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PVS > Pharmacology 2 > Flashcards

Pharmacology 2 Flashcards

1
Q

Define pharmacokinetics

A

What the body does to the drug

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2
Q

Define pharmacodynamics

A

What the drug does to the body

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3
Q

Define Cmax

A

The peak concentration of a drug

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4
Q

Define Tmax

A

The time required for a drug to reach Cmax

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5
Q

What is the significance of the area under the plasma-drug concentration time curve?

A

Reflects the actual body exposure to the drug after administration of a dose and is expressed as mg*h/L

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6
Q

What is the area under the curve dependent on?

A

The rate of elimination of a drug and the dose administered

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7
Q

Define absorption rate

A

The amount of drug absorbed from the administration site to measurement site per unit time

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8
Q

What is the unit of absorption rate?

A

Mass or Moles/unit time

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9
Q

Describe the absorption rate fro bolus IV adminstration

A

Can be considered instant

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10
Q

Describe the absorption rate from infusion administrations e.g. intravenous infusion, transdermal patch etc

A
  • Follow zero-order kinetics

- Rate of absorption is independent of concentration of drug

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11
Q

Describe the absorption from diffusion type administrations e.g. oral, intramuscular etc

A
  • First order kinetics
  • Unlikely to have all of drug absorbed
  • Proportional to amount of drug
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12
Q

What is the absorption from oral administration dependent on?

A
  • Initial rate depends on how much is in GIT

- Initially fast then more absorbed, less in GIT so less of a gradient and then less absorbed

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13
Q

What is a disadvantage of oral administration of a drug relating to its absorption?

A

It is unlikely that all of the drug will be absorbed

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14
Q

Define elimination rate

A
  • The amount of parent drug eliminated from the body per unit time
  • Irreversible removal of the original drug given
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15
Q

What are the units of elimination?

A

Mass or moles per unit time

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16
Q

How is elimination affected by the production of metabolites?

A

Eliminate rate does not include metabolites i.e. elimination only refers to the elimination of the parent drug and does not take into account the production of any metabolites

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17
Q

What parameters need to be defined with regards to elimination?

A

Parameters that relate the amount of parent drug in the body to blood/plasma and urine concentration

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18
Q

What is the elimination rate constant?

A

A constant relating the rate of elimination to the amount of drug in the body
= plasma clearance x plasma concentration
= (clearance/Vd) x amount of drug in the body
= clearance/Vd

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19
Q

What is the equation for calculation of the amount of drug in the body?

A

Volume of distribution x plasma concentration

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20
Q

Explain what is meant by the volume of distribution?

A

A way to describe the affinity of a drug to the tissue i.e. describes how much of a drug goes into the tissues vs how much stays in plasma

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21
Q

Define volume of distribution

A
  • The volume into which a drug appears to be distributed with a concentration equal to that of plasma
  • A proportionality constant relating the blood/plasma concentration to the amount of drug in the body
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22
Q

What are the units of volume of distribution?

A

Litres/kg

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23
Q

What happens tot he plasma concentration of a drug with high tissue affinity?

A

The concentration of the drug in the blood will be lower i.e. more drug in the tissue than the blood/plasma

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24
Q

What does a Vd 0.1-0.3L/kg suggest?

A

Drug is most likely water soluble and distributes mainly to the ECF

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25
Q

What does a Vd 0.6L/kg suggest?

A

The drug distributes to both ECF and ICF

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26
Q

What does a high Vd (e.g. 2L/kg) suggest?

A

The drug is likely accumulating at a particular tissue site

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27
Q

Give the approximate volumes of total body water and ECF normalised for weight

A
  • Total body water: 0.6L/kg

- ECF: 01-0.3L/kg

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28
Q

What are the units of decontamination/elimination?

A

Amount per unit time

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29
Q

What is elimination dependent on?

A
  • Concentration of contaminant in the solution
  • Pump flow rate (analogous to blood flow to organ of clearance)
  • Filter efficiency (analogous to extraction efficiency of organ)
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30
Q

Define total body clearance

A
  • Volume of blood/plasma cleared of parent drug per unit time
  • A constant relating the rate of elimination to the blood/plasma concentrateion
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31
Q

Give the equation for rate of elimination?

A

blood/plasma clearance x blood/plasma concentration

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32
Q

Give the equation for total body clearance

A

Cl(hepatic)+Cl(renal)+Cl(pulmonary)

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33
Q

How are elimination rate and clearance related?

A
  • Elimination rate is the removal of an amount over a unit of time
  • Clearance is the rate of removal and will affect the elimination rate
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34
Q

How is total body clearance determined from a concentration time curve?

A
  • After IV dosing: CL=dose/AUC

- After oral dosing: Cl-(FxDose)/AUC where F = oral availability

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35
Q

Define bioavailability as it relates to drugs

A

Measure of extent of absorption from administration site to measurement site
- i.e. the fraction/percentage of the administered dose that reaches the plasma

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36
Q

How is bioavailability affected by administration method?

A

IV administration has greater bioavailability (assume 100%), oral much lower
- Need to normalise for differences in dose depending on administration method

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37
Q

Give the equation for bioavailability

A

F = (DoseIv/Doseoral)x(AUCoral/AUCIv)

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38
Q

Define half life of a drug

A

The time for the concentration of a drug to halve

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39
Q

Describe the decay curve where there is single, exponential decay of a drug

A

Linear, following a natural logarithmic transformation of the concentration

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40
Q

Give the equation for a linear half life

A

(0.693xVd)/Cl

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41
Q

Describe the non-compartmental pharmacokinetic model

A
  • No specialist software required
  • No assumptions on disposition of drug, administration method or location
  • Can not use to simulate pharmacokinetics for different dosing regimens
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42
Q

Give the characteristics of compartmental models of pharmacokinetics

A
  • Assumes disposition of drug into compartments

- Way of predicting and extrapolating drug pharmacokinetics

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43
Q

Describe a one compartment model, with first order elimination following IV administration, with single exponential decay

A
  • Weak acid, low Vd
  • Vd = initial volume = dose
  • Assumes drug is instantly distributed
44
Q

Describe a one compartment model with first order absorption and elimination following PO, subcut or IM administration

A
  • Drug must first be absorbed

- Rise to peak plasma concentration (absorption phase) followed by elimination phase

45
Q

Describe a 2 compartment model, with first order elimination and distribution following IV administration

A
  • 2 constants
  • K1 = plasma, K2 = tissue
  • K12 = rate of movement from plasma to tissue
  • K21 = rate of movement from tissue to plasma
  • K10 represents elimination
  • Have 2 half lives (alpha and beta)
46
Q

What does a low K12 suggest?

A
  • Instant distribution through compartment 1 (ECF and rapidly perfused tissues) and slow distribution through compartment 2 (poorly perfused tissues)
  • IV administration
47
Q

What are the 2 phases of distribution following bolus administration of a drug?

A
  • Phase I: the drug partitions into tissues

- Phase II: the drug is slowly cleared from tissues

48
Q

What occurs in Phase I of distribution regarding plasma concentration and volume of distribution?

A
  • Plasma concentration drops (Vi)
  • Tissue concentration increases
  • Therefore volume of distribution increases
49
Q

What occurs in Phase II of distribution regarding plasma concentration and volume of distribution?

A
  • Plasma concentration continues to fall but at a slower rate (Varea)
  • Tissue concentration begins to fall following initial increase
  • Volume of distribution plateaus
50
Q

What is meant by first order kinetics?

A
  • Absorption rate is proportional to the amount of drug present
  • E.g. oral administration
  • Diffusion type administrations
51
Q

What is meant by zero-order kinetics?

A
  • The rate of absorption of the drug is independent of the concentration of the drug
  • Absorption rate from infusion administrations e.g. IV
52
Q

What is the effect of saturation on absorption kinetics of a drug?

A
  • Saturation of clearance
  • Approach Km (clearance constant)
  • Moving towards zero-order kinetics
  • Longer half life and accumulation of a drug
53
Q

Describe steady state kinetics

A
  • Usually following administration have a peak followed by trough in concentration
  • Multiple doses leads to steady state (average) level to be reached, over period of 5 half lives
54
Q

Give the equation for Average Concentration(ss)

A
  • AUC/dosing interval
  • (therapeutic dosexF)/Clxtau

tau = 2pi

55
Q

What is the Average Concentration (ss) of a drug dependent on?

A
  • Clearance only

- Independent of distribution

56
Q

What is a loading dose?

A

An initial higher dose of a drug, given at the beginning of a course of treatment before dropping down to the lower maintenance dose

57
Q

What is the purpose of a loading dose?

A
  • Usually for drugs eliminated slowly (long systemic half life)
  • Allows reaching of therapeutic dose and thus the steady state more quickly
58
Q

Give the equation for a loading dose

A

(Therapeutic Css x Vss)/F

59
Q

How is dosing frequency determined?

A
  • The half life of a drug
  • Aim to minimise peaks and troughs in concentration
  • Lower dose, higher frequency allows maintaining of steady state more easily
60
Q

What are the potential clinical consequences of saturation of elimination of the mechanisms of a drug?

A
  • Lengthen half life
  • Elevated and prolonged exposure
  • Therefore toxic or adverse effects more likely to occur
61
Q

What is Km ?

A

Constant of a reaction and is essentially the affinity of the substrate complex

62
Q

How can elimination of a drug become saturated?

A
  • Metabolic and secretory drug clearance is the sum of enzymatic and membrane transporter processes which follow Michaelis-Menten kinetics and thus can be saturated
63
Q

How can clearance of a drug be predicted across species?

A

Allometry or in vitro enzyme kinetics in tissue derived from metabolising organs e.g. liver, gut, kidney

64
Q

How can Vd of a drug be predicted?

A

From knowledge of drug plasma protein and tissue binding

65
Q

What is the effect of body weight on metabolic rate?

A 
Mass specific (per gram) metabolic rate needed to sustain an organism decreases with body weight to the 1/4th power 
- constant x BW(^-0.25)
66
Q

How is mass specific blood flow to eliminating organs affected by weight?

A
  • Decreases with weight according to allometic 1/5 power law
67
Q

Compare the clearance of a drug in smaller to larger species based on blood flow alone

A
  • Small mammals, faster heart rate therefore faster removal

- Clearance expected to be greater for smaller species vs larger ones

68
Q

How is in metabolic clearance assessed in vitro?

A
  • IF primarily metabolised in liver, take samples and isolate hepatocytes
  • Homogenise liver, get S9 fractions, separate cytosol from microsomes
  • Generate recombinant expressed species/synthesise enzymes
  • Test drug with enzymes and follow Michaelis-Menten kinetics
  • Can calculate Vmax and Km
  • Scale up to generate intrinsic clearance per gram of liver
69
Q

What is a limitation of in vitro assessment of clearance?

A

Shows clearance that would occur without physiological limitations e.g. hepatic blood flow

70
Q

What is intrinsic clearance?

A

The enzyme-mediated clearance that would occur without physiological limitations

71
Q

What factor is metabolic clearance of a drug meatbolised by the liver limited by?

A

The blood flow

72
Q

How is hepatic blood clearance calculated?

A
  • Venous equilibrium/”well-stirred” model used
  • (Qh x fu x Clint per liver)/(Qh + fu x Clint per liver)
  • Qh = hepatic blood flow rate
  • fu = fraction of drug unbound in plasma
  • Clint per liver = intrinsic clearance by the liver
73
Q

How is blood clearance by the liver calculated?

A

Blood flow x metabolic clearance from the liver

74
Q

What may affect drug plasma protein binding?

A
  • Elderly and neonates have lower concentration of plasma proteins vs healthy adults
  • Disease states can affect concentration of plasma proteins
  • Drugs may be displaced by drugs with higher affinity to PPBs
75
Q

What happens to the concentration of a drug if displaced from PPBs?

A
  • More free drug in blood

- Leads to increased clearance and increased distribution

76
Q

What is the total drug concentration of plasma?

A

It is the sum of the unbound and plasma protein bound drug

77
Q

How is free drug concentration calculated?

A

A measure of the fraction unbound using dialysis methods

78
Q

What happens to the free drug concentrations when the total drug concentration is decreased?

A
  • Free drug concentration stays the same
  • Due to Vd and clearance both compensating for change, fraction of free drug is the same
  • Half life does not change
79
Q

What happens to the free drug concentration when plasma proteins are decreased?

A
  • Less plasma proteins, more free drug
  • Therefore more cleared from blood
  • Change in volume cancelled out by clearance so free drug concentration stays the same
80
Q

In what situations do drug binding interactions (e.g. administration of a displacing agent) have a meaning/significance?

A
  • Rapid bolus injection
  • Parenteral administration of displaced drug with high organ extraction ratio (theoretical only)
  • Therapeutic drug monitoring and drug displacement from plasma binding site
81
Q

Explain how rapid bolus injection may affect drug binding

A
  • Lots of changes

- If displacing agent given quickly, then free concentration may increase dramatically, redistribution takes place

82
Q

Outline the advantages of controlled released (CR) drug delivery

A
  • Similar kinetics to intravenous infusion (zero-order)
  • Reduced risks of breaching therapeutic window
  • Drug delivery period can be over several months from single administration
83
Q

What is the depot effect?

A
  • Slow release of drug from a sequestered drug
84
Q

What are the areas of a depot drug?

A
  • Outer zone of drug diffusion/release (effective drug concentration
  • Dissolution boundary (area that drug particles dissolve from, non-effective drug concentration)
  • Inner insoluble/sequestered drug (non-effective drug concentration)
85
Q

How is the rate of diffusion/release of a depot drug calculated?

A

KxDrug

  • Where K is drug diffusion/release constant
  • [Drug] dissolution boundary = drug concentration at depot interface
86
Q

Explain why depot drugs have zero-order kinetics

A
  • Boundary losing material but being replaced by sequestered drug
  • Concentration stays constant
87
Q

Give examples of depot drugs

A
  • Bovine boluses
  • Spot-on anti-parasitics (e.g. fipronil, sequestered by sebaceous glands)
  • PRID
88
Q

Define therapeutics

A

The treatment of disease and the action of remedial agents

89
Q

List the core components of rational therapeutics and the therapeutic plan

A
  • Pharmacological and clinical rationale
  • Selection of drugs
  • Target (patho)physiological processes
  • Disease, drug, patient, client, practice and personal considerations
90
Q

What is the importance of correct therapeutic decision making?

A
  • Welfare of animal
  • Owner satisfaction
  • Own satisfaction
  • Drug resistance and loss of efficacy
91
Q

What are some alternatives to therapy?

A
  • Self resolution may be possible
  • Prevention
  • Culling
92
Q

Outline how disease factors affect therapeutic decisions

A
  • Diagnosis important - should be in pathophysiological terms
  • Symptomatic treatment may be appropriate vs treatment of primary cause
  • Impact of disease on drug
93
Q

Why might it be appropriate to treat symptomatically rather than the cause?

A
  • Where symptoms are life threatening and can be treated without knowing underlying cause
  • e.g. dysrhythmias, sepsis, support of blood pressure, vomiting
  • May be appropriate for antibiotics if fast progressing and potentially fatal infection
94
Q

How might disease affect drug pharmacokinetics?

A
  • Absorption may be affected
  • Plasma concentration may be altered which affects efficacy and elimination
  • Blood pressure/cardiac output
  • Plasma pH
  • Physical barriers e.g. BBB may be affected
  • Physiochemical properties of drug
  • Altered metabolism/excretion affecting half life
  • Altered efficacy
95
Q

Give an example of how disease status may reduce the efficacy of a drug

A

Potentiated sulphonamides are ineffective in purulent wounds

96
Q

Outline how drug considerations affect therapeutic planning

A
  • Licensing of drug for veterinary use
  • Formulation (preparation can alter time of onset)
  • Administration (frequency/method)
97
Q

Outline some administrations factors that affect drug choice

A
  • Route and frequency
  • Owner choice
  • Animal factors
  • Route may be affected by disease
  • Route may affect efficacy or safety
98
Q

Give an example of altered efficacy as a consequence of administration route

A

Lignocaine only effective for ventricular dysrhythmias when administered IV

99
Q

Outline some owner factors that may affect therapeutic choice

A
  • Financial considerations (but is not valid excuse for drug choice)
  • Owner compliance
100
Q

Give some potential reasons for owner non-compliance

A
  • Cost
  • Previous relationship/experience
  • False information
  • Pet considerations
  • Time/effort required
  • Perception of resolution of disease
  • Poor judgement of pain
  • Therapeutic options
101
Q

Outline some practice factors that may affect therapeutic decision making

A
  • Corportate practices
  • Drug buying power/deals
  • Shelf stock and turnover
  • Practice experience/policy
102
Q

Define adverse event

A

Unintended or noxious response to a drug that occurs within a reasonable time frame following

103
Q

Give some use patterns associated with adverse events

A
  • Off label use
  • Drugs with low therapeutic indices
  • Inappropriate trivial use
  • Lack of therapeutic goals
  • Polypharmacy
  • Young/old/altered PK
104
Q

Give some types of adverse events

A
  • Lack of efficacy
  • Exaggerated normal response
  • Hypersensitivity
  • Toxic effects
  • Idiosyncratic
105
Q

Outline exaggerated normal responses to drugs

A
  • Lower than expected/desired heart rate with an alpha-2 agonist
  • bacterail over/altered growth in gutwith antibiotic use
  • NSAIDs and gut uleration
  • Vaccine reaction
  • Often dose related
106
Q

Outline hypersensitivity to drugs

A
  • Non-dose related and non-predictable
  • Usually due to metabolites forming haptens that cause allergic response
  • Can lead to cross-reactivity within class of drug
  • Can be indirect/immediate
107
Q

Outline toxic effect of drugs

A
  • Not related to pharmacological action

- e.g. nephrotoxic effects gentamycin are unrelated to antimicrobial protein synthesis blocking effect

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