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MODA MVST1b > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

Tetracyclines

A

Soluble at acid pH but insoluble at neutral pH. Any that enters the intestines precipitates and is lost in faeces
Majority of absorption in the stomach

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2
Q

Levodopa

A

Absorbed via phenylalanine transporter

Used in treating Parkinson’s disease

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3
Q

Heparin

A

Anti coagulant
Unfractionated is a carbohydrate polymer of variable chain length MW 3-30 kDa, so cannot permeate between endothelial cells, and isn’t specifically transported, so is restricted to the plasma compartment

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4
Q

Ivermectin

A

Toxicity in collie dogs associated with a frameshift mutation and premature stop codon in mdr1a gene which is the P-glycoprotein ABC transporter across the BBBo

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5
Q

Gentamicin

A

Aminoglycoside antibiotic
Hydrophilic but small enough to cross endothelium
Vd similar to plasma + interstitial

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6
Q

Ethanol

A

Vd similar to total body water 42-45l

Acts on GABAA receptors

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7
Q

Codeine/morphine

A

Morphine Vd 250l due to sequestration in fat

Opiate widely used for pain relief, also cough suppression, antidiarrheal
Side effects respiratory depression, constipation, sedation, addiction
Act via mu opioid receptor
Codeine ineffective at plasma conc - seen as a prodrug

Small amount of codeine metabolised to morphine in liver by CYP2D6
Most directly glucoronidate or converted to norcodeine
Morphine-6-glucuronide (morphine glucorinidated) is a high affinity agonist and may be responsible for some of the action and side effects of codeine and morphine

Morphine secreted in protonated cationic form (it is a base) by OBTs

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8
Q

Thiopental

A 
General anaesthetic
Sequestered in fat as very lipophilic
Lipophilic also means crosses BBB
Binds to plasma proteins
Metabolised in liver - metabolism close to saturation, so can show zero order kinetics if maintained by infusion or repeated injection
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9
Q

Warfarin

A

Acidic

Binds to site on albumin

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10
Q

Salicylic acid

A

Acidic

Binds to site on albumin

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11
Q

Phenytoin

A

Acidic
Binds to site on albumin

Phase 1 hydroxylation by CYP2C9/19
Phase 2 glucuronidation by UDP-glucuronosyltransferases
Can inhibit both

Therapeutic doses close to saturation for hydroxylation by CYP2C9
Small increase in dose rate can lead to much greater plasma conc and toxicity

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12
Q

Sulfonamides

A

Bilirubin binds to plasma proteins, if displaced, eg by sulfonamides, C free will increase
Can lead to increased bilirubin in the brain and neurological damage

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13
Q

Fluoxetine (Prozac)

A

CYP2D6 especially, also CYP2C19 and CYP3A4 substrates
So can also inhibit these
Major source of adverse drug interactions
Reduces morphine formation from codeine and prevents its analgesic effect

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14
Q

Quinidine

A

Competitive inhibitor of CYP2D6 but not a substrate

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15
Q

Ketoconazole

A

Complexes with Fe3+ form of Haem in CYP3A4

Non competitive inhibitor

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16
Q

Grapefruit juice

A

Can inhibit CYP3A4
Affects DHPR calcium channel blockers, statins, anti cancer drugs, antibiotics like erythromycin and immunosuppressants like cyclosporine
Major site of action CYP3A4 in intestinal wall rather than the liver - mainly inhibits first pass metabolism

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17
Q

Phenobarbital

A

Can activate RXR (retinoid X receptor)

Inhiibts glucuronidation

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18
Q

Rifampicin

A

Antibiotic

Can activate RXR (retinoid X receptor)

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19
Q

Ritonavir

A

HIV protease inhibitor

Can activate RXR (retinoid X receptor)

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20
Q

St John’s Wort

A

Commonly used for mild and moderate depression

Can activate RXR (retinoid X receptor)

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21
Q

Amphetamines

A

Metabolised by FMO3

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22
Q

Clozapine

A

Anti psychotic

Metabolised by FMO3

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23
Q

Ranitidine

A

Histamine H2 receptor antagonist

Metabolised by FMO3

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24
Q

Carbamazepine

A

Anti epileptic drug
Prodrug activates by CYPs to generate a reactive and active epoxide
This is hydrolysed by microsomes EH, which also inactivates the drug

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25
Q

Valproic acid

A

Anti convulsant
Inhibits microsomal epoxide hydroxylases
Increaes conc of active metabolite of carbamazepine and delaying its elimination

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26
Q

Ethanol

A

Ethanol oxidised to toxic acetaldehyde by alcohol dehydrogenase and this concerted to acetate by aldehyde dehydrogenase

Metabolism saturated at a fairly low alcohol intake. Above this, zero order kinetics.

Chronic alcohol intake can increase the rate of ethanol metabolism through induction of CYP2E1

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27
Q

Aspirin

A

Hydrolysed to salicylic acid by esterases

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28
Q

Heroin

A

Diacetylmorphine
Also converted to morphine for action
It’s acetyl groups increase lipophilicity so can cross BBB
Conversion to morphine in the brain

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29
Q

N-acetyl cysteine

A

Exogenous GSH glutathione source

Can replenish during toxic doses of paracetamol

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30
Q

Paracetamol

A

Paracetamol hepatic injury - sulfonation phase 2 saturated so depletes GSH
Inhibitors of glucuronidation like phenytoin or pentobarbital can trigger injury
Induction of CYP2E1 by chronic alcohol consumption may also increase hepatotoxicity risk

Secreted by OATs as glucuronide and sulfide conjugate

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31
Q

Aminoglycoside antibiotics

A

Polar
Not heavily bound to plasma proteins
readily cleared by glomerular filtration

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32
Q

Penicillin

A

Secretion in kidney by OATs
Acidic
Transported in negatively charged anionic form
Competition with probenecid: prolongs action of penicillin by reducing its tubular secretion

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33
Q

Probenecid

A

Probenecid: prolongs action of penicillin by reducing its tubular secretion

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34
Q

Isoflurane

A

Stereospecific anaesthetic
Activate K2P family
Hyperpolarisation
Reduced neuronal activity

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35
Q

Barbiturates

A

Act on GABAA receptors

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36
Q

Propofol

A

IV anaesthetic, acts on beta subunit of GABA a

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37
Q

Etomidate

A

IV anaesthetic, acts on beta subunit of GABA a

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38
Q

Halothane

A

Mutation in TASK3 abolishes effect

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39
Q

Xenon

A

And nos

Inhibit excitatory NMDA receptors

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40
Q

Thiopental

A

Barbiturate
IV
rapid onset
Lipophilic
Binds to plasma proteins
Metabolised in liver, close to saturation
Rapid return of consciousness due to redistribution not metabolism
Slow metabolism means that sub-anaesthetic concs lead to side effect ‘anaesthetic hangover’

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41
Q

Propofol

A

IV
rapid anaesthesia, faster than thiopentone
More rapid metabolism
May have an anti-emetic effect

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42
Q

Etomidate

A

IV
Wider therapeutic window for anaesthesia over cardiovascular depression
Higher rate of vomiting and nausea during recovery compared to propofol

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43
Q

Define pharmacodynamics

A

The interaction between a drug and its receptors (including affinity and efficacy, and tissue distribution of receptors(

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44
Q

What does the relationship between the administered dose and concentration at the target site depend on?

A

Absorption, distribution, metabolism, excretion

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45
Q

Define minimum therapeutic concentration

A

The level the plasma concentration must be higher than to see the desired therapeutic effect

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46
Q

What is the gap between the minimum toxic concentration and the minimum therapeutic concentration called?

A

Therapeutic window

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47
Q

What are the advantages and disadvantages of IV infusion?

A

Advantages: fastest, most certain
Disadvantage: skilled practitioner, inconvenience to patient, if bolus initially very high concentration in right side of the heart and pulmonary circulation, infection risk

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48
Q

What does rate of diffusion across membranes depend on?

A

Concentration gradient
Surface area
How lipophilic the drug is

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49
Q

Which drugs absorb well in the stomach?

A

Weak acids - reassociate so uncharged form can diffuse across the membrane

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50
Q

Which drugs absorb well in the small intestine?

A

Weak bases - dissociate so can diffuse across the membrane

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51
Q

Which factors affect absorption of drugs in the gut?

A 
Gastric motility
Splanchnic blood flow
Food
Gastric emptying
Diarrhoea and vomiting
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52
Q

What are enteric coatings?

A

Coatings of drugs that would break down in acid. Coating is stable at acid pH but break down at higher pH.

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53
Q

What is the name of the metabolism of drugs by enzymes in the small intestinal wall or the liver?

A

First-pass effect

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54
Q

Define bioavailability

A

Fraction of the delivered dose that reaches the systemic circulation

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55
Q

Which factors affect bioavailability?

A

Ability to cross gut epithelium
Transport back into gut lumen
Drug metabolism in first pass effect or by bacteria
Patient-specific factors e.g. drug interactions, food, altered motility

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56
Q

What is the name of the compartments protected by specialised barriers?

A

Transcellular e.g. cerebrospinal compartment

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57
Q

What size molecules can pass freely through normal endothelia?

A

500-600 daltons

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58
Q

What are local anaesthetics chemically? Where do they act? What is the significance of this?

A

Weak bases
Act on intracellular side of NaV
Enter cells in their unionised form
Local inflammation decreases tissue pH, shifting eq to favour ionised form, so local anaesthesia is delayed or even prevented

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59
Q

Give examples of SLCs

A

Solute carrier superfamily
OAT organic anion transporter
OCT organic cation transporters
SERT

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60
Q

Give examples of ABCs

A

ATP-binding cassette

MDR-1

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61
Q

Describe the blood brain barrier

A

Capillaries supplying the brain have very tight junctions between endothelial cells and are further surrounded by astrocytes
So impermeable to drugs that are not sufficiently lipophilic to cross plasma membranes, be taken up by transporters or through transcytosis
Can be disrupted by inflammation

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62
Q

Why can ion trapping occur in the fetal-maternal circulations?

A

Fetal pH is usually slightly lower than maternal pH

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63
Q

Define volume of distribution

A

The volume that would contain the total amount of drug in the body at a concentration equal to the plasma concentration

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64
Q

List the reference values for Vd for a 70kg human

A

Plasma: 3L
ECF: 12L
Body water: 42L
Fat, or bound to protein in tissues: >42L up to 20000:

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65
Q

How does tissue sequestration affect Vd?

A

Increases apparent Vd
As more drug binds to tissues, the concentration of free drug there falls. More drug will leave the plasma, and the plasma concentration falls, so a larger amount of drug is accommodated with a lower plasma concentration.

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66
Q

How can heavy metals be sequestered?

A

Bind to bone

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67
Q

How does binding to plasma proteins affect Vd?

A

Increases apparent Vd
Plasma conc measured reflects total amount in the plasma C = Cfree + Cbound. As more drug binds to plasma proteins, the free plasma conc drops, so more drug remains in the plasma, increasing total plasma conc.

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68
Q

What is the major binding protein in plasma and what is its concentration? Describe it

A

Albumin
0.6mmol/l
2 binding sites for acidic drugs, binds many neutral drugs and some basic drugs
Acidic: warfarin, salicylic acid, phenytoin
Can become saturated

69
Q

When can albumin conc fall?

A

Liver disease, old age, nephrotic disease or major burns

70
Q

Which plasma protein do basic drugs bind to?

A

Alpha1 glycoprotein
Acute phase reactant increased during inflammation or stress
Binds betablockers and antidepressants

71
Q

Define xenobiotics

A

Foreign chemical substances that are not formed by the normal metabolism of the organism

72
Q

What type of xenobiotics need to be metabolised? What is the general pathway?

A

Hydrophobic/lipophilic

Convert it to a more water soluble molecule

73
Q

Describe the stages of hepatic drug metabolism

A

Phase 1: functionalization. Catabolic. Makes a more reactive metabolite by unmasking a reactive chemical group. Often drug is inactivated but not always. Sometimes this activates the drug (if the drug is a ‘pro-drug’)
Phase 2: conjugation. Anabolic. Adds a molecule to the reactive functional group to make a less reactive metabolite that is usually more hydrophilic and higher molecular weight. Sometimes inactivates the drug.

74
Q

Give an example of a drug that doesn’t require phase I metabolism

A

Paracetamol, already has an appropriate functional group.

75
Q

List the categories of phase I membranes

A
  1. Cytochrome P450
  2. FMO
  3. EH
  4. ADH
  5. Esterases
76
Q

What does CYP mean and how many of them are there?

A

Cytochrome P450 superfamily
18 families
57 genes

77
Q

What percentage of drugs are metabolised by CYP2D6? Give examples

A

25%
Tamoxifen
Beta blockers

78
Q

How many copies of CYP2D6 do we carry?

A

1 copy

Dysfunctional in 7-8% Caucasian americans

79
Q

What percentage of drugs are metabolised by CYP3A4?

80
Q

Where are CYPs located?

A

ER membrane

81
Q

What do CYPs use?

A

O2 and haem: Haem binds O2 into the CYP active site.

NADPH-cytochrome P450 oxidoreductase supplies H+ via NADPH

82
Q

Why is superoxide dismutase needed alongside CYPs?

A

CYPs often consume more O2 than is needed, so superoxide is produced. Superoxide dismutase converts this safely into water

83
Q

Define suicide inhibition

A

Product of oxidation binds covalently to the CYP, irreversibly blocking the enzyme

84
Q

How can xenobiotics increase the expression of genes encoding cytochromes?

A

Bind to flexible ligand binding site of nuclear receptors
PXR (pregnane X receptor) and CAR (constitutive androstane receptor) heterodimerise with RXR
Allows them to bind to XRE (xenobiotic response elements) in upstream promoter regions
Upreg CYP3A4

85
Q

Give examples of drugs that can activate PXR

A

Phenobarbital
Rifampicin
Ritonavir
St John’s Wort

86
Q

What are FMOs?

A

Flavin monooxygenases
Catalyse oxidation reactions using FAD
FMO3 most abundant
Can metabolise amphetamines, clozapine, ranitidine

87
Q

What can FMO3 mutation cause?

A

Fish odour syndrome

88
Q

What are EHs?

A

Epoxide hydroxylases
Detoxify the highly reactive epoxides generated by CYPs
CYP convers carbamazepine to generate a reactive and active epoxide
Hydrolysed and inactivated by microsomal EH

89
Q

What can inhibit microsomal EH? What is the effect?

A

Valproic acid - reduces carbamazepine reaction and delay its elimination
Relevant as carbamazepine is an anti-epileptic and valproic acid is an anti-convulsant

90
Q

What do ADH and ALDH do?

A

ADH = alcohol dehydrogenase
ethanol –> ethanal
ALDH = aldehyde dehydrogenase
ethanol –> acetate

91
Q

What do esterases hydrolyse? Where are they found?

A

Intestinal wall and plasma + liver

Aspirin

92
Q

Give some examples of phase 2 reactions and the enzymes that do them (5 examples)

A

Add:

  1. Sulfate = sulfotransferases SULT
  2. Glucuronic acid = UDP-glucuronosyltransferases UGT
  3. Glutathione = Glutathione-S-Transferases GST
  4. Acetyl = N-acetyltransferases NAT
  5. Methyl = methyltransferases MT
93
Q

What is the pKa of glucuronic acid? Why does this help in conjugation?

A

pKa = 3-3.5
Mostly ionised at physiological pH
So hydrophilic lipophobic
Can be excreted

94
Q

Describe phenytoin metabolism

A
  1. CYP-dependent hydroxylation by CYP2C19/CYP2C9 to hydroxyl-phenytoin
  2. Glucuronic acid conjugation UGT1
  3. Forms very water soluble phenytoin-glucuronic acid conjugate
95
Q

What is the difficulty with phenytoin metabolism?

A

Exists close to saturation so at a certain point a very small increase in dose increases plasma concentration a lot

96
Q

Draw codeine metabolism

A

5-15% Codeine - CYP2D6 - morphine - UGTs - either inactive morphine-3-glucuronide or active morphine-6-glucuronide
10-20% - CYP3A4 - inactive norcodeine - UGT - norcodeine-6-glucuronide
50-70% UGTs - inactive codeine-6-glucuronide

97
Q

How much higher is morphine’s affinity for the mu opioid receptor than codeine’s?

98
Q

What else apart from codeine is converted to morphine for its action?

A

Heroin - diacetylmorphine

99
Q

What is the difference between heroin and morphine?

A

Heroin = prodrug
Acetyl groups increase lipophilicity
Can cross BBB and be converted to morphine in the brain

100
Q

What effect does fluoxetine have on codeine metabolism?

A

Inhibit CYP2D6
Reduce morphine formation
Prevent analgesic effect

101
Q

What is the effect of CYP3A4 inhibition and induction on morphine production from codeine?

A

Inhibition, little effect as minor pathway

Induction, could reduce formation

102
Q

Describe paracetamol metabolism

A

Glucuronidation (55%) and sulfonation (35%) (both phase 2)
Minor fraction oxidised by CYP2E1 (phase I) to NAPQI, which is detoxified by conjugation to glutathione (GSH)
At supratherapeutic doses, the sulfonation pathway is saturated
At higher toxic doses, glucuronidation is also saturated, and a higher proportion is oxidised to NAPQI, leading to depletion of GSH and hepatic cell injury or cell death

103
Q

How do you replace depleted glutathione?

A

N-acetyl cysteine NAC

104
Q

What can increase paracetamol hepatotoxicity risk?

A

Inhibitors of UGT glucuronidation e.g. phenytoin or pentobarbital
Induction of CYP2E1 by chronic alcohol consuption

105
Q

What is renal plasma flow?

106
Q

What is glomerular filtration rate?

A

125 ml/min

107
Q

What is normal urine flow rate?

108
Q

Why does glomerular filtration not change either the concentration or amount of drug bound?

A
  1. Filters water and drug in proportion

2. Number of binding sites for drugs and bound drugs themselves 20% higher in efferent arterioles than afferent

109
Q

What is the effect of increasing plasma protein binding for freely filtered drugs?

A

Decreases clearance of the drug

110
Q

Which transporters carry out active secretion? Give examples

A

OAT: acidic drugs in negatively charged anionic form e.g. penicillin, probenecid, uric acid, glucuronide and sulphide conjugates
OCT: organic bases in their protonated cationic form e.g. morphine

111
Q

How does secretion change the proportion of drug bound?

A

Secretion lowers free conc in plasma as water doesn’t accompany the movement
Shifts equilibrium between bound and free drug. More drug released from plasma proteins. If secretion is fast enough, newly released drug is also secreted.

112
Q

What is the effect of increasing plasma protein binding for secreted drugs?

A

None. Clearance can be greater than GFR and can approach RPF

113
Q

Where are drugs reabsorbed?

A

Renal tubules

114
Q

How does ion trapping work in urine?

A

Urine pH lower than plasma

Excretion of basic drugs in cation form, favours reabsorption of acidic drugs

115
Q

How can ion trapping be clinically used?

A

If you infuse sodium bicarbonate, more weak acid is found in the charged, anion form, so less likely to be reabsorbed
Do this following OD of acidic drugs (Aspirin, barbiturates)
Will increase reabsorption of basic drugs

116
Q

Define enterohepatic circulation

A

When liver cells secrete drugs and their metabolites into bile. Delivered to small intestine. Conjugates (Especially glucuronides) hydrolysed, and reabsorbed.

117
Q

What is the effect of enterohepatic circulation?

A

Slows rate of elimination, and prolongs the effect of the drug

118
Q

What is coprophagy? What is its effect?

A

Eating shit

Can lead to complex dosing patterns if drug excreted in bile or if it is poorly absorbed in the first place

119
Q

Define first order kinetics

A

Assume that drug elimination follows linear kinetics, so that the rate of elimination is directly proportional to the plasma concentration
When Km»C

120
Q

What type of kinetics does elimination by metabolism and carrier-mediated drug transport follow and why?

A

They’re enzymes so
Michaelis-Menten
Means that rate of elimination is directly proportional to the plasma concentration if C<>Km then rate of reaction = Vmax.

121
Q

Why is filtration always first order?

A

Renal filtration is not enzyme dependent

122
Q

What is a zero order reaction?

A

When a reaction is independent of the concentration of the reactant, e.g. when elimination has been saturated and has reached the fixed, maximum rate

123
Q

Define the single compartment model

A

Assumes body behaves as a single, well mixed container, into which a dose of drug is rapidly added by IV injection
Ignores absorption, ignores distribution,
Assumes first order kinetics

124
Q

Define half life

A

Time taken for the plasma concentration to decrease by 1/2

125
Q

Describe the two-compartment model of single IV dose

A

Drug doesn’t appear to distribute instantaneously
Appears to distribute to some parts of the body more rapidly than others
Drug is injected into a central compartment and immediately distributes through this compartment(Blood. and other well perfused tissues like liver/kidney/heart/brain/lungs). Drug is eliminated from this compartment by metabolism/excretion.
The drug can also slowly distribute into a peripheral compartment, representing poorly perfused tissues like skin/fat/skeletal muscle

126
Q

How does apparent Vd change with time for the two compartment model? What else changes?

A

Initially low, later high

Affects plasma conc and hence rate of elimination

127
Q

What is rate of absorption affected by?

A

Proportional to amount of dose remaining, so rate of absorption decreases with time
Also formulation of the drug

128
Q

Why can you use comparisons of a single iv dose and a single oral dose to determine fractional bioavailability?

A

Clearance is independent of route of administration

And F = 1 for an iv dose

129
Q

During a constant IV infusion what determines the Css?

A

Just rate of infusion and clearance, not Vd

130
Q

What is the problem with using a loading dose?

A

Can give very high peak concentrations in the brain and heart

131
Q

In a multiple dosing regimen, when is steady state achieved?

A

When the amount of drug eliminated in each dose interval is equal to the amount of the dose

132
Q

What is the principle of superposition?

A

When looking at multiple oral doses, if you know what the concentration was during the first dose, you can work out what the total conc is now by adding conc at time t, t-T, t-2T etc.

133
Q

Give an example of a drug that has zero order kinetics

A

Ethanol - ethanol metabolism saturates at fairly low alcohol intake. Chronic alcohol intake can increase the rate of ethanol metabolism through induction of CYP2E1

134
Q

Name 3 inhalation anaesthetics

A

Ether
Nitrous oxide
Chloroform

135
Q

What is the shape of the curve between log conc anaesthetic and unconsciousness?

136
Q

What is the Meyer-Overton correlation?

A

Correlation between anaesthetic potency and its solubility in olive oil (oil:gas partition coefficient)

137
Q

What did the Meyer-Overton correlation lead to?

A

Theory that general anaesthetics act through accumulating in lipid bilayers and altering membrane function
WRONG

138
Q

Which properties of general anaesthetics do not fit the Meyer-Overton correlation?

A

Maximum molecule size cut off (anaesthetic potency increases with size to a point)
Discovery of some lipid soluble molecules that don’t cause anaesthesia
Stereo-specificity of some anaesthetics (the most major problem with the theory) e.g. isoflurane

139
Q

What is the Franks Lieb correlation?

A

Anaesthetic potency correlates with ability to inhibit a lipid-free protein luciferase

140
Q

What did the Franks-Lieb correlation show?

A

General anaesthetics bind to a hydrophobic pocket in one or more target proteins
Explains the stereo/size/some molecules not working problems

141
Q

What are the protein targets of general anaesthetics?

A
  1. GABAA
  2. K2P two pore K+ channel family
  3. NMDA
    Potential targets
  4. Glycine receptors
  5. HCN channels
  6. NaV
142
Q

What is the structure of the GABAA recepot?

A

Pentameric

Usually 2alpha 2beta gamma

143
Q

Explain how general anaesthetics act on GABAA receptors

A
  1. Potentiate Cl- currents through GABAA receptors
  2. Hyperpolarises postsynaptic membrane
  3. Reduces neuronal activity
    Propofol and etomidate act on beta subunits at distinct sites
    Volatile anaesthetics act on alpha and beta subunits
144
Q

What is the evidence that general anaesthetics act on GABAA receptors?

A

Point mutations in the GABAA alpha and beta subunits reduce anaesthetic potency.
Alpha = abolish volatile with no effect on propofol or etomidate
Beta = affect both

145
Q

Give examples of anaesthetics that activate the K2P family

A

Isoflurane and NO

Volatile

146
Q

What is the mechanism of anaesthetics that act on the K2P family

A

Activate K+ channel
Hyperpolarisation
Reduced neuronal activity

147
Q

What is the evidence that a specific amino acid is involved in binding of anaesthetics to K2P family receptors?

A

Point mutation in TASK3 abolished the effect of halothane and isoflurane

148
Q

How do NO and Xenon inhibit NMDA receptors?

A

Maybe compete with glycine, an essential cofactor for NMDA receptor activation (both need to bind Glu and Gly)

149
Q

What is the problem with using high concentrations of general anaesthetics?

A

Can lead to respiratory failure and death

150
Q

Name 3 injectable anaesthetics

A

Thiopental
Propofol
Etomide

151
Q

What are IV anaesthetics useful for?

A

Rapid induction

152
Q

Name 2 drugs close to saturation of their metabolism

A

Thiopental

Phenytoin

153
Q

Why is consciousness rapidly recovered after a single IV injection?

A

Initial fall in plasma concentration due to redistribution (into lower blood flow tissues, over the course of minutes)

154
Q

What causes the very slow reduction in plasma concentration slightly delayed from injection of thiopental?

A

Thiopental metabolised by liver

As metabolised, slowly equilibrates back from the low blood flow tissues and the fat

155
Q

What can the sub-anaesthetic concentrations of general anaesthetics lead to?

A

Side effect of anaesthetic hangover

156
Q

Why would you use propofol rather than thiopental?

A

More rapid redistribution
More rapid metabolism
May have an anti-emetic effect

157
Q

Why are the benefits and disadvantages of etomidate?

A

Higher therapeutic window over cardiovascular depression

Higher rate of vomiting and nausea during recovery than propofol

158
Q

What is the key determinant of rate of induction of gaseous anaesthetics?

A

Blood:gas partition co-efficient (solubility) - affects how quickly the alveolar air comes into equilibrium with inspired air

159
Q

Why is alveolar air not the same partial pressure as inspired air?

A

Diluted with residual air in the lungs

160
Q

What happens if the blood:gas partition coefficient is high?

A

Gas in alveoli rapidly crosses and is removed by blood flow
Alveolar partial pressure stays low
Takes longer for equilibrium between inspired air and alveoli to be achieved
Induction is relatively slow

161
Q

What happens if the blood:gas partition coefficient is low?

A

Less gas crosses in each breath
Partial pressure of anaesthetic in the alveoli rapidly increases
Equilibrium between inspired air and alveoli is rapidly achieved
Induction is rapid

162
Q

What is the effect of cardiac output on induction rate?

A

High cardiac output slows induction rate

More gas is removed during each breath

163
Q

What is the effect of alveolar ventilation rate on induction rate?

A

Low alveolar ventilation slows induction rate

Less anaesthetic delivered to alveoli in a given timq

164
Q

So which conditions optimise induction?

A
  1. Low blood:gas partition coefficient
  2. Low CO
  3. High ventilation rate
165
Q

Define induction

A

The induction of anaesthesia refers to the transition from an awake to an anaesthetized state.

166
Q

How are gaseous and volatile anaesthetics mainly removed?

A

Lungs unchanged (excretion by ventilation)

167
Q

What affects rate of excretion of volatile anaesthetics?

A

If blood:gas partition coefficient is low, anaesthetic rapidly crosses into alveoli and is removed. Arterial plasma conc falls quickly and recovery is rapid.
If high, anaesthetic crosses slowly and recovery is slow
So recovery faster with low blood gas partition coefficient

168
Q

Define potency

A

Measure of drug activity expressed in terms of amount required to produce an effect of given intensity

169
Q

What affects potency of a volatile anaesthetic?

A

Blood gas partition coefficient - potency higher with higher blood gas partition coefficient

MODA MVST1b (11 decks)

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