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355 Cards in this Set

  • Front
  • Back
What classes of drugs are CNS depressants?
Benzos, Barbituates, Hypnotics, Ethanol, General anesthetics
What are the degrees of CNS depression?
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.
MOA of benzos?
Act on GABA-A receptor
MOA of other CNS depressents?
Alter GPCR, ion channels (including GABA-A receptor), alter signal transduction. Specific action varies w/ drug.
What is GABA?
Major inhibitory transmitter in the CNS. There are two GABA receptors...*GABA-A (ion channels), GABA-B (GPCR).

***Glycine major inhibitory in spinal cord.
What is unique about GABA-B?
It is a heterodimer GPCR
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
How can you open the GABA-A receptor?
Only by GABA binding
What sub-unit do you need for benzo effect?
Gamma subunit
What are the effects of benzos binding to different alpha subunits on GABA-A receptor?
See notes - went too fast to catch
Is there a barbituate binding site on GABA-A? Ethanol? Anesthetic?
Yes to all, but not well defined
What is MOA of benzo?
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
What is effect on dose-response curve when Benzo is added?
Shifts to left
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
Do benzos have effect on any other binding site?
No
What are other MOAs of Barbituates?
- Inhibit glutamate receptors
- Inhibit Na+ & K+ channels
- Inhibits nicotinics
What is MOA of ethanol?
- 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
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.
What affects the fate of onset of CNS effects of the CNS depressants?
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
What acts for a reservoir for the drugs that act on the CNS?
Muscle and fat

The drug circulating to the brain will decrease as the drug is picked up by these tissues
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
Are benzodiazapenes used to treat insomnia?
Yes
Are benzodiazapenes used to treat epilepsy and seizures?
Yes
Are benzodiazapenes used to treat anxiety?
Yes
Are benzodiazapenes used to promote sedation, amnesia, and as preanesthetic medication?
Yes
Are benzodiazapenes used to treat muscle relaxation?
Yes
What benzodiazapene is used to decrease muscle spasticity and muscle spasm?
Diazepam
What is the site of action of diazepam in controlling muscle spasms?
GABA-A receptors on the spinal cord on the presynaptic endings of the primary efferent nerves
Are benzodiazapenes used to treat symptoms of alcohol and sedative-hypnotic withdrawal?
Yes
Which benzodiazapenes are used to treat symptoms of alcohol and sedative-hypnotic withdrawal?
Chlordiazepoxide

Diazepam

Lorazepam
What two things are the approved uses of benzodiazepines based on?
Marketing strategies

Half-life of the drugs

**They can be used interchangeably
What are the CNS effects of benzodiazepines?
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?
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)
What are the CV side effects of benzodiazepines?
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
Are benzodiazepines weak acids or weak bases?
Weak bases
How are benzodiazepines usually given and why?
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?
Local pain and thrombophlebitis
What is the primary means of eliminating benzodiazepines?
Metabolism
What are the long acting benzodiazepines?
Clorazepate

Diazepam

Flurazepam
How are the long acting benzodiazepines metabolized?
Oxidation and conjugation (Phase I and Phase II active metabolites)

Active metabolites are formed which have half-lives greater than active compounds
What are the short acting benzodiazepines?
Alprazolam
Midazolam
Triazolam

Lorazepam
Temazepam
How are the short acting benzodiazepines metabolized?
Metabolized by a-hydroxylation and conjugation (Phase I and II):
Alprazolam
Midazolam
Triazolam

Metabolized by conjugation only (Phase II):
Lorazepam
Temazepam
Is metabolism involving glucoronide conjugation or oxydation more affected by old age of the liver?
Oxidative metabolism
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
How long does it take benzodiazepenes to reach steady state blood levels?
Days to weeks
Is there any clinically significant induction of hepatic drug metabolizing enzymes in benzodiazepenes?
No
What inhibits benzodiazepene metabolism?
Cimetidine

Oral contraceptives

Isoniazid

Grapefruit juice
What are the most common side effects of benzodiazepenes at therapeutic doses?
Drowsiness

Sedation

Impaired moto coordination

Weakness

Dizziness

Confusion

Memory loss
Does tolerance develop to the side effects of benzodiazepenes?
Yes
What effect of benzodiazepenes develops slowly or doesn't develop tolerance at all?
Anti-anxiety effects
What are the two main signs of toxicity in benzodiazepene use?
Drowsiness and ataxia
What 3 classes of CNS depressants are additive to benzodiazepenes?
General anesthetics

Hypnotics

Anti-anxiety drugs
Do benzodiazapenes given orally produce fatal toxicity?
No, unless they are combined with alcohol
May benzodiazepenes be additive when given with other drugs that act on the CNS?
Yes

Ex. Opioids, antihistamines, antipsychotics/depressants, anticholinergics, central acting antihypertensives
What condition are hypnotic benzodiazepines absolutely contraindicated in?
Pregnancy
(they are in category X)
Are anxiolytic benzodiazepines contraindicated in pregnancy?
No, but they may cause a large risk
Why are benzodiazepines contraindicated in pregnancy?
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?
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
What is the benzodiazepine antagonist that we need to know?
Flumazenil
What is the use of Flumazenil?
Reverse the sedative effect of benzodiazepines after anesthesia/sedation

Reverse effects of benzodiazepine overdose
What is Flumazenil not effective in doing?
Reversing efects of opioids, non-benzo sedative hypnotics, or anesthetic drugs
What type of reaction will occur if a patient dependent on benzodiazepines is given Flumazenil?
Withdrawal
How is Flumazenil given and how is it metabolized?
IV

Liver
What two effects of benzodiazepines does tolerance develop in?
Anticonvulsant

Hypnotic
What effect of benzodiazepines does little tolerance occur in?
Anti-anxiety
Does dependence of benzodiazepines occur?
Not really, there is little tendency to increase the dosage
What schedule is benzodiazepines?
IV
What can discontinuing use of benzodiazepines cause?
Symptom recurrence (like pre-therapy)

Rebound (

Withdrawal
What is the definition of dependence?
Altered physiological state that requires continuous drug administration to prevent appearance of withdrawal symptoms
What happens during withdrawal of benzodiazepines?
Increased CNS excitation which can lead to convulsions
Is the intensity of withdrawal less severe with long or short acting benzodiazepines?
Long because the CNS can gradually return to normal state
What is the rebound phenomenon with benzodiazepines?
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
Are rebound symptoms similar to withdrawal in benzodiazepines?
Yes
What are the symptoms of withdrawal in benzodiazepines?
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
What is the goal for removing benzodiazepine treatment?
Lower dose by 25% each week
What is cross-dependence in benzodiazepines?
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
Is psychological or physical dependence more common in benzodiazepines?
Psychological
What is buspirone used for?
Relieves generalized anxiety but not effective in other types of anxiety
What is the MOA of buspirone?
Partial agonist at 5HT receptor
What are the advantages of buspirone over benzodiazepines?
Little sedative or euphoric effects

No rebound anxiety or withdrawl signs on discontinuation

Does not potentiate CNS depressants
What are the side effects of buspirone?
Tachycardia, palpitations, nervousness, GI distress, paresthesias (more common than with benzo's)
What 4 barbiturates should we know?
Pentobarbital

Phenobarbital

Secobarbital

Thiopental
What causes the hypnotic effects of barbiturates?
Lipophillic hydrocarbon groups at C5 position
What causes an increase in the lipid solubility of a barbiturate?
Substitution of sulfur for oxygen and addition of methyl group to nitrogen
Are barbiturates a weak acid or weak base?
Weak acid
What is the long acting barbiturate we need to know?
Phenobarbital
What is phenobarbital used for?
Sedative and anticonvulsant
What is the ultra short barbiturate we need to know?
Thiopental
What is thiopental used for?
IV anesthetic
What is the intermediate acting barbiturate we need to know?
Pentobarbital
What is pentobarbital used for?
Hypnotic
What is the short acting barbiturate we need to know?
Secobarbital
What is secobarbital used for?
Hypnotic
What is the order of potentcy of the barbiturates?
Thiopental > secobarbital > pentobarbital > phenobarbital
What are the CNS effects of sedative and hypnotic doses of barbiturates?
Act on multiple receptors to reversibly depress all excitable tissues
-can alter a patient's sleep patterns
What are the CNS effects of toxic and anesthetic doses of barbiturates?
Depress the vasomotor center

Depress respiratory center which is the primary cause of death

Depress thermoregulation

Do not raise the pain threshold
Are actions of barbiturates additive with other CNS depressants?
Yes
How are barbiturates absorbed?
Any route of admin
Why is the onset of action greater in thiopental greater than that of phenobarbital?
Thiopental has a much greater lipid solubility so it can penetrate the brain faster
How are barbiturates eliminated?
Oxidation via cytchrome P450 enzyme complex
Are metabolites of barbitures active or not active?
Not active
What inherent property of the classes of barbiturates causes it to be metabolized faster and more completely?
Lipid solubility which means thiopental is 100% eliminated and eliminated faster
What enzyme of the liver do barbiturates induce?
Cytochrome P450 enzymes
What general property besides lipid solubility allows thiopental to have a short onset of action?
Redistribution - concentration in brain increases quicker than muscles (not at the same rate like phenobarbital)
Does the redistribution effect occur in phenobarbital?
No
How are barbiturates excreted from the body?
Kidney
How can you enhance the excretion of phenobarbital and thiopental barbiturates?
Make the urine alkaline

This isn't true for other barbiturates since their pKa is high
What are the 4 contraindications of barbiturate use?
Acute intermittent porphyria

Severe liver disease

Hypersensitivity reactions

Uncontrolled pain
Is the therapeutic index for barbiturate toxicity wide or narrow?
Narrow

Only 10 times the normal dose can be fatal
Why does tolerance occur in barbiturate use?
Increased rate of metabolism of the drug and CNS adaptation
What effect of barbiturates is not prone to tolerance?
Respiratory depression
Does cross-tolerance develop with barbiturates and other CNS drugs?
Yes
What schedule of drugs are barbiturates?
II and III
What are the withdrawal effects of barbiturate use?
Minor: tremors, restlessness, anxiousness, weakness, N/V, insomnia

2 days after last dose: seizures

Delirium due to increased sympathetic activity
What is the treatmen of withdrawal from a barbiturate?
Gradual decrease in dose of a long-acting one
What are they hypnotic drugs that we need to know?
Amitriptyline
Flurazepam
Pentobarbital
Secobarbital
Temazepam
Triazolam
Zolpidem
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
What are two other classes of drugs besides hypnotics that can induce sleep?
Antihistamines

Antidepressants
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?
Transient

Short-term

Long-term
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
What is short-term insomnia?
Personal stressor and lasts 3 days - 3 weeks

Sleep hygeine education

Hypnotics prescribed for 7-10 nights
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?
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
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
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
Are hypnotic agents first line for help with sleep problems?
No, treat underlying cause
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
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
What are the 3 general classes of hypnotics in terms of duration of action?
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
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