2. Anti-anxiety, Sedative, Hypnotic Drugs Flashcards
Increasing Levels of CNS Depression • Anxiolysis – take the \_\_\_\_ off • Sedation – feel \_\_\_\_ • Hypnosis - induce sleep but \_\_\_\_ • General Anesthesia – A \_\_\_\_ state of patient unresponsiveness, analgesia and muscle \_\_\_\_ that allows the goals of surgery to be accomplished
edge drowsy rousable pharmacological relaxation
Uses of ASH Drugs in Dentistry
• ____ before so anxious patient gets good night of sleep
• ____ patient both before and during procedure
• Muscle relaxation as in ____ patient
night
calm
TMD
Categories of ASH Drugs • Barbiturates • Benzodiazepines • Carbamates • Antihistamines (H-1 receptor blockers) • Alcohols • Others
Barbiturates are rarely used today
◦ They have a ____ therapeutic index (about 4-10), easy to unintentionally overdose
‣ Benzodiazepines have a ____ therapeutic index (about 20-60) so they’re used more often
• BTW, if you take these with alcohol of opioids, all bets are off
• The higher the therapeutic index, the safer the drug is
Carbamates are highly promoted as muscle ____
◦ Flexeril (cyclobenzaprine) was one of the few drugs that has shown, in a clinical trial, some efficacy in ____ pain. but there’s a lot of side effects.
low
higher
relaxant
musculoskeletal TMJ
Antihistamines. This makes sense. ◦ They've shown up in Parkinson's and an alternative for patients with local anesthetic allergy ◦ They are \_\_\_\_, pediatric dentists love them ◦ [tells story about his grandson taking this for tx] ◦ BTW, if a kid is totally uncooperative, you gotta bring them to the OR ‣ Otherwise, all you end up doing is throwing too many drugs into them which can get you in trouble, like the kid stops breathing
Alcohols. This makes sense, having a glass of wine is a little sedating
◦ ____ is an old drug that pediatric dentists use. It goes on and off the market
‣ It’s related to an industrial solvent, ____
• In a test tube, trichloroethylene is mutagenic
◦ But guess what? If you put a Coors Light in a test tube, that’s mutagenic too “There’s a couple of Others that I may mention…”
sedating
chloral hydrate
tricholorethylene
Barbiturate Structures
• These are some of the classic Barbiturates
◦ [red circle] This makes it a barbiturate, this is the barbiturate ____
• ____ was mainly used to knock people out, but there are drugs with better therapeutic indices
• If a patient is on chronic Phenobarbital, what do they probably have?
◦ ____ disorder, that’s its major use
◦ It kinda makes sense that drugs that dull the brain have anti-seizure activity
‣ BTW, these more-so than opioids because these indirectly affect ____ channels
nucleus
thiopental
seizure
chloride
Barbiturate vs. Benzodiazepine Dose Response Curves
The dose response curve for a ____ (Phenobarbital) is much steeper than a ____ (Diazepam or Midazolam)
◦ With a barbiturate, it’s much ____ transition to transition from Sedation and Hypnosis into Coma and Death
BTW, the type of respiratory depression you get from barbiturates is usually a little different than opioids
◦ With opioids, you’re not responding to ____
◦ With barbiturates, you tend to lose ____ reflexes, like the ability to keep the airway open
• Benzos have a much ____ dose response curve
◦ Easier to stay in
Sedation/Hypnosis and not
bring pt to Coma/Death
◦ This is another way to show how ____ have a higher therapeutic index
barbiturate benzodiazepine easier CO2 protective flatter benzos
Other Barbiturate Limitations
• ____ and physical dependence can rapidly appear
• Withdrawal if dependent is life-threatening-____
• Some drugs DEA schedule ____–seco and pento
• Lots of drug interactions –____ inducers
• Depress ____ sleep
• No ____ for overdose
• ____ compounds
tolerance seizures 2 CYP REM antagonist hyperalgesic
Molecular Pharmacology Differences Between Benzodiazepines and Barbiturates/Alcohols
• Benzodiazepines increase frequency of ____ channel openings
• Barbiturates and alcohols:
– increase duration of ____ channel opening
– physically open ____ channels w/o ____
– depress action of excitatory amino acids like ____
chloride chloride chloride GABA glutamate
Thiopental (Pentothal®) and Methohexital (Brevital®)
- Given for ultrashort acting ____
- “Cocktailed” with other intravenous sedation drugs to produce deep ____ or twilight anesthesia
- No ____ agent (no antagonist)
- More about these in injectable GA lecture
general anesthesia
sedation
reversal
Secobarbital (Seconal®) and Pentobarbital (Nembutal®)
• Available ____ and intravenous formulations
• DEA Schedule ____ drugs
• ____ therapeutic index
– Therapeutic blood levels = ____ ug/ml
– Coma/respiratory depression = ____ ug/ml
oral and intravenous 2 low 1-3 10
Phenobarbital (Luminal®)
• Considered ____ in class
– Therapeutic blood levels – ____ ug/ml
– Coma/respiratory depression – ____ ug/ml
- DEA Schedule ____
- Major use today is in control of ____ disorders
- Chronic use can produce both ____ and pharmacodynamic tolerance
safest
5-10
50
4
seizure
metabolic
Benzodiazepines
- diazepam
- midazolam
- triazolam
- flumazenil (benzo antag)
- benzos- main reason replaces barbs as anti- anxiety sedative hypnotic drugs (hypnotic–> sleeping aid) is bc they’re ____ is much higher if you take them alone of 20-50
- even w the most powerful need a 20 fold OD to get into trouble. If drink w booze and opioids all bets are off. then you may have additive effects (1+1= 20)
- for benzo to be agonist- need bottom 6 membered ring * points to the arrows*. won’t have to draw structures, just get CONCEPT!
- btw the benzo antagonist ____- for diazepam, mid, triaz. BUT doesn’t have the bottom ring and its ____ on the side chain (why its an antagonist) binds receptor but doesn’t activate it
- naloxone (morphine, fentanyl, heroin)
TI
flumazenil
bulky
Benzodiazepines
• the other thing you can do w this is add more HALOGENS (Cl, Fl) –> increase ____ and ____! doesnt mean better just need less
• ex. IV sedation of diaz. diff for everyone cuz titrate to effect, usually 10-12 mg vs mida. 3-4mg (3x more powerful, doesnt mean its better). like oxycodone and coding (oxy is just more powerful)
• add 5 membered ring–> decrease production of ____ metabolites
• diaz.- 1/2 life in young adult of 24 hrs, but few ____ metabolites (methydiazepam, oxazepam–> extent duration of action). take to prevent seizures then its good just 1 dose vs pt for dental appt its bad (tired all day)
• triaz.- orally taken over. also w potency- halogenating, oral dose of diaz. in an adult (for anxiety) need 5-10mg vs .25-.5mg-
triaz. that additional Cl makes the difference.
lipid solubility
potency
active
active
- EXAM: ask- what could flumazenil fix an OD of? ____, ____, ____
- what wouldn’t it reverse? pick answer thats not a benzo
diazepam
midaxolam
triazolam
Advantages of Benzodiazepines vs. Barbiturates 1
• Much ____ therapeutic index
• More ____ than barbiturates as anti- anxiety agents
– In animal studies doses needed to calm animal 1/10 that needed to induce ataxia and sleep
– With barbiturates in animals see ____ and sedation with anti-anxiety doses
higher
selective
ataxia
Advantages of Benzodiazepines vs. Barbiturates 2
• Less abuse potential than barbiturates
– DEA Schedule ____ drugs
– ____ reactions if physically dependent generally less severe than barbiturates
• Less drug interactions than barbiturates. Do not induce ____ enzymes. However a few (midazolam, triazolam) are ____ substrates. Potential for adverse drug interactions especially with other agents that impair their metabolism especially following oral administration.
4
withdrawal
CYP
CYP3A4
- substrate- means drug is partially or fully inactivated by that isoform, at least made more water soluble, less lipid soluble, and excreted ore easily
- inhibitors- block enzyme that metabolizes substrates. this is why statins cant take w grapefruit juice cuz will increase blood lvls–> muscle aches and rarely rhabdomlysis (breakdown skeletal muscles–> clog renal tubules)
- the 2 benzos starred (triazolam and midazolam), if people allergic to penicillin V then use ____, but instead w odontogenic infections use ____
- clarithromycin- used for URI
• these 2 antibiotics (erythromycin and clarithromycin) can jack up ____
• review: phenobarbitals (could have been other barbs), they increase metabolism of alot of drugs (blood levels of
substrates can fall SUBtheraputic)
• warfarin- hits VIT K epoxide receptor complex (decrease clotting factors), levels of warfarin increase if take ____–> warfarin ____–> clots/ pulmonary embolism (cuz initially took warfarin cuz “<3 was beating like jello”)
• at the other end- ____ (good for anaerobes) dont give w warfarin they’ll bleed out!! same for azole ____
drugs (fluconazole, diflucan, clotrimazole) cuz they increase warfarin too
• estrogen/progesterone can be decreased by ____ also st. johns wort
erythromycin clindamycin statins and benzos phenobarb decrease metronidazole antifungal phenobarbitals
Midazolam
- 25 ppl take therapeutic dose of oral midazolam
- 6mg midaz. used in peds
- instead of taking w water, took w 10 oz of grapefruit juice—> blood levels ____
- issue was this is a kid using it on, they’ll become a zombie, over sedated, now in deep sedation where the level of training you need must be more advanced, sometimes they can loose ability to maintain patent ____
- reversal agent by injection: ____. Poor ____ orally cuz takes 30-60min for oral drugs to work.
doubled
airway
flumanezil
bioavailability
- Erythromycin- blood levels midazolam w placebo for 6 days vs erythromycin 6 days then 1 dose of midaz. blood levels ____!! cuz midaz. is 3A4 substrate w enzyme inhibitor–> over sedated kid–> maybe obstruct ____. child gone from office but still passed out
- if force kids head forward when sleep kid will ____ (protective reflex), but now they dont and not breathing well.
tripled
airway
resist
Advantages of Benzodiazepines vs. Barbiturates 3
- More ____ as muscle relaxants
- Do not depress ____ sleep much
- Respiratory depression unlikely with ____ medications unless combined with other CNS depressants (____ a major red flag)
- Reversal agent (antagonist) exists= ____ (Romazicon®). Main use is from overdose with intravenous ____ (Versed®) or ____ (Valium) although more combined overdoses with oral formulations plus opioids now seen.
selective REM oral out-patient opioids flumazenil midazolam diazepam
Oral benzodiazepines have a ____ therapeutic index, however bad things occasionally happen, especially in a ____ child given high therapeutic doses!!!!
high
young
• Midazolam- screaming kid can get IV in and realistically cant get nose dropper in for some of these plus it
stings
◦ dose is ____ than diaz., wouldn’t expect this but its bc the oral absorption isn’t high. IV the potency
ratio shows up but not apparent w ____
• diazepam- ____ half life and ____ metabolites, isn’t used much anymore
• triazolam- powerful one, ____ with Cl, see .02mg/kg. SO 36lb kid thats 15kg–> .3mg of drug,
equivalent of 40mg of chloral hydrate
- triazolam- kind of slick but not approved, you can use ____, you’ll get higher levels than orally. some dentists promote this but you need to know what you’re doing
- bad things can even happen w oral medazolam
higher oral long active halogenated sublingually
Oral Midazolam Mishap
Three year old, 35 pound female in need of 5 stainless steel crowns and other work. Procedures are scheduled over 4 visits. Patient administered 16 mg (1 mg/kg) oral midazolam syrup. Thirty minutes later clinician hears a “choking/gagging sound, O2 saturation has dropped to 95. Clinician repositions head, initiates assisted breathing, activates 911. EMTs arrive, O2 saturation 98, child is spontaneously breathing (16/min) but unresponsive to verbal commands. Unable to establish intravenous access. Decide to intubate, several failed attempts, child goes into respiratory arrest. Transported to nearby hospital emergency room, given ____ (Romazicon®) 0.35 mg intravenously. Child awakens and makes a full recovery
Flumazenil dosing: 0.2 mg – 1 mg (____ IV, ____ IM or sublingual)
flumazenil
lower
higher
Molecular Pharmacology Differences Between Benzodiazepines and Barbiturates/Alcohols
• Benzodiazepines binds to own receptor and increases affinity for ____ to its receptor leading to increased frequency of ____ channel openings
• Barbiturates and alcohols:
– increase ____ of chloride channel opening
– physically open ____ channels w/o GABA
– depress action of excitatory amino acids like ____
GABA chloride duration chloride glutamate
SEE NOTES ON THE RECEPTOR TYPES
MAKE SURE YOU BREAK THIS DOWN!
Diazepam (active, t1/2 = 24 hours) -> ____ (active, t1/2 = 12 hours) -> ____ (active, t1/2 = 6 hours) -> inactive
strategy: administer short-acting benzodiazepines without active metabolites
- elderly: every 1/2 increases by ____ fold -> enzyme metabolizing capacity is ____
- ____ is down, heart is not pumping as efficiently, causes less ____ per unti time appearing at the liver and kidney
- you’ve got action beyond the ____ of the drug -> drug has ____ metabolites
desmethyldiazepam
oxazepam
3-4 down cardiac output drug half life active
Sublingual triazolam
- absolute dose depending on weight of kid is between 0.25 and 0.375 mg
- maximum dose to never exceed: ____
after 60 minutes of sublingual deliver -> starts ____ off.
- > may have ____
- > ____ effect of drugs -> forget stuff after the drug was administered
- > all could ____ their names
-> placing them at moderate level of sedation
0.5 falling gait ataxia anterograde amnesic remember
- > sublingual triazolam -> started to ____ (difficult to do sublingual)
- > hit w ____ at 60 min, and ____ at 90 min
- > procedure ends at 90 min-2 hours -> blood levels are still ____ up
titrate
0.5
0.25
going
adults were also hitting ____; need a higher level of ____ if putting someone into deep sedation
ADAS says if you’re titrating triazolam -> do not exceed ____
deep sedation
training
0.5 mg
Other Benzodiazepine Uses
• Alprazolam (Xanax®) – ____
• Diazepam (Valium®), Clonazepam (Klonopin®) – ____
• Midazolam (Versed), Diazepam (Valium) – ____ sedation.
• Chlordiazepoxide (Librium®) and others – lessen ____ symptoms (prevent seizures) from ____ and barbiturates.
anxiety, panic, disorders and depression
anxiety and seizures
intravenous
withdrawal
alcohol
Other Adverse Reactions to Benzodiazepines
- Most have mild ____ activity. Relative contraindication in patients with ____.
- ____ especially in kids at low doses
- Intravenous diazepam not ____ soluble. Propylene glycol vehicle ____ on injection and causes phlebitis (venous irritation).
anticholinergic narrow angle glaucoma disinhibition water burns
Carbamates 1
• Carisoprodol (Soma®), Meprobamate (Miltown®), Cyclobenzaprine (Flexeril®)
• Marketed mainly as ____ but like other ASH drugs the only muscle they relax is the one between your ears (the ____ – dampens ____ pathways coming out of CNS)
• Safety somewhere in between ____
muscle relaxants
brain
polysnaptic
benzodiazepines and barbiturates
Carbamates 2
• Meprobamate DEA Schedule ____
• Carisoprodol just moved from unscheduled to DEA Schedule ____
• Drugs cause lots of ____
• Cyclobenzaprine (Flexeril) one of few drugs that have ever demonstrated efficacy in clinical study of ____ pain. ____, tachycardia, increased ____ in glaucoma patients.
4 4 drowsiness muscular TMJ xerostomia intraocular
Chloral Hydrate
Chloral Hydrate -> Trichloroethanol
- Old but still popular (among older dentists) ASH in ____
- ____ is the active metabolite
- Highly ____ bound
- Concern about ____ and mutagenicity.
- CH, TCE, and trichloroacetic acid related to industrial solvent ____.
kids TCE protein carcinogenicity trichloroethylene
Chloral Hydrate
- Disinhibition of kids at ____ doses (20 -40 mg/kg)
- Most effective dose ____ mg/kg – often deep sedation
- ____, vomiting at higher doses (stomach irritant, CTZ)
- Partial loss of ____ at high doses
- Overdose can produced ____ by sensitizing myocardium to endogenous and exogenous ____ like halothane .
low 50-60 nausea protective reflexes cardiac arrhythmias catecholamines
Antihistamines – Promethazine (Phenergan®) and Hydroxyzine (Vistaril®)
- Block ____ receptors in CNS and periphery. (____, mild allergy treatment)
- Block ____ receptors in CNS and periphery. (____, antiemetic, dry mouth)
- Promethazine also blocks ____ receptors so very effective at preventing drug-induced nausea and vomiting. Given in combination with ____.
- Both agents have mild ____ action and when combined with chloral hydrate reduce the dose of ____ needed to produce sedation.
histamine 1 sedation muscarinic cholinergic sedation dopamine chloral hydrate sedative chloral hydrate
hydroxyzine -> blocks ____ because it also blcoks ____ receptors, not just H1
scopalamine -> blocks ____ -> the ____ part of motion sickness
nausea from opioids, cancer chemo, hormones -> block the ____ receptors
odanestron (serotonin receptor antagonists) -> approved for ____ becasue of hormones
Ach
muscarinic cholinergic
Ach
vestibular
dopamine and serotonin
motion sickness
