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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
Effect of thiopental on cardiovascular system When is most caution needed
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,
26
Does thiopental cross the placenta
Crosses the placenta but then diffuses back as maternal levels fall so doesn’t usually cause issues.
27
Effect of thiopental on uterine tone
Nil
28
How is thiopental metabolised
Hepatic Phase 1 oxidation producing pentobarbital then cleavage into urea and small hydrocarbon
29
How is thiopental metabolism effected by liver failure? What happens in repeated doses
Not much really In repeated doses accumulates as clearance insufficient
30
Examples of anaesthetic steroids
Non available for use clinically Eltanolone Hydroxydione Minaxolone
31
What are the effects of steroid anaesthetics
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!
32
Why are the steroid anaesthetics not used
Eltanolone - cutaneous reactions Hydroxydione - slow onset of action and pain on injection Minaxolone - slow onset and excitatory (seizures), hepatic issues
33
What class of drug is ketamine
Phencyclidine derivative
34
How does ketamine present
In an aqueous solution with varied concentrations Usually racemic mixture of the two sterioisomers Weak acid ph 3.5-.5.5
35
How does ketamine work
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
36
Onset of action for ketamine for anaesthesia Duration of anaesthetic im
1 minute iv 2-5 minutes im Im anaesthetic lasts 12-25 minutes
37
Effect of ketamine in CNS
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
38
What can reduce dissociative side effects of ketamine
Use of other agents eg morphine or benzos Male gender, children less at ris
39
CVS effects of ketamine
Increase heart rate and blood pressure Increases catecholamine levels Myocardial depression countering the above to some extent
40
Ketamine effect on respiratory system
Bronchodialation Some maintenance of protective reflexes Little to no depressive effect
41
Effect of ketamine on uterine tone Issue with this
Increases Problem if placental abruption or umbilical cord prolapse
42
Metabolism of ketamine
Hepatic to Norketamine (has about 1/3rd potency of ketamine) Mainly excreted in the bile.
43
What class of drug is etomidate
Imidazole
44
What is etomidate mixed with Which preparation is least painful on injection
Lipid emulsion or water and propylene glycol Lipid is less painful
45
What isomers of etomidate exist, which is most active How does it work
Sterioisomers with R+ being the predominant GABAa enhancer
46
Characteristics of etomidate induction
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
Cardiovascular and respiratory effect of etomidate
Less depression in both systems than thiopental
48
Why is etomidate not infused long term
Inhibits cholesterol cleavage in gluco/mineralocorticoid production Lasts 3-6hrs post induction but this is not usually clinically significant unless infused
49
Etomidate metabolism
Plasma esterases and in liver producing inactive metabolites excreted in urine and bile
50
What class of drug is propofol How is it presented
Phenol Isotonic emulsion in soya bean oil, purified egg phosphatide, glycerol, sodium hydroxide
51
Propofols ph and pKa Ionisation state
Ph 6-8.5 PKa 11 99% non ionised.
52
How protein bound is propofol
98%
53
How can injection pain of propofol be reduced
Add 1ml 1% lidocaine
54
How does propofol work
Potentiate gabaa Blocks voltage gated na channels
55
Characteristics of propofol induction
Action within 1 arm brain circulation time Attenuates laryngeal reflex better than barbiturates
56
Why might you not use propofol for ect
Antiepileptic properties shortens seizures
57
Effect of propofol neurologically
Cortical depression EEG shows alpha then delta waves
58
Effect of propofol on cvs
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
Issues with propofol infusion
Hyperlipidaemia Fine in adults but in children can cause heptaomegally and metabolic acidosis
60
Metabolism of propofol
Conjugated in liver by glucuronidation 88% excreted in urine, 2% in faeces
61
Effect of propofol on urine
Can turn it green
62
Factors that influence propofol related injection pain
Site Speed of injection Concentration Speed of carrier fluid Temp of the propofol Use of adjunct drugs
63
Structure of a bendzodiazapine
Two rings - a benzene and a diazepine ring Series of r sites around mainly the diazepine ring
64
What are the benzodiazepine receptors? What do they do?
BDZ1 - central - GABA - sedation and hypnosis BDZ2 - central - GABA - anticonvulsant BDZ3 - central and peripheral - not GABA - not known
65
Why do benzos have a relatively high therapeutic index?
They act by enhancing GABA - not acting directly to cause chlorine ion conductance themselves, thus rely on GABA concentration
66
Effect of lipid solubility of benzos on pharmacokinetics
Readily absorbed from gi tract Readily enters CNS
67
Rank benzos based on lipid solubility
Midazolam > diazepam > temazepam > lorazepam
68
CNS effects of benzos
Anxiolytic Sedation Hypnosis Anterograde amnesia Anticonvulsant Skeletal muscle relaxation Reduction in REM sleep
69
Characteristics of a benzo as induction agent
Slow onset > one arm brain circulation time Prolonged recovery
70
Effect of benzos on cvs
Minimal except some in elderly or hypovolaemia
71
Effect of benzos on resp
Minimal from oral IV causes impaired airway maintainance, reduced tidal volumes, reduced sensitivity to CO2, esp if opiates also used
72
How do benzos effect skeletal muscle tone
Effect on dorsal horn of spinal cord
73
Which benzos are metabolised by oxidation
Diazepam and midazolam
74
Which benzos are metabolised by conjugation
Lorazepam and temazepam
75
How is diazepam presented Why
Water insoluble so iv preparation in either an acidic mix of propylene glycol and ethanol or a soy bean lipid emulsion.
76
What benzos sits at the top of the metabolism cascade
Chlordiazepoxide
77
Which benzo enters at the bottom of the metabolism cascade just requiring conjugation prior to excretion
Lorazepam
78
Which benzo is formed from diazepam metabolism
Temazepam
79
Why is midazolam water soluble How is storage arranged to take advantage of this
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
Why is midazolam duration of action less than diazepam
Less protein bound and redistributed faster
81
How is midazolam metabolised
Hydroxylated in liver to 4-hydroxymidazolam then conjugated for excretion
82
Why is midazolam more long lasting in elderly
Slower hepatic blood flow and lower metabolic activity
83
Oral bioavailability of lorazepam Protein binding of lorazepam
90% Also 90%
84
Elimination of lorazepam
Glucuronidation conjugation with urinary excretion
85
Elimination t1/2 of lorazepam
10-20hrs
86
What is flumanzenil
An imidazobenzodiazepine that acts as a competative benzo receptor antagonist
87
Pharmacokinetics of flumazenil
50% protein bound Rapidly redistributed High hepatic extraction ratio Elimination t1/2 is 50 minutes Metabolised to a carboxylic acid derivative and glucuronide
88
Implication of flumazenil t1/2 Other issues
Less than most benzos by some margin so will probably wear off before the benzo. May provoke acute withdrawal and raise ICP
89
How does zolpidem work
Acts at BNZ1 receptors on GABAa producing similar effects (anxiolytics and sedation) without anticonvulsant or ataxia side effects from BNZ2.
90
What is zopiclone
A cyclopyrrolone
91
How does zopiclone work
GABA enhancement but not at BNZ site
92
Effect of zopiclone on REM sleep
Nil
93
Routes of administration for diazepam
Oral Iv Rectal IM
94
Oral bioavailability of diazepam Midazolam?
86-100% Diaz Midazolam 44%
95
T1/2 distribution and elimination for diazepam
70 mins 30hrs
96
What drug reduces diazepam clearance
Cimetidine
97
Bolus dosing of flumazenil
100mcg increments up to 2mg
98
IV vs IM ketamine dosing Analgesia iv dose
IV 1-4.5mg/kg (2mg/kg) IM 4-13mg/kg (10mg/kg) 0.1-0.3 (pushing it) mg/kg
99
Dose range of iv midazolam for sedation
0.03-0.3mg/kg!
100
T1/2 midazolam
5hrs

Primary Pharmacology (18 decks)

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