by muscle contraction confined to one body part

• may spread and become generalized

atonic seizure

• characterized by loss of muscle tone

• individual falls, which may result in head injury

absence seizure

• AKA petit mal

• characterized by brief impairment of consciousness

• staring and rapid eye blinking

types of partial seizures

• simple partial

• complex partial

simple partial seizure

• involves limited area of the brain

• may be sensory or motor

• no loss of consciousness

complex partial seizure

• may involve entire body

• no memory of attack

• impaired consciousness

reflex epilepsy

• provoked by environmental stimulus

• ex. photosensitive epilepsy, eating epilepsy

drugs for generalized tonic-clonic AND partial seizures

anticonvulsants, antiepileptic, barbiturates, hydantoins, carbamazepine, valproic acid, primidone, topiramate, zonisamide

anticonvulsant drug MOA

• help terminate convulsive seizures

• administered IV or IM

• some produce significant sedation

antiepileptic drug MOA

• prophylaxis to reduce/prevent seizures

• DECREASE excitability of neurons

• administered PO

barbiturate MOA

• anticonvulsant, some with antiepileptic properties

• pharmacological effects include sedation and hypnosis

• modulate GABA_A receptor and DECREASE glutamate release

phenobarbital

• preferred treatment for infant seizures

hydantoin MOA

• produce minimal sedation

• prolong inactivation of Na⁺ channels in nerves, INCREASE GABA, and DECREASE glutamate

• administered IV (acutely)

• ex. phenytoin (Dilantin)

hydantoin adverse effects

• dizziness, ataxia, visual disturbances, postural imbalance, skin rash, birth defects

phenytoin, carbamazepine, valproic acid

• preferred treatment for generalized tonic-clonic and partial seizures in ADULTS

carbamazepine (Tegretol) MOA

• related to tricyclic antidepressants

• prolong inactivation of Na⁺ channels in nerves, DECREASE influx of Na⁺ ions, and prevent high frequency neural firing

carbamazepine (Tegretol) clinical indications

• generalized tonic-clonic and partial seizures, mania, bipolar disorder, trigeminal neuralgia

carbamazepine (Tegretol) adverse effects

• dizziness, N/V, drowsiness, jaundice, bone marrow depression

• overdose = convulsions, respiratory depression

valproic acid MOA

• can be used with any type of epilepsy

• inhibits Na⁺, blocks glutamate NMDA receptor, and DECREASES GABA

drugs for partial seizures

• gabapentin, pregabalin, Felbamate, Lacosamide, Lamotrigine, Tiagabine

gabapentin (Neurontin) and pregabalin (Lyrica) MOA

• similar in structure to GABA

• block Ca²⁺ ion channels and DECREASE glutamate

topiramate (Topamax), Lamotrigine

• preferred treatment for generalized tonic-clonic and partial seizures in CHILDREN

drugs for absence seizures

• ethosuximide, oxazolidinediones, benzodiazepines, valproic acid, Lamotrigine

succinimide and oxazolidinedione MOA

• prevent T-type Ca²⁺ currents

benzodiazepine MOA

• INCREASE frequency of opening of GABA receptor

• ex. diazepam, clonazepam, lorazepam

valproic acid, Lamotrigine

• preferred treatment for absence seizures in ADULTS

ethosuximide (Zarontin)

• preferred treatment for absence seizures in CHILDREN

status epilepticus

• series of seizures without interruption

• requires immediate treatment to prevent severe CNS/cardiovascular/respiratory depression

drugs for status epilepticus

• lorazepam, diazepam, fosphenytoin/phenytoin

Parkinson’s disease

• progressive neurodegenerative disease that affects ~1 million in the US

Parkinson’s disease symptoms

• resting tremor in hands and jaw

• cogwheel rigidity of joints

• hypokinesia (slowed movement)

• flat, mask-like facial expression

• drooling

• weight loss

• stooped posture

• shuffling gait

neurotransmitters affecting basal ganglia

• acetylcholine (excitatory) and dopamine (inhibitory) regulate motor nerve activity

dopamine neuron

• axon reaches caudate nucleus and stimulates initiation of movement

• loss of these neurons in midbrain contributes to PD symptoms

• INCREASE in ACH and DECREASE in DA result in excess motor stimulation

L-dopa (Levodopa) MOA

• crosses blood-brain barrier, converts to dopamine, DECREASES PD symptoms

• administered PO with carbidopa (inhibits DOPA decarboxylase which turns L-dopa into dopamine)

L-dopa (Levodopa) adverse effects

• N/V, loss of appetite

• orthostatic hypotension, fainting

• irregular, elevated HR

• behavioral disturbances

• immobility, dyskinesia, dystonia, on-off phenomenon

• does not slow disease progression

L-dopa + antipsychotic drug interaction

• drug blocks dopamine, resulting in a decrease in effectiveness of L-dopa

L-dopa + MAO-A inhibitor interaction

• drug increases levels of NE, resulting in an increase in L-dopa metabolism to dopamine

L-dopa + vitamin B₆ interaction

• drug interaction results in an increase in L-dopa metabolism to dopamine

dopamine receptor agonists

• similar to dopamine, have longer duration of action

• bromocriptine (Parlodel)

• pramipexole (Mirapex)

• ropinirole (Requip)

• adverse effects = nausea, postural hypotension, dizziness, CNS and mental disturbances

drugs used to treat Parkinson’s disease

• L-dopa, apomorphine, amantidine, anticholinergic drugs, bromocriptine, pramipexole, ropinirole

mild cognitive impairment

• duration = 7 years

• location = medial temporal lobe

• symptoms = short-term memory loss

mild Alzheimer’s disease

• duration = 2 years

• location = spreads to lateral temporal and parietal lobes

• symptoms = reading problems, poor object recognition, poor sense of direction

moderate Alzheimer’s disease

• duration = 2 years

• location = spreads to frontal lobe

• symptoms = poor judgment, impulsivity, short attention span

severe Alzheimer’s disease

• duration = 3 years

• location = spreads to occipital lobe

• symptoms = visual problems

drugs used to treat Alzheimer’s disease

• donepezil, galantamine, rivastigmine, memantine

monitored anesthesia care (MAC)

• IV sedation with midazolam, followed by propofol and/or fentanyl (also ketamine)

• conscious sedation + pain relief

• used in surgical centers for minor surgery, biopsy, and endoscopy

general anesthesia

• complete loss of consciousness and absolute CNS depression

balanced anesthesia

• +1 anesthetic + skeletal muscle relaxant + antianxiety drug

stage I of anesthesia with CNS depression

• analgesia

• causes euphoria, giddy, loss of pain, and loss of consciousness

stage II of anesthesia with CNS depression

• excitement/delirium

• increases sympathetic tone (increases BP and HR, hyperreaction to stimulation)

stage III of anesthesia with CNS depression

• surgical anesthesia

• sleep, normal BP and RR, dilated pupils, loss of corneal reflex, skeletal muscle relaxation, diaphragm paralysis, hypotension

stage IV of anesthesia with CNS depression

• medullary paralysis

• respiratory paralysis, which results in circulatory collapse and death

induction

• time required for patient to go from conscious state to stage III

maintenance

• ability to keep patient safely in stage III

• VS, temp, ECG, EEG are continuously monitored

• IDEALLY = rapid induction and slow maintenance without entering stage IV

general anesthesia MOA

• interaction with GABA_A receptor and NMDA receptor

general anesthesia + GABA_A receptor

• interaction with inhaled anesthetics, benzodiazepines, barbiturates, etomidate, and propofol

• barbiturates and propofol directly enhance Cl^- channel remaining open

general anesthesia + excitatory NMDA receptor

• antagonized by NO, propofol, and ketamine, blocking cation movement and depolarization

minimal alveolar concentration

• volatile anesthetics modulate excitatory and inhibitory synaptic transmission

• DECREASES when IV anesthetics enhance inhibitory receptors and antagonize excitatory receptors

inhalation anesthetics

• enflurane, desflurane, isoflurane, sevoflurane, NO

inhalation anesthetics MOA

• volatile liquids and gases are inhaled through nose/mouth by face mask

• high gas partition coefficient = high solubility of drug in blood

• produce all stages of general anesthesia (except NO)

• potency is measured by concentration of drug in alveoli

methohexital MOA

• barbiturate injection anesthetic

• ultrashort acting

• no analgesia at any dose

• may cause laryngospasm/bronchospasm

benzodiazepine injection anesthetics

• midazolam (Versed), lorazepam (Ativan), diazepam (Valium)

midazolam (Versed) MOA

• short acting CNS depressant

• administered IV or rectal

• given with neuromuscular blocking drugs

nonbarbiturate injection anesthetics

• propofol (Diprivan), etomidate (Amidate), ketamine (Ketalar), dexmedetomidine (Precedex), opioid (fentanyl) + tranquilizer (droperidol)

propofol (Diprivan) MOA

• initiates and maintains MAC sedation

• narrow margin of safety

• NOT an analgesic

• depresses cardiovascular and respiratory activity

• antiemetic

• psychological dependence

etomidate (Amidate) MOA

• NOT for continuous/maintenance anesthesia

• causes postoperative N/V

• used for high risk patients (has less depressive effects on cardiovascular and respiratory centers)

ketamine (Ketalar) MOA

• short acting dissociative anesthetic

• analgesic

• not a skeletal muscle relaxant

• inhibits excitatory pathway by direct interaction with NMDA receptor, stimulating sympathetic nervous system

• causes vivid dreams and hallucinations during recovery period

dexmedetomidine (Precedex)

• potent alpha₂-adrenergic agonist

• analgesic, sedative, and lowers anxiety

opioid (fentanyl) + tranquilizer (droperidol)

• combination produces neuroleptanalgesia

• + NO causes loss of consciousness

• droperidol causes extrapyramidal symptoms and Parkinsonian syndrome

general anesthesia effects on CNS

• regulation of cerebral blood flow

• change in intracranial pressure

• seizure induction

• N/V

general anesthesia effects on GI system

• postoperative N/V (volatile anesthetics are emetogenic)

• increase sensitivity of vestibular center of inner ear

• caused by rapid movement

general anesthesia effects on respiratory system

• postoperative ventilatory failure, hypoxia

• production of secretions

• respiratory muscle spasms

general anesthesia effects on cardiovascular system

• increased BP and HR

• CV depression following depression of medullary vasomotor centers

• high doses cause CV collapse

general anesthesia effects on skeletal muscle

• relaxation at stage III

• inhaled anesthetics facilitate muscle incision and manipulation

• benzodiazepines interrupt excess contraction in spasticity disorders and dyskinesia

general anesthesia effects on liver and kidneys

• volatile anesthetics temporarily decrease hepatic and renal blood flow, glomerular filtration, and urine output

• volatile anesthetics are associated with hepatitis

• IV anesthetics are metabolized by microsomal enzyme system of liver

special considerations for general anesthesia

• allergic reaction

• black box warning

• vital signs

• CNS depression

• malignant hyperthermia

• drug interactions

early opiate products

• opium and heroin

• elixirs and pills marketed to treat pain, asthma, cough, pneumonia

• Paregoric (mixture of opium and alcohol, manufactured by Stickney & Poor and McCormick)

• Bayer made aspirin and heroin

• Fraser Tablet Company made heroin tablets for asthma

opium alkaloids

• found in resin of opium poppy (Papaver somniferum) that grows in SE Asia, Middle East, Latin and S America

• morphine, codeine, thebaine, and ~20 more

natural narcotics

• opium

• morphine, codeine, thebaine from opium

semisynthetic narcotics

• heroin and hydromorphone from morphine

• oxycodone and etrophone from thebaine

totally synthetic narcotics

• pentazocine, meperidine, fentanyl, methadone, LAAM, propoxyphene

endogenous opioids

• enkephalins, endorphins, dynorphins

opioid clinical indications

• analgesia, sedation, cough, diarrhea suppression

current opioids

morphine, Demerol, Darvon, Vicodin, Oxycontin

• relief of chronic pain and post-surgical pain

• antidiarrheal for dysentery and other intestinal parasites

codeine

• cough suppression

behavioral effects of opiates

• increasing dose, decreasing alertness

• analgesia, sleep,

• euphoria, rush, anxiety, N/V

• unconsciousness, lowered BP

• respiratory depression

• death

patient controlled analgesia (PCA)

• dosing is under patient control

• allows use of lowest effective dose of opioid before intensity becomes unbearable

opioid pharmacokinetics

• available in nasal sprays, lozenges, and patches

• absorption depends on lipid solubility, absorbed in intestines

opioid metabolism

• metabolized in liver by P450 enzymes, high risk for drug-drug interaction with drugs also metabolized by these enzymes

• metabolism results in production of inactive and active metabolites

opioid excretion

• become more hydrophilic to facilitate excretion in urine

• tubular reabsorption can result in increased blood concentrations and risk of drug toxicity

codeine pharmacokinetics

• 10% is metabolized into morphine

• was used as cough suppressant until dextromethorphan was introduced

morphine pharmacokinetics

• taken orally, absorbed into the bloodstream slowly, little gets into the brain

• active metabolite (morphine-6-glucuronide) gets into brain quicker and is more potent

heroin pharmacokinetics

• longer side-chains make it more lipid soluble

• a larger portion of the heroin dose reaches the brain (more potent)

• injection enhances absorption

• in the brain, heroin is converted to morphine

nociception

• receiving painful stimuli from injury

• irritation in PNS and recognition of pain in CNS

• nociceptors respond to tissue injury and painful stimuli

endogenous opioids

• substance P (neuropeptide) relays pain message into spinal cord

• endorphin/enkephalin bind to opioid receptors on axon terminals of substance P neurons, preventing the release of substance P and blocking the pain signal

• opiates relieve pain by the same mechanism