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Primary Pharmacology > Hypnotics And Intravenous Anaesthetic Drugs > Flashcards

Hypnotics And Intravenous Anaesthetic Drugs Flashcards

1
Q

How do IV anaesthetics typically distribute

A

Peak in vessel rich tissues quickly (eg brain)
Redistribute after a few minutes to muscle groups
Reach near equilibrium in around 15 mins
Redistribute into fat over several hours

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2
Q

What is the consequence of iv anaesthetic distribution into fat

A

Prolongs elimination

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3
Q

Examples of barbiturates

A

Pentobarbital, phenobarbital, thiopental

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4
Q

What are barbiturates based on?
How are they made active

A

Barbituric acid which contains a pyramidine nucleus
Substitution of alkyl groups on the c5

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5
Q

How do barbiturates work

A

GABAa to increase effect and duration of GABA
Block APMA receptors and inhibit glutamate release

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6
Q

Subcatagories of barbiturates, example and characteristics

A

Oxybarbituates - phenobarbital - slow onset, long duration
Thiobarbiturates - thiopental - rapid onset, short action
Methylbarbiturates - methohexital - rapid onset, short action, sporadic movements (thus not good anaesthetics)

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7
Q

Onset time of thiopental?

A

One arm brain circulation time

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8
Q

Characteristics of thiopental

A

Water soluble
Lipophilic
Highly alkaline

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9
Q

Complications from barbiturate use

A

Porphyria - triggers attacks
Subcutaneous extravasation - very alkaline thus cause pain and tissue damage
Interarterial injection - severe endothelial damage, precipitation of micro crystals causing blockage as artery narrows (carried away in vein), local NA and ATP release with vasospasm and loss of pulse

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10
Q

What is porphyria

A

Diverse group of metabolic disorders
Result in secretion of excessive amounts of porphyrins and precursors

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11
Q

What are porphyrins

A

Pyrrole rings linked together
Fundamental in haemoglobin, myoglobin, cytochromes and catalases
Contain iron

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12
Q

What is the effect of build up of porphyrins?

A

Photosensitivity (light sensitive rash)
Effect live function
Effect cyp450 (thus drug metabolism)
Neurotoxic (seizures, psychosis)

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13
Q

Other than barbiturates what other drugs risk porphyria exacerbation

A

Benzodiazepines
Steroids

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14
Q

What are the two most common porphyria’s in uk relevant to anaesthesia
How are they inherited

A

Acute intermittent
Variegate

Autosomal dominant

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15
Q

Management of suspected intra arterial thiopental

A

Stop injection
Dilute with saline though injection cannula immediately
Administer local anaesthetic and or vasodilator into artery
Administer systemic papaverine
Consider sympathetic neural blockade (eg Stella the ganglion or brachial plexus block)
Start IV heparin
Consider interarterial hydrocortisone
Postpone non urgent surgery

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16
Q

What doses of substances should be injected interarterially in case of thiopental interarterial injection

A

Lidocaine 50mg (5ml 1%)
Phenoxybenzamine 0.5mg or infusion at 50-200mcg/min

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17
Q

What drug and dose should be injected systemically in case of interarterial thiopental injection

A

Papaverine 40-80mg (10-20ml of 0.4% solution)

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18
Q

What is papaverine

A

An opium alkaloid antispasmodic

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19
Q

How is thiopental presented

A

Rubber topped bottle of pale yellow powder
Contains 6% anhydrous sodium carbonate to prevent CO2 forming free acid that could react with the thiopental
Gas in bottle is nitrogen

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20
Q

How is thiopental prepared and characteristics in solution, how does it alter when injected

A

Soluble in water forming a 2.5% solution (2.5g/100ml) with a pH of 11
As pKa is 7.6 it is almost entirely ionised .
When injected ph falls to 7.4 and about 61% becomes non-ionised (and thus lipid soluble able to cross the bbb).

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21
Q

Taste associated with thiopental injection

A

Onions/garlic

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22
Q

Redistribution half life of thiopental

A

4 minutes

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23
Q

Effect of thiopental on ICP
Why

A

Lowers cerebral oxygen consuption
Thus cerebral vasoconstriction, decreased blood flow and lower ICP

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24
Q

What is acute tolerance in relation to thiopental

A

A single large dose results in a return to wakefulness faster than a small dose
Due to more rapid fall in cerebral concentrations

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25
Q

Effect of thiopental on cardiovascular system
When is most caution needed

A

Dose dependant reduction in vascular tone
Reduced SVR, cvp, PCWP, preload, afterload, MAP
Slight increased in heart rate

Most caution in high doses and patients who cannot compensate for a drop in SVR eg aortic stenosis, tamponade,

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26
Q

Does thiopental cross the placenta

A

Crosses the placenta but then diffuses back as maternal levels fall so doesn’t usually cause issues.

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27
Q

Effect of thiopental on uterine tone

A

Nil

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28
Q

How is thiopental metabolised

A

Hepatic
Phase 1 oxidation producing pentobarbital then cleavage into urea and small hydrocarbon

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29
Q

How is thiopental metabolism effected by liver failure?
What happens in repeated doses

A

Not much really
In repeated doses accumulates as clearance insufficient

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30
Q

Examples of anaesthetic steroids

A

Non available for use clinically

Eltanolone
Hydroxydione
Minaxolone

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31
Q

What are the effects of steroid anaesthetics

A

Generally good
Rapid onset and offset
Minimal cvs depression
Less rs depression
Low incidence of ponv
Minimal toxicity
High therapeutic index

Why aren’t we using this shit!

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32
Q

Why are the steroid anaesthetics not used

A

Eltanolone - cutaneous reactions
Hydroxydione - slow onset of action and pain on injection
Minaxolone - slow onset and excitatory (seizures), hepatic issues

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33
Q

What class of drug is ketamine

A

Phencyclidine derivative

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34
Q

How does ketamine present

A

In an aqueous solution with varied concentrations
Usually racemic mixture of the two sterioisomers
Weak acid ph 3.5-.5.5

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35
Q

How does ketamine work

A

Non- competitive antagonist at NMDA receptor
Also interacts with m k d opioid receptors - mainly m
Evidence of fast sodium channel blockade acting like a local anaesthetic
Sterioselective antagonism at muscurinc ach receptors

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36
Q

Onset of action for ketamine for anaesthesia
Duration of anaesthetic im

A

1 minute iv
2-5 minutes im
Im anaesthetic lasts 12-25 minutes

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37
Q

Effect of ketamine in CNS

A

Dissociative anaesthesia (eyes remain open, eyelid reflex preserved)
Muscle tone increased
Involuntary movements common
Limbic inhibition (effecting emotional response to pain)
Significant rise in cbf, ICP and IOP

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38
Q

What can reduce dissociative side effects of ketamine

A

Use of other agents eg morphine or benzos
Male gender, children less at ris

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39
Q

CVS effects of ketamine

A

Increase heart rate and blood pressure
Increases catecholamine levels
Myocardial depression countering the above to some extent

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40
Q

Ketamine effect on respiratory system

A

Bronchodialation
Some maintenance of protective reflexes
Little to no depressive effect

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41
Q

Effect of ketamine on uterine tone
Issue with this

A

Increases
Problem if placental abruption or umbilical cord prolapse

42
Q

Metabolism of ketamine

A

Hepatic to Norketamine (has about 1/3rd potency of ketamine)
Mainly excreted in the bile.

43
Q

What class of drug is etomidate

A

Imidazole

44
Q

What is etomidate mixed with
Which preparation is least painful on injection

A

Lipid emulsion or water and propylene glycol
Lipid is less painful

45
Q

What isomers of etomidate exist, which is most active
How does it work

A

Sterioisomers with
R+ being the predominant
GABAa enhancer

46
Q

Characteristics of etomidate induction

A

Anaesthesia rapidly within one arm brain circulation time
Many excitatory muscle movements
EEG often shows epileptiform activity
Cerebral blood flow, ICP and IOP reduced

47
Q

Cardiovascular and respiratory effect of etomidate

A

Less depression in both systems than thiopental

48
Q

Why is etomidate not infused long term

A

Inhibits cholesterol cleavage in gluco/mineralocorticoid production
Lasts 3-6hrs post induction but this is not usually clinically significant unless infused

49
Q

Etomidate metabolism

A

Plasma esterases and in liver producing inactive metabolites excreted in urine and bile

50
Q

What class of drug is propofol
How is it presented

A

Phenol
Isotonic emulsion in soya bean oil, purified egg phosphatide, glycerol, sodium hydroxide

51
Q

Propofols ph and pKa
Ionisation state

A

Ph 6-8.5
PKa 11
99% non ionised.

52
Q

How protein bound is propofol

A

98%

53
Q

How can injection pain of propofol be reduced

A

Add 1ml 1% lidocaine

54
Q

How does propofol work

A

Potentiate gabaa
Blocks voltage gated na channels

55
Q

Characteristics of propofol induction

A

Action within 1 arm brain circulation time
Attenuates laryngeal reflex better than barbiturates

56
Q

Why might you not use propofol for ect

A

Antiepileptic properties shortens seizures

57
Q

Effect of propofol neurologically

A

Cortical depression
EEG shows alpha then delta waves

58
Q

Effect of propofol on cvs

A

Dose dependant reduction in vascular tone reducing SVR and cvp causing fall in preload
Fall in contractility
Both of the above lower cardiac output

59
Q

Issues with propofol infusion

A

Hyperlipidaemia
Fine in adults but in children can cause heptaomegally and metabolic acidosis

60
Q

Metabolism of propofol

A

Conjugated in liver by glucuronidation
88% excreted in urine, 2% in faeces

61
Q

Effect of propofol on urine

A

Can turn it green

62
Q

Factors that influence propofol related injection pain

A

Site
Speed of injection
Concentration
Speed of carrier fluid
Temp of the propofol
Use of adjunct drugs

63
Q

Structure of a bendzodiazapine

A

Two rings - a benzene and a diazepine ring
Series of r sites around mainly the diazepine ring

64
Q

What are the benzodiazepine receptors?
What do they do?

A

BDZ1 - central - GABA - sedation and hypnosis
BDZ2 - central - GABA - anticonvulsant
BDZ3 - central and peripheral - not GABA - not known

65
Q

Why do benzos have a relatively high therapeutic index?

A

They act by enhancing GABA - not acting directly to cause chlorine ion conductance themselves, thus rely on GABA concentration

66
Q

Effect of lipid solubility of benzos on pharmacokinetics

A

Readily absorbed from gi tract
Readily enters CNS

67
Q

Rank benzos based on lipid solubility

A

Midazolam > diazepam > temazepam > lorazepam

68
Q

CNS effects of benzos

A

Anxiolytic
Sedation
Hypnosis
Anterograde amnesia
Anticonvulsant
Skeletal muscle relaxation
Reduction in REM sleep

69
Q

Characteristics of a benzo as induction agent

A

Slow onset > one arm brain circulation time
Prolonged recovery

70
Q

Effect of benzos on cvs

A

Minimal except some in elderly or hypovolaemia

71
Q

Effect of benzos on resp

A

Minimal from oral
IV causes impaired airway maintainance, reduced tidal volumes, reduced sensitivity to CO2, esp if opiates also used

72
Q

How do benzos effect skeletal muscle tone

A

Effect on dorsal horn of spinal cord

73
Q

Which benzos are metabolised by oxidation

A

Diazepam and midazolam

74
Q

Which benzos are metabolised by conjugation

A

Lorazepam and temazepam

75
Q

How is diazepam presented
Why

A

Water insoluble so iv preparation in either an acidic mix of propylene glycol and ethanol or a soy bean lipid emulsion.

76
Q

What benzos sits at the top of the metabolism cascade

A

Chlordiazepoxide

77
Q

Which benzo enters at the bottom of the metabolism cascade just requiring conjugation prior to excretion

A

Lorazepam

78
Q

Which benzo is formed from diazepam metabolism

A

Temazepam

79
Q

Why is midazolam water soluble
How is storage arranged to take advantage of this

A

When ph less than 4 reaction favoured that allows water to open the Diazepine ring causing solubility
Kept in ph 3 solution, when administered ph rises and ring closes causing midazolam to become lipid soluble and able to cross bbb

80
Q

Why is midazolam duration of action less than diazepam

A

Less protein bound and redistributed faster

81
Q

How is midazolam metabolised

A

Hydroxylated in liver to 4-hydroxymidazolam then conjugated for excretion

82
Q

Why is midazolam more long lasting in elderly

A

Slower hepatic blood flow and lower metabolic activity

83
Q

Oral bioavailability of lorazepam
Protein binding of lorazepam

A

90%
Also 90%

84
Q

Elimination of lorazepam

A

Glucuronidation conjugation with urinary excretion

85
Q

Elimination t1/2 of lorazepam

A

10-20hrs

86
Q

What is flumanzenil

A

An imidazobenzodiazepine that acts as a competative benzo receptor antagonist

87
Q

Pharmacokinetics of flumazenil

A

50% protein bound
Rapidly redistributed
High hepatic extraction ratio
Elimination t1/2 is 50 minutes
Metabolised to a carboxylic acid derivative and glucuronide

88
Q

Implication of flumazenil t1/2
Other issues

A

Less than most benzos by some margin so will probably wear off before the benzo.
May provoke acute withdrawal and raise ICP

89
Q

How does zolpidem work

A

Acts at BNZ1 receptors on GABAa producing similar effects (anxiolytics and sedation) without anticonvulsant or ataxia side effects from BNZ2.

90
Q

What is zopiclone

A

A cyclopyrrolone

91
Q

How does zopiclone work

A

GABA enhancement but not at BNZ site

92
Q

Effect of zopiclone on REM sleep

A

Nil

93
Q

Routes of administration for diazepam

A

Oral
Iv
Rectal
IM

94
Q

Oral bioavailability of diazepam
Midazolam?

A

86-100% Diaz
Midazolam 44%

95
Q

T1/2 distribution and elimination for diazepam

A

70 mins
30hrs

96
Q

What drug reduces diazepam clearance

A

Cimetidine

97
Q

Bolus dosing of flumazenil

A

100mcg increments up to 2mg

98
Q

IV vs IM ketamine dosing
Analgesia iv dose

A

IV 1-4.5mg/kg (2mg/kg)
IM 4-13mg/kg (10mg/kg)
0.1-0.3 (pushing it) mg/kg

99
Q

Dose range of iv midazolam for sedation

A

0.03-0.3mg/kg!

100
Q

T1/2 midazolam

A

5hrs

Primary Pharmacology (18 decks)

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