Primary FRCA > Pharmacology 3 > Flashcards

Pharmacology 3 Flashcards

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1
Q

What is the concept of pharmacokinetics?

A

The considerations relating to the movement of a drug into, through and out of the body.

‘What the body does to the drug’

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2
Q

How is drug absorption defined?

A

The movement of a drug from its site of administration into the plasma

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3
Q

What factors affect drug absorption?

A
  • Formulation
  • Route of administration
  • Physiochemical properties of the drug (eg. ionization)
  • Local blood flow
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4
Q

How does drug movement across cellular barriers vary within the body?

A

Epithelial surfaces:
-Tightly connected cells across (or through) which drugs must cross

Vascular endothelium:

  • Variable permeablility
  • Most capillaries have pores allowing relatively free passage of drug molecules
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5
Q

By what mechanisms may drugs cross cell membranes?

A
  • Diffusion
  • Channels
  • Cell-mediated transport (active vs. facilitated diffusion)
  • Pinocytosis (relatively unimportant in drug absorption)
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6
Q

What factors affect GI tract absorption?

A
  • Gut motility
  • pH
  • Molecule size
  • Physiochemical reactions with GI contents
  • First-pass metabolism
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7
Q

What is first-pass metabolism?

A

aka. pre-systemic metabolism.

FPM is breakdown of a drug to inactive form by the liver before entering the systemic circulation. Occurs with enteral drug administration.

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8
Q

Name some drugs with high first-pass metabolism rates

A
  • Morphine
  • Midazolam
  • Lidocaine
  • Aspirin
  • GTN
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9
Q

Define bioavailability

How may it be expressed?

A

The fraction (F) of the drug which reaches the systemic circulation in tact and is therefore available to the site of action

May be ‘absolute’ or ‘relative’

Absolute:
F = AUC (chosen route) / AUC (IV)

AUC = area under curve

Relative:
-For drugs that cannot be administered IV, bioavailability may be compared to that of a different route of administration (ie. the denominator of the above equation is changed)

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10
Q

How may distribution of inhalational agents in the body be conceptualised?

A

Three compartments:

  • Alveolar (PA)
  • Blood (Pa)
  • Brain (PB)

Partial pressures in each of these compartments govern the speed and direction of movement of the drug

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11
Q

What factors affect speed of onset time for volatile anaesthetics?

A

Agent:
-Blood:gas partition coefficient

Delivery:

  • Vaporiser settings
  • Ventilation settings eg. MV
  • Uptake of agent by rubber/plastic components
  • ‘Pumping effect’

Patient:

  • Physiology
  • Cardiac output (steeper wash-in curve but reduced distribution to downstream compartments)
  • MV if spontaneously breathing
  • FRC (higher FRC -> slower wash-in)
  • CBF
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12
Q

What are the features of a wash-in curve for volatile anaesthetic agents?

A

FA/Fi on y axis, time on x axis

Negative exponential curve

  • Exponential because rate of change towards equilibrium is related to the concentration gradient
  • Negative because the rate reduces with time
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13
Q

How long does it take for inhalational anaesthetic agents to reach equilibrium?

Is this the same for all agents?

A

Around 6h

YES - but the rates at which the agents approach equilibrium (ie. the AUC) are different

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14
Q

Rank the inhaled anaesthetic agents in order of their onset times (fastest-slowest)

A 
N2O [fastest]
Desflurane
Sevoflurane
Isoflurane
Enflurane
Halothane [slowest]
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15
Q

What is the ‘pumping effect’ relating to concentration of volatile agents?

A
  • During IPPV, the bellows increase back-pressure into the back bar
  • This can cause retrograde flow of fresh gas into the vaporising chamber
  • This gas then flows forward between cycles with a higher concentration than set on the dial
  • More pronounced effect at low-flow and low-settings
  • Can be reduced by placing a non-return valve downstream of the back bar
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16
Q

Why are low cardiac output states associated with faster speed of onset of volatile anaesthetics?

A
  1. Steeper wash-in curve and increased A-a gradient [questionable??]
  2. Relative increase in brain perfusion (thus faster equilibration of a-B gradient)
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17
Q

Outline the interaction between CBF and speed of onset of volatile anaesthetics

A

Higher CBF -> Faster onset

Thus factors which increase CBF will increase speed of onset:
-Hypercapnia / hypoventilation

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18
Q

What effect do volatile anaesthetics have on ICP?

A

Increase CBF -> Increase ICP

Includes N2O (best avoided in rasied ICP)

1 MAC is usually ok for newer volatiles

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19
Q

What are the important pharmacokinetic properties of volatile anaesthetic agents?

A

Partition coefficients:

  • Oil:gas (potency)
  • Blood:gas (speed of onset/offset)

Lipid solubility (potency)

Chemical structure

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20
Q

Explain the Meyer-Overton hypothesis

A

States that the MAC value of an anaesthetic agent is inversely proportional to the oil:gas partition coefficient

Thus potency is directly proportional to oil:gas partition coefficient

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21
Q

List the physiochemical properties of the volatile anaesthetic agents

A

Halothane:

  • MW 197
  • B:GPC 2.4
  • O:GPC 224
  • MAC 0.75%
  • SVP (20°C) 32.5 kPa
  • BP 50°C
  • Biotransformation 20%

Enflurane:

  • MW 184
  • B:GPC 1.9
  • O:GPC 98
  • MAC 1.8%
  • SVP (20°C) 23 kPa
  • BP 56.5°C
  • Biotransformation 2%

Isoflurane:

  • MW 184
  • B:GPC 1.4
  • O:GPC 91
  • MAC 1.15%
  • SVP (20°C) 32 kPa
  • BP 48.5°C
  • Biotransformation 0.2%

Sevoflurane:

  • MW 200
  • B:GPC 0.69
  • O:GPC 53
  • MAC 2.05%
  • SVP (20°C) 21.3 kPa
  • BP 59°C
  • Biotransformation 3-5%

Desflurane:

  • MW 168
  • B:GPC 0.42
  • O:GPC 19
  • MAC 6%
  • SVP (20°C) 88.5 kPa
  • BP 23°C
  • Biotransformation 0.02%

Nitrous Oxide:

  • MW 44
  • B:GPC 0.47
  • O:GPC 1.4
  • MAC 105%
  • Critical temperature 36.5°C
  • BP -88°C
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22
Q

Why is halothane much more potent than the other volatiles?

A

As a halogenated hydrocarbon it is signficantly more lipid soluble than the newer halogenated ethers, thus it is more potent

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23
Q

What is the relationship between isoflurane and enflurane?

A

They are structural isomers

The position of the fluorine atoms in isoflurane confer less water solubility, more lipid solubility and less susceptibility to metabolism than enflurane

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24
Q

What is the concentration effect?

A

The tendency for FA to rise more rapidly towards Fi when high concentrations are used

Particularly relevant to N2O, as this can be administered in high concentrations

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25
Why is the concentration effect so marked for N2O?
N2O is roughly 20x more soluble in blood than nitrogen. This means that is rapidly absorbed into blood down its A-a gradient. The loss of this volume in the alveolus draws more fresh gas to replace it, which contains more N2O. The higher the concentration of N2O, the bigger the concentration effect
26
What is the second gas effect?
This is the result of the concentration effect. The rapid uptake of N2O in the alveolus and replacement with fresh gas increases the conc. of co-administered gases in the alveolus, increasing the A-a gradient. This has a significant effect on speed of induction of volatile anaesthetics
27
Explain diffusion hypoxia
This is the reverse of the second gas effect N2O diffuses rapidly out of the blood on abrupt discontinuation of administration. This displaces other alveolar gases, reducing their PA. The reduced A-a gradient of O2 can lead to hypoxia Thus following anaesthetics with N2O, supplemental O2 must be given
28
When should N2O not be used?
Raised ICP Pathological air-filled cavities (eg. PTX) Airway obstruction
29
Does N2O support combustion?
Yes
30
Compare the features of wash-in and wash-out curves
Wash-out curves are essentially the opposite to a wash-in curve, with the steepest upward gradients of wash-in replaced with the steepest downward gradients of wash-out. They are still negative exponential functions. However, the y-axis represents FA/FAE rather than Fi as the Fi will be zero, thus making the above equal infinity.
31
What is the context-sensitive half time of volatile agents? How helpful is this?
Very little difference between ethers -around 5 mins or less irrespective of duration. More relevant to long operations is the 90% decrement time, which does vary between agents, similarly to speed of onset
32
Outline the mechanisms and consequences of liver metabolism of volatile agents
Liver metabolism is by CYP2E1, which attacks the carbon-halogen bonds producing various metabolites. An important metabolite - Trifluoroacetic acid (TFA) has been implicated in hepatitis. This is produced in the breakdown of all agents except for sevoflurane. ``` Order of metabolism: Halothane (20%) [most] Sevoflurane (3-5%) Enflurane (2%) Isoflurane (0.2%) Desflurane (0.02%) [least] ```
33
What type of metabolism do the P450 enzymes perform?
Phase 1 | aka. mixed function oxidases
34
From where is the name cytochrome p450 derived? Where are they found?
'cytochrome' = 'cell colour' - due to haem content, giving liver red colour - In reduced state combines with CO forming a complex which maximally absorbs light of 450nm wavelength, hence '450' Found primarily in SER of hepatocytes but also in kidneys, brain, adrenals, gut and lungs
35
Which important named enzymes are also CYP450s?
``` 11 beta hydroxylase (adrenal) thromboxane a2 (platelets) ```
36
Outline the nomenclature of the P450 enzymes
CYP - root First position (number) - genetic family Second position (letter) -subfamily Third position (number) - gene Fourth position (*number) - allele (variant if >*1) eg. CYP2D6*4
37
How many families/subfamilies of human CYP450s are known? What is the level of genetic similarity between the enzymes?
18 families, 44 subfamilies 40% within family 55% within subfamily
38
What are the roles of cytochrome enzymes in the liver?
1. Bile acid synthesis - CYP7A 2. Endogenous steroid synthesis - CYP11, 17, 19, 21 - CYP19 is present in adipose tissue and produces oestrogen 3. Toxin metabolism
39
Outline the role of the P450 enzymes in the kidneys
Mainly production of arachidonic acid metabolites: - EET (CYP2C) - renal vasodilators - HETE (CYP4A) - renal vasoconstrictors, also inhibits sodium reuptake
40
Outline the role of the P450 enzymes in the brain
Steroid and prostaglandin metabolism, resulting in: - Regulation of peptide hormone release by hypothalamus/pituitary - Regulation of cerebrovascular tone - Regulation of progesterone and corticosteroids in the brain which influence GABA receptors and affect mood
41
Summarise the characteristics of the CYP1 family
CYP1A are the most important for drugs Metabolise polycyclic aromatic compounds such as: - Theophylline - Propranolol - Caffeine All CYP1As are induced by: - Smoking - Chargrilled meat - Phenytoin - Barbiturates CYP1A2 inhibitors: - Ciprofloxacin (strong) - Fluvoxamine (strong) - Cimetidine (moderate)
42
Summarise the characteristics of the CYP2 family
Large family of which CYP2C/D/E are most important CYP2C and CYP2D are responsible for the majority of drug metabolism and exhibit significant genetic variation CYP2C9: - Absent in 1% of caucasians and most African-Americans - Metabolises S-warfarin, losartan, phenytoin and most NSAIDs - Inhibited by fluconazole (strong) and amiodarone (moderate) CYP2C19: - Absent in 20-30% of Asians and 3-5% of Caucasians - Metabolises diazepam, phenytoin and omeprazole - Inhibited by PPIs (strong), ketoconazole and cimetidine CYP2D6: - Absent in 7-10% of Caucasians and 1-3% of non-Caucasians. Up to 30% of East Africans have multiple copies of the enzyme and metabolise extensively. - Metabolises >25% of all drugs including codeine, tramadol, beta blockers, TCAs, SSRIs, flecainide, ondansetron - Inhibited by fluoxetine (strong), paroxetine (strong), quinidine (strong), amiodarone (moderate) and cimetidine (moderate) CYP2E1: - Metabolises volatile anaesthetic agents including sevoflurane, isoflurane and methoxyflurane - Also metabolises ethanol and paracetamol - Induced by isoniazid and chronic alcohol use - Inhibited by disulfiram and acute alcohol use
43
Summarise the characteristics of the CYP3 family
CYP3A is the main subfamily with four isoforms - 3A3, 3A4, 3A5 and 3A7 -Accounts for 70% of the CYPs found in the gut Metabolise a large number of drugs: - CCBs - Benzodiazepines - Antihistamines - Cisapride - Lidocaine - Fentanyl and alfentanil Induced by: - Carbamazepine - Rifampicin - Phenobarb - Glucocorticoids - Phenytoin - St John's Wort Inhibited by: - Grapefruit juice - Erythromycin - Amiodarone - Cimetidine - Ketoconazole
44
Which CYP genes show the most important genetic variation?
Those encoding: - CYP2C9 - CYP2C19 - CYP2D6
45
What CYP variations can predispose to disease?
21 hydroxylase deficiency is responsible for congenital adrenal hyperplasia Smokers with increased CYP1A1 activity are more prone to lung cancer and CYP2D6 may also be implicated CYP2E1 may also be involved in the formation of procarcinogens
46
How long do orally administered drugs take to reach steady state?
Roughly 5 elimination half-lives or 3 time constants
47
How is plasma concentration at a given time calculated using a one-compartment model?
C = C0e^-kt ``` C = Drug concentration CO = C at time 0 k = elimination rate constant (per min) t = time ``` CO can be calculated using: CO = dose / Vd
48
What is the 'time constant' for a drug? How is it related to half-life?
The time taken for the concentration of the drug to reduce by a factor of e It is the inverse of the rate constant (ie. 1/k) As e>2, a drug's time constant (T) is longer than its half-life
49
How are clearance, time constant and Vd related?
Cl = Vd / T
50
How long following a dose does it take for a drug to become undetectable in quantity?
Roughly 3 time constants (or 5 half-lives)
51
What equation governs steady state concentration?
C = Css(1 - e^-kt)
52
What factors determine rate constants for distribution and redistribution in a >1 compartment model?
- Physiochemical properties - Blood supply - Transport processes
53
In a single compartment model, how is clearance defined and found?
Cl = V1 x k10 Or, Cl = V1 / T (time constant)
54
Which two commonly used drugs have a Michaelis constant close to clinically used concentrations? Why is this important?
Thiopental and phenytoin This means that there is a risk of exceeding Vmax, resulting in zero order kinetics
55
How can steady state volume of distribution be calculated from terminal elimination?
Vss = Cl / Tz (terminal elimination time constant)
56
What factors, other than hepatic or renal failure, affect inter-individual variability in drug clearance?
- Age - Gender - Genetics - Co-adminiastration of other drugs
57
How may liver failure affect drug clearance?
- Increased initial Vd due to altered fluid distribution eg. ascites. - Reduction in plasma protein synthesis may affect required loading dose - Reduced metabolism will reduce maintenance requirements for hepatically metabolised drugs due to decreased clearance.
58
How may renal failure affect drug clearance?
- Increased initial Vd due to altered fluid distribution - may increase required loading dose - Reduced GFR will reduce clearance for drugs depending on renal excretion
59
Which drugs are excreted unchanged by the kidneys?
Highly polar drugs eg. muscle relaxants Morphine-6-glucuronide
60
What is the rate constant for the effect site compartment called?
Ke0
61
How does context-sensitive half-time vary for propofol?
Initially: 3 mins | At steady state: 18 mins
62
How does context-sensitive half time vary for remifentanil?
Initially: 3 mins | At steady state: 8 mins
63
What is the maximum CSHT for Alfentanil?
45 mins
64
Why is thiopental not given as an infusion?
- Rapid enzyme saturation leads to early zero-order kinetics | - Active metabolite, pentobarbital, which has a longer half-life
65
What are the ideal properties of a drug for TCI?
- Short and predictable CSHT - Rapid elimination and slow redistribution if lipid-soluble - No active metabolites - Non-organ dependent metabolism - Minimal adverse effects (eg. CVS) - Pain-free on injection
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