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355 Cards in this Set
- Front
- Back
What classes of drugs are CNS depressants?
|
Benzos, Barbituates, Hypnotics, Ethanol, General anesthetics
|
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What are the degrees of CNS depression?
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Sedation - dec. responsiveness to external stimuli, but not asleep
Sleep (hypnotic state) - hypnotic drugs induce this. Not the same as being hypnotized. Unconsciousness - unresponsive to ext. stimuli but response of muscles to painful stimuli Anesthesia - unresponsive to pain or any stimuli. No memory. Death ***A spectrum of depression |
|
What is a major difference b/w benzos and the rest of the CNS depressent drugs?
|
Most of the other depressents are dose dependent. That is, as you increase dose, you move up on the CNS depression scale. In benzos, you can never reach anesthesia. Benzo effect is not linear with dose.
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MOA of benzos?
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Act on GABA-A receptor
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MOA of other CNS depressents?
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Alter GPCR, ion channels (including GABA-A receptor), alter signal transduction. Specific action varies w/ drug.
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What is GABA?
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Major inhibitory transmitter in the CNS. There are two GABA receptors...*GABA-A (ion channels), GABA-B (GPCR).
***Glycine major inhibitory in spinal cord. |
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What is unique about GABA-B?
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It is a heterodimer GPCR
|
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What is unique about GABA-A?
|
- 5 subunits
- Multiple binding sites for diff. drugs - GABA binds main site, other drugs bind allosteric sites - Activation via GABA > Cl- influx > hyperpolarization > "inhibition" - Multiple subunits |
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How can you open the GABA-A receptor?
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Only by GABA binding
|
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What sub-unit do you need for benzo effect?
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Gamma subunit
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What are the effects of benzos binding to different alpha subunits on GABA-A receptor?
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See notes - went too fast to catch
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Is there a barbituate binding site on GABA-A? Ethanol? Anesthetic?
|
Yes to all, but not well defined
|
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What is MOA of benzo?
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Increases affinity of GABA for its receptor. Therefore increases hyperpolarization. Not a direct stimulator, allosteric.
With benzo alone, no effect on GABA receptor. Need GABA to be present for benzo to work. -Antagonists and inverse agonists present - Regional heterogeneity in subunits - Blah blah blah |
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What is effect on dose-response curve when Benzo is added?
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Shifts to left
|
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What is MOA of barbituates?
|
Act at GABA-A receptor to potentiate action of GABA. But, have diff. binding site than benzos. Therefore, do not interfere w/ benzo binding.
- At high conc. can act as direct GABA agonists |
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Do benzos have effect on any other binding site?
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No
|
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What are other MOAs of Barbituates?
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- Inhibit glutamate receptors
- Inhibit Na+ & K+ channels - Inhibits nicotinics |
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What is MOA of ethanol?
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- Potentiates GABA at GABA-A
- Nicotinic ACh receptor - Inhitibts excitatory neuron - Activates Serotonin 5HT receptor Bunch of other shit...see notes. |
|
What is MOA of general anesthetics?
|
- Potentiate GABA at GABA-A
- Inhibits excitatory receptors - Activates Serotonin 5HT - Inhibits Ca+2 channels Couple other things...see notes |
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Why do Benzos not have as much CNS depression as other depressants?
|
Because unlike the other depressants, Benzos have a very specific action. Other drugs have many actions leading to severe depression.
|
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What affects the fate of onset of CNS effects of the CNS depressants?
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Based on lipid solubility (more lipid soluble = faster onset of action
Duration of action is based on redistribution into a second compartment (more lipid soluble = shorter duration of action) -Muscle and CNS are the two compartments |
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What acts for a reservoir for the drugs that act on the CNS?
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Muscle and fat
The drug circulating to the brain will decrease as the drug is picked up by these tissues |
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What happens to the drug in the brain due to the two compartment model?
|
The blood circulating through the brain will have a lower drug level than the brain itself (due to muscle and fat taking drug out of serum)
The drug will diffuse back out of the brain and into the blood to be carried to the peripheral tissues |
|
When a CNS drug is given IV what limits the redistribution? Chronically given?
|
Redistribution
Rate of metabolism |
|
What are the commnly used benzodiazapenes not used for insomnia?
|
Alprazolam (Xanax)
Clorazepate (Tranxene) Diazepam (Valium) Lorazepam (Ativan) Midazolam (Versed) |
|
What are the commnly used benzodiazapenes used for insomnia?
|
Flurazepam (Dalmane)
Temazepam (Restoril) Triazolam (Halcion) |
|
Are benzodiazapenes used to treat anxiety?
|
Yes
|
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Are benzodiazapenes used to treat insomnia?
|
Yes
|
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Are benzodiazapenes used to treat epilepsy and seizures?
|
Yes
|
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Are benzodiazapenes used to treat anxiety?
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Yes
|
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Are benzodiazapenes used to promote sedation, amnesia, and as preanesthetic medication?
|
Yes
|
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Are benzodiazapenes used to treat muscle relaxation?
|
Yes
|
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What benzodiazapene is used to decrease muscle spasticity and muscle spasm?
|
Diazepam
|
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What is the site of action of diazepam in controlling muscle spasms?
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GABA-A receptors on the spinal cord on the presynaptic endings of the primary efferent nerves
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Are benzodiazapenes used to treat symptoms of alcohol and sedative-hypnotic withdrawal?
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Yes
|
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Which benzodiazapenes are used to treat symptoms of alcohol and sedative-hypnotic withdrawal?
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Chlordiazepoxide
Diazepam Lorazepam |
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What two things are the approved uses of benzodiazepines based on?
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Marketing strategies
Half-life of the drugs **They can be used interchangeably |
|
What are the CNS effects of benzodiazepines?
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Decrease anxiety
Hypnosis Anticonvulsant Muscle relaxation Anterograde amnesia Interferes with learning Additive or greater than additive CNS depressant with other CNS depressants |
|
What are the respiratory effects of benzodiazepines?
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No effect at normal doses in normal individuals
May suppress if have sleep apnea or lung disease May need respiratory support if CNS depressants are combined (ex. alcohol) |
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What are the CV side effects of benzodiazepines?
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Minor except in overdose
Preanesthetic concentrations may cause a decrease in BP and a reflex increase in HR Normal doses may cause CV depression in patients with low volume, CHF |
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Are benzodiazepines weak acids or weak bases?
|
Weak bases
|
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How are benzodiazepines usually given and why?
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Given orally because absorbed best in higher pH in small intestine
Can be injected into muscle with irregular absorption |
|
What can IV injections of diazepam cause?
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Local pain and thrombophlebitis
|
|
What is the primary means of eliminating benzodiazepines?
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Metabolism
|
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What are the long acting benzodiazepines?
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Clorazepate
Diazepam Flurazepam |
|
How are the long acting benzodiazepines metabolized?
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Oxidation and conjugation (Phase I and Phase II active metabolites)
Active metabolites are formed which have half-lives greater than active compounds |
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What are the short acting benzodiazepines?
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Alprazolam
Midazolam Triazolam Lorazepam Temazepam |
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How are the short acting benzodiazepines metabolized?
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Metabolized by a-hydroxylation and conjugation (Phase I and II):
Alprazolam Midazolam Triazolam Metabolized by conjugation only (Phase II): Lorazepam Temazepam |
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Is metabolism involving glucoronide conjugation or oxydation more affected by old age of the liver?
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Oxidative metabolism
|
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What aspect of older people makes a lipid soluble drug less prone to be eliminated?
|
Increased proportion of fat to total body weight which will increase volume of distribution
|
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How long does it take benzodiazepenes to reach steady state blood levels?
|
Days to weeks
|
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Is there any clinically significant induction of hepatic drug metabolizing enzymes in benzodiazepenes?
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No
|
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What inhibits benzodiazepene metabolism?
|
Cimetidine
Oral contraceptives Isoniazid Grapefruit juice |
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What are the most common side effects of benzodiazepenes at therapeutic doses?
|
Drowsiness
Sedation Impaired moto coordination Weakness Dizziness Confusion Memory loss |
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Does tolerance develop to the side effects of benzodiazepenes?
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Yes
|
|
What effect of benzodiazepenes develops slowly or doesn't develop tolerance at all?
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Anti-anxiety effects
|
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What are the two main signs of toxicity in benzodiazepene use?
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Drowsiness and ataxia
|
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What 3 classes of CNS depressants are additive to benzodiazepenes?
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General anesthetics
Hypnotics Anti-anxiety drugs |
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Do benzodiazapenes given orally produce fatal toxicity?
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No, unless they are combined with alcohol
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May benzodiazepenes be additive when given with other drugs that act on the CNS?
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Yes
Ex. Opioids, antihistamines, antipsychotics/depressants, anticholinergics, central acting antihypertensives |
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What condition are hypnotic benzodiazepines absolutely contraindicated in?
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Pregnancy
(they are in category X) |
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Are anxiolytic benzodiazepines contraindicated in pregnancy?
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No, but they may cause a large risk
|
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Why are benzodiazepines contraindicated in pregnancy?
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Adverse effect on fetus during pregnancy, delivery, breast feeding
Concentration of drug is higher in fetus than mother |
|
What is the MOA of a benzodiazepine antagonist?
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Binds to site on GABA receptor and prevents drug from bidning
Has no effect on the Cl channel opening Also prevents action of inverse agonist at binding site |
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What is the benzodiazepine antagonist that we need to know?
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Flumazenil
|
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What is the use of Flumazenil?
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Reverse the sedative effect of benzodiazepines after anesthesia/sedation
Reverse effects of benzodiazepine overdose |
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What is Flumazenil not effective in doing?
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Reversing efects of opioids, non-benzo sedative hypnotics, or anesthetic drugs
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What type of reaction will occur if a patient dependent on benzodiazepines is given Flumazenil?
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Withdrawal
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How is Flumazenil given and how is it metabolized?
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IV
Liver |
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What two effects of benzodiazepines does tolerance develop in?
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Anticonvulsant
Hypnotic |
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What effect of benzodiazepines does little tolerance occur in?
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Anti-anxiety
|
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Does dependence of benzodiazepines occur?
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Not really, there is little tendency to increase the dosage
|
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What schedule is benzodiazepines?
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IV
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What can discontinuing use of benzodiazepines cause?
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Symptom recurrence (like pre-therapy)
Rebound ( Withdrawal |
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What is the definition of dependence?
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Altered physiological state that requires continuous drug administration to prevent appearance of withdrawal symptoms
|
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What happens during withdrawal of benzodiazepines?
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Increased CNS excitation which can lead to convulsions
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Is the intensity of withdrawal less severe with long or short acting benzodiazepines?
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Long because the CNS can gradually return to normal state
|
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What is the rebound phenomenon with benzodiazepines?
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Symptoms are similar to before taking drug but of greater intensity
Intensity is greater with short-half life, high dose, and the longer use of the drug |
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Are rebound symptoms similar to withdrawal in benzodiazepines?
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Yes
|
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What are the symptoms of withdrawal in benzodiazepines?
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General anxiety like generalized anxiety disorder
Autonomic like symptoms Flu like symptoms Sensory disturbances (light/sound sensitivity, metallic taste) Seizures and deliurim if long and high dose |
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What is the goal for removing benzodiazepine treatment?
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Lower dose by 25% each week
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What is cross-dependence in benzodiazepines?
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Ability of one drug to suppress abstinence symptoms from discontinuance of another drug
Longer acting benzodiazepines can be used to prevent withdrawal of shorter acting drugs like alcohol |
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Is psychological or physical dependence more common in benzodiazepines?
|
Psychological
|
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What is buspirone used for?
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Relieves generalized anxiety but not effective in other types of anxiety
|
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What is the MOA of buspirone?
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Partial agonist at 5HT receptor
|
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What are the advantages of buspirone over benzodiazepines?
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Little sedative or euphoric effects
No rebound anxiety or withdrawl signs on discontinuation Does not potentiate CNS depressants |
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What are the side effects of buspirone?
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Tachycardia, palpitations, nervousness, GI distress, paresthesias (more common than with benzo's)
|
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What 4 barbiturates should we know?
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Pentobarbital
Phenobarbital Secobarbital Thiopental |
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What causes the hypnotic effects of barbiturates?
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Lipophillic hydrocarbon groups at C5 position
|
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What causes an increase in the lipid solubility of a barbiturate?
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Substitution of sulfur for oxygen and addition of methyl group to nitrogen
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Are barbiturates a weak acid or weak base?
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Weak acid
|
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What is the long acting barbiturate we need to know?
|
Phenobarbital
|
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What is phenobarbital used for?
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Sedative and anticonvulsant
|
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What is the ultra short barbiturate we need to know?
|
Thiopental
|
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What is thiopental used for?
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IV anesthetic
|
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What is the intermediate acting barbiturate we need to know?
|
Pentobarbital
|
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What is pentobarbital used for?
|
Hypnotic
|
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What is the short acting barbiturate we need to know?
|
Secobarbital
|
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What is secobarbital used for?
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Hypnotic
|
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What is the order of potentcy of the barbiturates?
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Thiopental > secobarbital > pentobarbital > phenobarbital
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What are the CNS effects of sedative and hypnotic doses of barbiturates?
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Act on multiple receptors to reversibly depress all excitable tissues
-can alter a patient's sleep patterns |
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What are the CNS effects of toxic and anesthetic doses of barbiturates?
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Depress the vasomotor center
Depress respiratory center which is the primary cause of death Depress thermoregulation Do not raise the pain threshold |
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Are actions of barbiturates additive with other CNS depressants?
|
Yes
|
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How are barbiturates absorbed?
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Any route of admin
|
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Why is the onset of action greater in thiopental greater than that of phenobarbital?
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Thiopental has a much greater lipid solubility so it can penetrate the brain faster
|
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How are barbiturates eliminated?
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Oxidation via cytchrome P450 enzyme complex
|
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Are metabolites of barbitures active or not active?
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Not active
|
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What inherent property of the classes of barbiturates causes it to be metabolized faster and more completely?
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Lipid solubility which means thiopental is 100% eliminated and eliminated faster
|
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What enzyme of the liver do barbiturates induce?
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Cytochrome P450 enzymes
|
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What general property besides lipid solubility allows thiopental to have a short onset of action?
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Redistribution - concentration in brain increases quicker than muscles (not at the same rate like phenobarbital)
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Does the redistribution effect occur in phenobarbital?
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No
|
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How are barbiturates excreted from the body?
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Kidney
|
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How can you enhance the excretion of phenobarbital and thiopental barbiturates?
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Make the urine alkaline
This isn't true for other barbiturates since their pKa is high |
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What are the 4 contraindications of barbiturate use?
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Acute intermittent porphyria
Severe liver disease Hypersensitivity reactions Uncontrolled pain |
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Is the therapeutic index for barbiturate toxicity wide or narrow?
|
Narrow
Only 10 times the normal dose can be fatal |
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Why does tolerance occur in barbiturate use?
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Increased rate of metabolism of the drug and CNS adaptation
|
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What effect of barbiturates is not prone to tolerance?
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Respiratory depression
|
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Does cross-tolerance develop with barbiturates and other CNS drugs?
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Yes
|
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What schedule of drugs are barbiturates?
|
II and III
|
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What are the withdrawal effects of barbiturate use?
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Minor: tremors, restlessness, anxiousness, weakness, N/V, insomnia
2 days after last dose: seizures Delirium due to increased sympathetic activity |
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What is the treatmen of withdrawal from a barbiturate?
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Gradual decrease in dose of a long-acting one
|
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What are they hypnotic drugs that we need to know?
|
Amitriptyline
Flurazepam Pentobarbital Secobarbital Temazepam Triazolam Zolpidem |
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What are the 5 stages of sleep?
|
1: Between wakefuleness and true sleep
2 3&4: Delta/slow wave sleep and is the deepest level of sleep REM: Dreaming, muscle atonia |
|
What are 3 frequent complaints of insomniacs?
|
Inability to fall asleep
Difficulty remaining asleep Sleep is not restful |
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What are two other classes of drugs besides hypnotics that can induce sleep?
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Antihistamines
Antidepressants |
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What are some common causes of insomnia?
|
Poor sleep hygeine
Drugs Psychological states Sleep apnea Movement disorders Disorders of timing of sleep/wake cycle |
|
What are the 3 categories of insomnia?
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Transient
Short-term Long-term |
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What is transient insomnia?
|
Situational and lasts less than 3 days
May respond to sleep hygeine Give lose dose hypnotics for only 2-3 nights |
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What is short-term insomnia?
|
Personal stressor and lasts 3 days - 3 weeks
Sleep hygeine education Hypnotics prescribed for 7-10 nights |
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What is long-term insomnia?
|
Lasts for more than 3 weeks and is due to a specific stressor that is not identifiable
Need a more complete medical evaluation |
|
What are some characteristics of an ideal hypnotic drug?
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Allows sleep to occur with normal sleep architecture
No effects the next day or rebound anxiety No interaction with other meds Could be used chronically without causing dependence |
|
Is exercise good for treating insomnia?
|
Yes
|
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What does it mean to have good sleep hygeine?
|
Regular sleep and wake times
Stop alcohol, caffeine, stimulants in early afternoon or evening |
|
What are the 4 benzodiazepines that can be used to induce sleep?
|
Flurazepam
Temazepam Triazolam Zolpidem |
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Why would someone want to use a hypnotic agent?
|
Shorten the onset time of sleep
Prolong sleep duration Reduce nocturnal wakefulness Provide anxiolytic effect during next day when insomnia has anxiety component |
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Are hypnotic agents first line for help with sleep problems?
|
No, treat underlying cause
|
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On the first night of sleep, what do hypnotics usually do?
|
Decrease sleep latency (can fall sleep faster)
Lengthen duration Decrease awake time and number of awakenings Decrease delta sleep time Decrease REM sleep time Increase Stage II sleep |
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On chronic use of hypnotics for sleep, what happens?
|
Tolerance develops
REM sleep returns to normal levels Rebound insomnia occurs if stop use REM rebound occurs if stop use |
|
What is sleep latency?
|
Amount of time it takes to fall asleep
|
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What are the 3 general classes of hypnotics in terms of duration of action?
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Ultrashort
Short Long Acting |
|
What are the advantages of using ultrashort hypnotics?
|
Little effect in the daytime
|
|
What are the disadvantages of using ultrashort hypnotics?
|
Rebound insomnia
REM rebound in early morning hours Tendency to use high doses to increase duration |
|
What is the half-life of ultra- short acting hypnotics?
|
2-3 hours
|
|
What is the half-life of short acting hypnotics?
|
5 hours
|
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What is the half-life of long acting acting hypnotics?
|
24-120 hours
|
|
What are the advantages of long acting hypnotics?
|
Drug may be more effective on second night than first night
REM rebound and rebound insomnia unlikely Residual daytime antianxiety effects in anxious patient |
|
What are the disadvantages of long acting hypnotics?
|
Residual daytime drowsiness that may be severe
Increased plasma levels as steady-state approached |
|
What class of drugs is flurazepam?
|
Benzodiazepene
|
|
What is the effect flurazepam on sleep?
|
Suppresses delta and REM sleep
REM returns to normal after cconstant use |
|
Does tolerance develop to flurazepam?
|
No, but not recommendended for long-term use
|
|
Are REM rebound and rebound insomnia occur with flurazepam? Why or why not?
|
No, because active metabolites hang around
|
|
Is flurazepam more effective on the first or second night of use?
|
Second
|
|
Does interfere daytime wakefulness?
|
Yes because it is long acting
|
|
What class of drugs is temazepam?
|
Benzodiazapene
|
|
Is temazepam short or long acting?
|
Long duration of action with a prolonged onset of onset
Steady state reached in 3 days |
|
Does temazepam accumulate in the body?
|
No
|
|
Does tolerance develop to temazepam?
|
No
|
|
Do REM rebound and rebound insomnia occur in temazepam?
|
Yes after discontinuation
|
|
Does temazepam cause daytime drowsiness?
|
No
|
|
Do you get drug interactions with temazepam? Why or why not?
|
No because it is not metabolized by P450
|
|
What class of drugs is triazolam?
|
Benzodiazapene
|
|
What is the half-life of triazolam?
|
Ultra short
|
|
Does daytime drowsiness occur with triazolam?
|
No
|
|
Do rebound insomnia and REM rebound occur with triazolam?
|
Yes, in a single night
|
|
What condition is higher in triazolam use compared with the other hypnotics?
|
Anterograde amnesia
|
|
What are the adverse effects of using triazolam?
|
Hyperexcitability
Daytime anxiety Agitation Confusion Affective disturbances Somnambulism |
|
What is unique about the class of drugs zolpidem belongs to?
|
Acts at the benzo binding site on GABAa but is not a benzo in structure
|
|
Does zolpidem cause muscle relaxation or anticonvulsant effects?
|
No
|
|
What are zolpidem's effects on sleep?
|
Do not suppress REM sleep or delta sleep at therapeutic doses
|
|
What is the half life of zolpidem?
|
Ultra short
|
|
What causes an increase in the half-life of zolpidem?
|
Elderly
Chronic hepatic insufficiency |
|
Does zolpidem cause residual effects the next day?
|
No
|
|
What are the 2 most common side effects of zolpidem?
|
Drowsiness
Drugged feeling |
|
Does rebound insomnia occur in zolpidem use?
|
Mildly
|
|
Is there a risk in devloping tolerance with zolpidem?
|
Yes, but way less than a benzodiazapene
|
|
Does zolpidem cause amnesia?
|
No
|
|
What are the over the counter sleep aids we need to know?
|
Antihistamines
|
|
What happens on the first night of taking an antihistamine?
|
Same as benzo's and barbiturates
|
|
Does tolerance develop to antihistamine use for sleep?
|
Yes, within one week
|
|
Does rebound insomnia and REM rebound occur with antihistamine use?
|
Yes
|
|
What are the side effects of using an antihistamine for sleep?
|
Anticholinergic
|
|
What are some general dosing strategies when prescribing sleep meds?
|
Individualize the dose
Prescribe lowest effective dose Lower the dose if combined with CNS depressants, alcohol, elderly, liver disease Avoid using everynight and limit duration of use Taper during withdrawal |
|
What is chronic use of sleep meds defined as?
|
Greater than 2 weeks (taper during withdrawal)
|
|
What are contraindications for the use of all hypnotics?
|
Alcohol
Pregnancy Sleep apnea If the patient needs nighttime alertness for a job |
|
Under what conditions should hypnotics be used with special precaution?
|
Elderly
Heavy snoring Kidney, liver, lung function Concurrent mediation that interacts Tendency to abuse drugs Skill jobs Suicidal risk |
|
How is serotonin synthesized?
|
Tryptophan transport into cells (neurons)
Tryptophan hydroxylase tryptophan ≡ 5-hydroxytryptophan (5-HTP) Aromatic amino acid decarboxylase 5-hydroxytryptophan ≡ serotonin (5-hydroxytryptamine; 5HT) |
|
What are the 3 places that serotonin is stored?
|
Synaptic vesicles in serotonergic neurons
Platelets Enterochromaffin cells |
|
How is serotonin metabolized?
|
Reuptake by transporter
Monoamine oxidase and aldehyde dehydrogenase serotonin ≡ 5-HIAA (5-hydroxyindoleacetic acid) |
|
What are the 2 important serotonin receptors for migraines?
|
5HT1B and 5HT1D
|
|
What is the mechanism of action of 5HT1B receptors?
|
5HT1B act as autoreceptors in CNS, reducing serotonin neuronal activity
Produce vasoconstriction selective for cranial blood vessels |
|
What is the mechanism of action of the 5HT1B serotonin receptor?
|
5HT1D are found on neurons of the trigeminal nerve, reduce activity in trigeminal pain pathways
Reduce release of peptides (CGRP, Substance P) that produce vasodilatation. |
|
Where are the 5HT1 receptors present?
|
CNS, smooth muscle, blood vessels
|
|
Where are the 5HT2 receptors present?
|
Platelets, CNS
Plow role in platelet aggregation |
|
Where are the 5HT3 receptors present?
|
Found in CNS - only G protein ones
Involved in emesis |
|
What are the functions of the neurotransmitter serotonin?
|
vasoconstriction
mood sleep temperature regulation pain blood pressure regulation platelet aggregation emesis |
|
Where are migraines most likely to occur?
|
Temporal and front regions
|
|
Is a migraine usually unilateral or bilateral?
|
Unilateral
|
|
What other symptoms are a migraine associated with?
|
nausea, vomiting, photophobia, phonophobia, irritability, GI tract activity greatly reduced
|
|
What is the theory for what causes a migraine?
|
Decreased activity of serotonergic neurons in the raphe nucleus
|
|
What are the 3 theories for what causes pain in a migraine?
|
Vasodilation of cranial blood vessels
Plasma extravasation from cranial blood vessels Pressure on cranial nerves |
|
Two of the following 4 symptoms produces a migraine?
|
1. Headache - unilateral site.
2. Headache - pulsating quality. 3. Associated nausea (90%). 4. Associated photophobia or phonophobia (80%). |
|
Two of the following 4 symptoms plus 1 of these other two symptoms produces a migraine?
|
Any two of the following four features:
1. Unilateral pain 2. Throbbing pain 3. Pain made worse by movement 4. Moderate or severe pain Plus one of the following two symptoms 1. Nausea or vomiting 2. Photophobia or phonophobia |
|
What triggering factors should be avoided in a migraine?
|
alcohol (e.g., red wine)
time zone changes certain foods (chocolates, cheeses) altitude changes irregular sleep weather/barometric pressure change increased stress menstrual cycle |
|
What percentage of patients with migraine drugs help?
|
70-80%
|
|
What constitutes a mild migraine?
|
Infrequent (<1 per month)
Lasts 4-8 hours Normal activities continue Discomfort to moderate pain |
|
What constitutes a moderate migraine?
|
More than 1/month
Lasts 4-24 hours Moderate impairment Moderate to severe pain May vomit |
|
What constitutes a severe migraine?
|
More than 3/month
Lasts more than 24 hours Severe impairment Moderate to severe pain Vomiting likely |
|
What are the mild analgesics that should be used to treat a mild migraine?
|
caffeine, aspirin, acetaminophen, ibuprofen, naproxen
|
|
What are the combination mild analgesics used to treat a mild migraine
|
MIDRIN
Butalbital and caffeine |
|
What are the side effects of MIDRIN?
|
sedation, dizziness, skin rash
|
|
What are the side effects of butalbital and caffeine?
|
Overuse can lead to rebound headaches, dependence
|
|
What is the antiemetic that is used to treat a mild migraine headache and what does it do?
|
Metoclopramide (REGLAN)**
Controls the symptoms |
|
What are the 3 treatments for moderate migraine headaches?
|
1. Combination analgesics (first)
2. Triptans or ergot alkaloids 3. Antiemetics nearly always |
|
What are the 3 treatments for severe migraine headaches?
|
1. Triptans or ergot alkaloids
and 2. Prophylactic treatment and 3. Antiemetics |
|
What is the Triptan that we need to know?
|
Sumatriptan
|
|
What is the MOA of sumatriptan?
|
5HT1 receptor agonist, especially B and D subtypes
Reduces nausea and vomiting Increases GI motility |
|
How is sumatriptan given?
|
Subq
|
|
How is sumatriptan metabolized?
|
Metabolized by MAO-A – so do not combine with MAO-A inhibitors (antidepressants)
|
|
What are the side effects of sumatriptan?
|
pain
stinging or burning at injection site heaviness or pressure in head feeling of warmth drowsiness dizziness chest discomfort increase blood pressure |
|
How should you not give sumatriptan?
|
IV because it can cause a coronary vasospasm
|
|
What population is sumatriptan not indicated in?
|
Children < 12
|
|
What are the drug interactions of sumatriptan?
|
Other triptans or ergots- vasoconstriction is additive
MAO-A inhibitors-contraindicated Propranolol increases plasma levels |
|
What are the 2 contraindications of sumatriptan?
|
Ischemic heart disease
Prinzmetal’s or variant angina |
|
What is the MOA of ergot alkaloids?
|
Non-specific in actions
Stimulation of 5HT1B and 5HT1D receptors |
|
What are the two effects of ergot alkaloids?
|
Vasoconstriction
Prevent plasma extravasation |
|
What is the ergot alkaloid drug we need to know?
|
Dihydroergotamine
|
|
How is dihydroergotamine given?
|
i.v., i.m., s.c., nasally
|
|
Why is dihydroergotamine preferred over ergotamine?
|
Less side effects
|
|
What are the side effects of the ergotamines (dihydroergotamine)?
|
nausea, vomiting - 20%
muscle weakness and pain numbness and tingling of extremities pain similar to angina gangrene in toxic doses hypersensitivity high doses – retroperitoneal fibrosis, valvular fibrosis |
|
What are the 5 contraindications of giving dihydroergotamine?
|
pregnancy
peripheral vascular disease coronary heart disease hypertension impaired hepatic or renal function |
|
With what drug is dihydroergotamine abosolutely contraindicated in giving with?
|
CYP3A4 inhibitors
severe vasospasm - cerebral and peripheral ischemia |
|
What are the other drugs that dihydroergotamines are contraindicated in?
|
ketoconazole, itraconazole - anti-fungals
troleandomycin***, erythromycin, clarithromycin - macrolide antibiotics protease inhibitors (ritonavir, saquinavir) grapefruit juice, fluoxetine, fluvoxamine, nefazodone, verapamil verapamil (used prophylactically) |
|
What is butorphanol?
|
A nasal spray that has proven useful in reducing pain due to migraine. This is a
partial agonist opioid with the attendant side effects. Cases of abuse have begun to appear. Should only be used in patients not responsive to other treatments. |
|
What Beta receptor antagonist is used to treat migraine prophylactically?
|
propranolol (classic tx)
|
|
What are the side effects of propranolol?
|
lethargy, GI upset, orthostatic hypotension
|
|
What anti-depressant is used to treat migraine prophylactically?
|
Amitriptyline
Used in mixed headache cases |
|
What are the side effects of amitriptyline?
|
atropine-like effects, sedation, weight gain
|
|
What anti-epilepsy agents are used to treat migraine prophylactically?
|
Valproic acid
Topiramate |
|
What are the side effects of valproic acid?
|
nausea, vomiting, anorexia, sedation, ataxia, tremor, hepatitis rare
|
|
What are the side effects of topiramate?
|
somnolence, fatigue, weight loss, cognitive effects
|
|
What other cosmetic drug has been used to try to prevent migraines with mixed sucess?
|
Botulinum toxin
|
|
What part of the brain is most affected in Parkinson's disease?
|
Nigrostriatal dopamine neuron
degeneration – projection from substantia nigra zona compacta to caudate-putamen Also can lose noradrenergic, serotonergic neurons |
|
Is parkinson's progressive?
|
Yes
|
|
What are the symptoms of parkinson's?
|
TRAP
Tremor at rest Rigidity (loss of flexibility) Akinesia or Bradykinesia Postural instability (should appear late in disease) Also lack of facial expression, difficulty swallowing, small shuffling steps, decreased arm swing, GI & visual disturbances |
|
What is the basic goal in Parkinson's treatment?
|
Compensate for loss of dopamine
|
|
How is dopamine synthesized?
|
Tyrosine to l-dopa by tyrosine hydroxylase (rate limiting step and only in CA neurons)
L-dopa to dopamine by dopamine decarboxylase (found in neurons/glia) |
|
What are the advantages of using Levadopa?
|
It works well, reduces all symptoms!
By-passes tyrosine hydroxylase (skips rate limiting step by using enzyme outside of neurons) Crosses BBB and is converted to dopamine in CNS Beneficial effects for about 4 hours |
|
What is levadopa always given with?
|
Carbidopa
|
|
Should levadopa dosing be monitored closely?
|
Yes
|
|
What are the side effects of levadopa?
|
Nausea, vomiting, anorexia – stimulates CRTZ (carbidopa)
CV: orthostatic hypotension***, arrhythmias (carbidopa) -hypertension with MAO-A inhibitors Dyskinesia: dose related Hallucinations, vivid dreams, psychosis*** - increases with continued use Depression, anxiety, agitation, insomnia, daytime somnolence |
|
What are the limitations of using levadopa?
|
On-off phenomenon
End-of-dose akinesia (Try sustained release form or MAO and/or COMT inhibitor) Vitamin B6 (increases metabolism) MAO inhibitors reduce metabolism (the point of selegiline use) -Good for selegiline (MAO-B), bad for antidepressant MAO-I (MAO-A/B) |
|
What are the 4 contraindications of using levadopa?
|
Psychotic disturbances (quetiapine)
Angle-closure glaucoma Cardiac arrhythmias Melanoma |
|
What does carbidopa do?
|
Inhibits peripheral aromatic amino acid decarboxylase which reduces levodopa metabolism so a lower dose can be used
Reduces peripheral SE such as nausea, vomiting, anorexia and hypotension Increases central SE such as dyskinesia |
|
Does carbidopa cross the BBB?
|
No
|
|
What is the most common combo prep of levadopa and carbidopa
|
SINEMET (sustained release)
ATAMET |
|
What are dopamine receptor agonists?
|
Bypass the synthetic process
|
|
What dopamine receptors are responsible for Parkinson's?
|
D2 more effected (all effective agonists stimulate this receptor)
D1 has unknown effect in Parkinson's |
|
At what age should dopamine agonists be used?
|
If < 60-70
|
|
How do the side effects of dopamine agonists compare to levadopa?
|
Similar side effects but less dyskinesia
Compulsive gambling may be increased |
|
What are the dopamine receptor agonists?
|
Pramipexole (may have antidepressant side effects, less dyskinesia than levadopa)
Rotigotine (patch with better compliance, less on-off side effects, application site reaction side effect, not clea if as effective as others yet) Ropinirole (can cause sudden sleep onset and compulsive gambling) |
|
What class of drugs is bromocriptine?
|
Ergot alkaloid
Dopamine agonist |
|
What is bromocriptine also used for?
|
Block prolactin release postpartum
|
|
Is bromocriptine used alone?
|
No, usually with levadopa
|
|
Why is bromocriptine not used much anymore?
|
Expensive
Lots of side effects because ergot |
|
What is Apomorphine?
|
Non-ergot dopamine receptor agonist
Used for For advanced Parkinson’s disease to treat hypomotility (“off” episodes) |
|
What are the side effects of apomorphine?
|
Severe nausea so must be taken with antiemetic
Also associated with CV SE Do not use with Metoclopramide (decreases effect) or ondansetron (severe hypotension) |
|
What is Selegiline?
|
MAO inhibitor
MAO B >>> MAO A reduces metabolism of levadopa/dopamine |
|
Does Selegiline exhibit tyramine syndrome?
|
No
|
|
What is Selegiline comboed with?
|
Levadopa
Reduces motor fluctuations, end-of-dose wearing off. |
|
What are the side effects of Selegiline?
|
Insomnia, agitation – due to metabolites
May increase central levodopa side effects Atrial fibrillation >10 mg/day non-selective: tyramine syndrome |
|
What does Selegiline have drug interactions with?
|
Meperidine
Antidepressants → serotonin syndrome |
|
What is Rasagiline?
|
MAO inhibitor
|
|
How is Rasagiline different than selegiline?
|
More potent (1 mg/day)
Approved for monotherapy in early PD in addition to combo with levodopa NOT metabolized into amphetamine-like compounds so fewer SE Neuroprotective?? |
|
What do COMT inhibitors do?
|
Inhibit COMT, reduce peripheral metabolism of levodopa.
Only used with levodopa. |
|
What are the COMT inhibitor we need to know?
|
Entacapone
|
|
What are some properties of Entacapone?
|
Does not cross BBB
Reduces off time from end-of-dose-wearing-off Doubles half-life of l-dopa w/o increasing plasma levels |
|
What are the SE of entacapone?
|
Dyskinesia is major side effect
Increases side effects of levadopa |
|
Why are anticholinergics used to treat Parkinson's?
|
In normal caudate-putamen dopamine and acetylcholine are functionally in balance.
In Parkinsonian caudate-putamen there is a loss of dopamine so the balance is lost – acetylcholine dominates. Therefore, block of acetylcholine action should help. In Cpu major ACh receptors are muscarinic, so atropine-like compounds are useful. |
|
What are the muscarinic receptor antagonists we need to know?
|
Trihexyphenidyl (Artane)
Benzotropine (Cogentin) -main help is with tremor -atropine like side effects (memory impairment/psychosis) |
|
What is Amantadine and what is it good for?
|
Anti-viral drug
Reduces tremor, dyskinesia in about 2/3 of patients. Effectiveness fades, sometimes quickly |
|
What is the MOA of amantadine?
|
Block glutamate/NMDA receptors
|
|
What are the side effects of amantadine?
|
*Ankle edema
*Confusion *Livedo reticularis – harmless but a nuisance Worsens congestive heart failure Psychiatric toxicity |
|
Is neuroprotective treatment for PD working?
|
No it is dissapointing
SAD SAD SAD |
|
What is another name for anti-psychotics?
|
Neuroleptics
They are not transquilizers |
|
Are anti-psychotics curative?
|
No, only palliative -- decrease symptoms (esp. schizo, but in other diseases as well)
|
|
What is a major issue with anti-psychotics?
|
Side effects
|
|
What is psychosis?
|
- Cannot comprehend reality
- Cannot think coherently - Behavioral impairment - Lack of awareness of the above issues |
|
What are the three types of psychosis?
|
Psychiatric - Ex: Schizo
Non-psychiatric - Ex: Drugs Part of other psych illness - Ex: PD |
|
What is a major concern in a schizo patient?
|
Suicide
|
|
What causes schizo?
|
Genetics - positive family history = inc. risk
Environment - winter births, maternal infection, maternal nutrition, obstetric complications |
|
What are the Positive Sx (beyond normal behavior) of schizo?
|
- Delusions - false beliefs
- Thought disorders - ideas not coherent - Perceptual disturbance - Ex: hallucination - Inappropriate affect - Ex: laughing at bad ideas - Altered Motor Function - Ex: strange posture |
|
What are Negative Sx (lack of normal behavior) of schizo?
|
- Lack of normal speech - Ex: one word answer
- Loss of emotion - flat affect - Loss of spontaneous behavior - motor poverty - Social isolation |
|
Factoid: Positive and Negative Sx occur in separate episodes. Negatve Sx get worse over time.
|
Blah
|
|
What is the DA hypothesis?
|
Psychotic symptoms are due to excess DA.
|
|
What are the four DA systems of the brain?
|
Mesolimbic-Mesocortical
Nigro-striatal Tubero-Infundibular Medullary-Periventricular |
|
What is the mesolimbic-mesocortical system?
|
Emotion & Cognitive circuitry respectively
Regulate affect, reinforcement circuity, psychomotor activity, and sensory perception |
|
What is the nigro-striatal system?
|
Parkinsonism by antagonism of DA actions in this circuit.
|
|
What is the Tubero-Infundibular system?
|
Hyperprolactinemia mediated by antagonism of DA inhibition of prolactin secretion.
Recall: DA inhibits prolactin secretion. |
|
What is the medullary-periventricular system?
|
Eating (Obesity, Diabetes)?
Chemoreceptor trigger zone - DA agonist = emetic, DA antagonist = anti-emetic |
|
What are positive symptoms due to?
|
Excess DA function
|
|
What are the negative symptoms due to?
|
Deficit in DA function (may not be the complete story)
|
|
Factoid: The higher the affinity of the drug, the lower the dose. Visa versa is true as well.
|
Blah
|
|
What is an example of a high affinity drug?
|
Haloperidol
|
|
What is an example of a low affinity drug?
|
Chlorpromazine
|
|
What is an example of an atypical drug?
|
Clozapine, Olanzapine, Risperidone
|
|
What symptoms do anti-psychotics work best against?
|
Positive symptoms - but they can decrease negative as well.
|
|
What is the prototype low affinity (low potency) drug? Side effects?
|
Chlorpromazine - lower extrapyrimidal side effects, higher sedative effects (related to chronic use from lower potency)
|
|
What is the prototype high affinity (high potency) drug? Side effects?
|
Haloperidol - higer extrapyrimidal side effects (related to acute use and higher potency), lower sedative side effects
|
|
Are the prototype drugs still used?
|
Yes, they are cheap
|
|
What is MOA of anti-psychotics?
|
Inhibition of D2 receptors (for pos. symptoms, neg. work thru a diff. mechanism?)
|
|
How long do you need to take the drugs b/f you get an effect?
|
2 weeks to 6 mths -- no drug can have a quick, acute effect
|
|
Are anti-psychotics plasma protein bound? Are they lipid soluble?
|
Yes
Yes |
|
Metabolism of drugs?
|
Hepatic P450 system
First pass metabolism extensive - orally Excreted by kidney |
|
How do antacids effect anti-psychotics?
|
Slow down there absorption
|
|
Why are parenteral anti-psychotics used?
|
For acute psychotic episodes - no first pass metabolism
|
|
Why are depot preps used?
|
Non-compliant patients - correct dose should be figured out first
|
|
What is the basis of side effects?
|
If stimulate D2 system too much (inhibit MAO, excess Dopa, DA agonist,...) --> symptoms of psychosis. *Recall that DA is inhibitory in CNS.
ACh system will dominate causing side effects if DA system too inhibited. Balance of DA system and ACh system |
|
Can anti-psychotics act on receptors other than the DA receptor?
|
Yes, they often do and this interaction is often the cause of side effects. Certain anti-psychotics act more or less on a particular receptor and therefore cause different side effects.
|
|
Side effect of Muscarinic receptor?
|
Dry mouth, blurred vision, sedation, etc...
|
|
Side effect of Adrenergic receptor?
|
Sedation, orthostatic hypotension, lightheadedness, etc...
|
|
Side effect of Histamine receptor?
|
Drowsiness and sedation
|
|
Side effect of Serotonin receptor?
|
He wrote nothing on the slide
|
|
Sedation side effect characteristics?
|
Through adrenergic blocker
Chlorpromazine Can cause seizures |
|
What are the extra-pyrimidal side effects?
|
Dystonia - muscle spasms
Akathesia - "ants in the pants" Parkinsonism Tardive Dyskinesia - associated w/ long term treatment of DA blockers. May be antagonized by muscarinic blockers (worsen w/ anti-cholinergics?). Could also decrease DA blocker. May be irreversible. |
|
How do you manage reversible EPSEs?
|
Decrease dosage
Anti-histamine |
|
How do you manage irreversible EPSEs (tardive dyskinesia)?
|
Clozapine
|
|
What is neuroleptic malignant syndrome?
|
Hyperthermia, muscular rigidity, autonomic dysfunction, fluctuating consciousness
Measure creatine kinase Resembles severe Parkinsonism |
|
Autonomic side effects?
|
Related to anticholinergic, antiadrenergic
*Histaminergic, and serotonergic receptor effects also possible. |
|
What is the neuroendocrine side effect?
|
Hyperprolactinemia - all drugs but Clozapine. Sexual dysfunction, wt. gain
|
|
What drug has a cardiac side effect?
|
Chlorpromazine - direct effect on the heart and effects heart thru CNS
|
|
What is a common hematologic side effect?
|
Agranulocytosis - very rare (Esp. Clozapine & Chlorpromazine)
|
|
MOA of Haloperidol?
|
D2 agonist
|
|
Side effects of Halo?
|
EPSE
NMS Dystonia Hypotension |
|
MOA of Chlorpromazine?
|
Low affinity D2 agonist
|
|
Side efffects of Chlorpromazine?
|
Low risk EPSE
High sedative effect (adrenergic related) Hypotension |
|
What DR is Clozapine selective for?
|
D2 and D4
|
|
What receptor has the largest effect on anti-psychotic effect?
|
D2
Followed by Serotonin and ??? receptors |
|
What receptor does Clozapine act on?
|
D4>D2>5HT2
So, since Clozapine is an atypical drug and b/c of its receptor activity, atypical drugs are called dopaminergic-serotinergic antagonists |
|
MOA of Clozapine?
|
D4 antagonist
|
|
Side effects of Clozapine?
|
No EPSE
??? Agranulocytosis, other shit... |
|
What is Risperidone?
|
Atypical drug
No agranulocytosis (unlike Clozapine) |
|
What is Olanzapine?
|
Unique drug for treating the negative symptoms of schizo. Similar efficacy for positive symptoms as other anti-psychotics.
|
|
Adverse effects of Olanzapine?
|
Low EPSE
Sedation, wt. gain, orthostatic hypotension, seizures, hyperglycemia |
|
Uses of Olanzapine?
|
Schizophrenia
Acute mania in bipolar Psychosis in Dementia |
|
There is a good chart in the notes for all these drugs...
|
...look at it
|
|
There is another giant table...
|
...he says to look at it
|
|
What is Li used for?
|
Bipolar disorder and can be used concomitantly with anti-psychotics or anti-depressants
|
|
What is MOA of Li?
|
No effect in normal patient!
Inhibition of inositol phosphate signaling pathway and therefore block Ca+2 release -- a signaling pathway |
|
What is MOA Lithium Carbonate?
|
A form of Li. Basically the same as the last slide in terms of MOA and effect on normal patient.
|
|
Side effects of Li?
|
Effect on electrolyte and ion xport
Effect on other neurotransmitter systems |
|
Kinetics of Li?
|
Well absorbed
Steady state in 5 days Renal elimination |
|
Factoid: Li has a very narrow therapeutic window, monitor regularly!!
|
Awesome
|
|
There are many side effects with Li...
|
...if you want to memorize the list, go for it
|
|
What is the most impt. side effect of Li?
|
Thyroid enlargement/hypothyroidism - always do TFTs
|
|
What drug interaction do you have to be careful of when taking Li?
|
Iodine - have anti-thyroid effects that are additive w/ Li
|