Unit 06: premedications

Question 1

what are premedications? what are the main types?

Answer 1

• also called pre-anaesthetics, refer to variety of injectable drugs
• main types are sedatives or anxiolytics, hypnotics and analgesics
• sedatives or anxiolytics - act as tranquillizers to calm patient and reduct
• hypnotics - used to induce sleepiness
• analgesics minimize or abolish intra and post operation pain

Question 2

what are the main classes of sedatives, gives an exmaple of a drug in that class

Answer 2

• alpha 2 agonists ex: demedetomidine

benzodiazepines ex: diazepam

Question 3

mechanism of action of sedatives

Answer 3

• stimulation of alpha 2-receptors which open K+ channels and inhibit neurotransmitter release in various brain pathways
• act primarily on α2 receptors in brian and spinal cord as opposed to the periphery

Question 4

what is the effect of α2 receptor stimulation in the CNS

Answer 4

inhibition of several importnat neural pathways including those that mediate wakefulness (sedation), pain (analgesia), blood pressure control (hypotension), motor activity (muscle relaxation) and respiration (dramatic drop in O2 exchange)

Question 5

what are the side effects of α2 agonists

Answer 5

• side effects arise because sympathetic outflow tracts from the brain are also inhibited - reduces norepinephrine release peripherally
• have lower affinity for peripheral alpha receptors but still have some effect at both α1 and α2 receptors in the periphery
• stim of α1 in periphery causes vasoconstriction
• also causes adverse effects on cardiovascular system
• can potentiate epinephrine-induced arrhythmias and produce significant skeletal muscle relaxation

Question 6

effects of sedatives on cardiovascular system

Answer 6

Effects on blood pressure (BP) include vasoconstriction (peripheral α1 effect) which causes an initial rise in BP followed by bradycardia due to α2 stimulation in the brain stem which inhibits SNS outflow and hypotension occurs in a dose-dependent manner.

These agonists can also potentiate epinephrine-induced arrhythmias and produce significant skeletal muscle relaxation.

Question 7

what drugs are alpha-2 antagonist? what are the effects?

Answer 7

yohimbine and atipamezole

• can reverse effects of alpha2 receptor agonists
• drugs can reverse sedation and most cardiovascular effects
• need to be titrated to have desired effect and caution must be taken to avoid increased SNS effects and pain

Question 8

how can dexmedetomidine be administered?

Answer 8

• alone to cause sedation and analgesia or with other sedative class to cause heavy sedation
• when administered with opioids can be utilized for a short surgical procedure or for epideral analgesia

Question 9

what is medetomidine

Answer 9

• mixture of 2 enantiomers - dexmedetomidine and levomedetomidine

(dexmedetomidine is the biologically active)

• when ued at moderate dosages with general anesthetic there is usually no significant change in BP

Question 10

what is the purpose of premedication with dexmedetomidine

Answer 10

reduced the amount of induction agent (thiopental, propofol etc) needed to induce unconsciousness by at least 50% and provide intra-operative analgesia

Question 11

benzodiazepines as sedatives

Answer 11

• ex are diazepams and lorazepams
• benzos differ mainly in rate of onset of effect and duration of action (diazepam ~ 2 days and lorazepam ~ 20 hours)
• diazepam also called valium and very useful pre-medivation for its anxiolytic or sedative, hypnotic and muscle relaxant effects

Question 12

benzodiazepines and anticonvulsant activity

Answer 12

• benzodiazepines facilitate binding of GABA (major inhibitory neurotransmitter in the CNS) to GABBAR

*GABAAR = hetero-pentameric ligand gated chloride channel

• binding of GABA to alpha subunit upons the channel and hyperpolarizes the cell inhibiting excitation

*overall effect depends on region of the brain that is inhibited

Question 13

why are benzodiazepines relatively safe

Answer 13

they do not directly activate the GABAAR

• GABA itelf must be presnt and the lethal dose is approx 1000x the effective dose

Question 14

effects of benzodiazepines on organs

Answer 14

• have little effect on cardiovascualar system unlesss pulmonary or cardiovascular disease is present
• dose dependent respiratory depression can occur but little effect at therapeutic dosages

Question 15

adverse effects of benzodiazepines

Answer 15

drowsiness and confusion - benefit when used as a premedication

• sedative effects are additive with other CNS depressants and particularly dangerous when combined with alcohol which can elad to fatalities
• overdose can be reversed by the GABA R antagonist Flumazenil which is a competitive inhibitor of the benzodiazepine site

Question 16

what is flumazenil

Answer 16

• GABA R antagonist: competitive inhibitor of benzodiazepine site
• reverses overall effects of benzodiazepines

Question 17

what are opiods

Answer 17

• class of premedications administered for analgesic effects
• ex = morphine, codeine, heroin etc.

**term opiate refers tot he matural component of opium whereas opioid refers to opiates and synthetic drugs that are related to morphine

Question 18

what are opioid drugs used for?

Answer 18

• analgesia (moderate - severe pain)
• sedation

cough suppresion (antitussive)

• treatment of diarrhea (constipation is a major side effect of opioids which can be taken advantage of to manage diarrhea)

Question 19

mechanism of action of opioids

Answer 19

• stimulation of pre-sympathetic opioid receptors in the CNS which inhibits neurotransmitter release in pain pathways, respiratory and cough centres and some ANS pathways
• receptors include: µ; MOR, δ; DOR, κ; KOR and σ - each have subtypes
• receptors are located throughout the brain, spinal chord and peripheral nerve terminals

Question 20

side efefcts of opioids

Answer 20

constipation, nausea, urinary retention, respiratory depression (death from overdose is typically a result of respiratory failure)

Question 21

result of MOR stimulation

Answer 21

Analgesia

Euphoria (leads to dependence)

Miosis (in humans)

Respiratory depression (à less sensitive to CO2)

Question 22

rsult of DOR stimulation

Answer 22

Mainly analgesia but also similar to mu (euphoria, resp depression)

Question 23

result of opioid stimulation of KOR

Answer 23

• analgesia (less intense effec than mu stimulation)

Question 24

effect os sigma R stimulation of opioid receptor

Answer 24

Dysphoria: feeling of unease

Hallucinations

Respiratory and vasomotor stimulation

Stimulated by some opioids, some non-opioids (e.g. ketamine)

*atypical effects

Question 25

What is fentanyl

Answer 25

mu receptor agonist with intense analgesic effect, known as the “full Mu agonist”

• 100x more potent than morphine and used for profound pain relief
• commonly admin as transdermal patch and must be used with caution bc overdose can cause seizures
• patch releases small amount (50 micrograms) of drug per hour - pateints must be aware of situations that could inc absorption
  ex: sweating may dramatically inc blood flow and abs which could be fatal

Question 26

what is pentazocine

Answer 26

kappa agonist with good analgesic effect

also produces a weak effect at mu receptors, making it act like an antagonist to other mu opioids

*if you combine with fentanyl get weaker analgesia compared to fentayl alone

Question 27

how are most opioids administered?

Answer 27

parenterally

Question 28

describe pharmacokinetics of morphine

Answer 28

• subject to significant first pass effect (large portion is broken down by the liver) - so IV injection is most common route of administration
• heatpic P450 enzyme ivnvoled with drug metabolism converting morphine to glucoronide and the syhntehtic opioids fentanyl into inactive conjugates

Question 29

metabolism of codeine

Answer 29

10% is metabolized into morphine which provides the main source of the codeine effect.

Question 30

opioids and the cardiovascular system

Answer 30

most opioids have little effect but morphine can cause histamine release which results in vasodilation and hypotension

Question 31

physiological effects of opioids

Answer 31

• CNS effects
• provide 4-6 hours of analgesia and sedation (not sleep)
• espiratory system
• dose dependent: intense effects can be observed when opioids are combined with general anesthetic
• death from overdose due to respiratory arrest
• can use nalozone to reverse effects on resp system

GI system

• increase segmentation but reduce propulson in large bowel, stool becomes dehydrated and get constipated
• constriction of bile duct sphincter which causes increase in gall bladder pressure and biliary colic
• neaseua and vomiting from stimulation of chemoreceptor trigger zone via mu receptors

Other

• increase tone of urinary blasser psincter and detrussor mucle - urgency to urinate but hard to do so
• slow down uterine contractions- inhibit birth reflexes and depress enonatal respiration

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Question 33

what it etorphine

Answer 33

M-99, renders large animals ataxic within seconds and reveral agent is required for recovery to occur

• 1000x -8000x more potent than morphine used to capture wildlife
• need two people incase one person has reveral agent incase other acidentally self injects etorphine

Question 34

anti-diarrhead opioids

Answer 34

• lots of opioids cause constipation
• can only use those with virtually no addictive porperties
• over the counter anti-diarrheal = loperamide (imodium) and diphenoxylate) lomotil)
• both reduce propsulive gut motility in large bowel, decrease gut secretions and cause constiction of anal spincter
• stool remians in large colon longer which allows more water to be reabsorbed - potent constipating effect