Pharmacology 2 Flashcards
1
Q
Define pharmacokinetics
A
What the body does to the drug
2
Q
Define pharmacodynamics
A
What the drug does to the body
3
Q
Define Cmax
A
The peak concentration of a drug
4
Q
Define Tmax
A
The time required for a drug to reach Cmax
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
6
Q
What is the area under the curve dependent on?
A
The rate of elimination of a drug and the dose administered
7
Q
Define absorption rate
A
The amount of drug absorbed from the administration site to measurement site per unit time
8
Q
What is the unit of absorption rate?
A
Mass or Moles/unit time
9
Q
Describe the absorption rate fro bolus IV adminstration
A
Can be considered instant
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
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
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
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
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
15
Q
What are the units of elimination?
A
Mass or moles per unit time
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
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
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
19
Q
What is the equation for calculation of the amount of drug in the body?
A
Volume of distribution x plasma concentration
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
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
22
Q
What are the units of volume of distribution?
A
Litres/kg
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
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
25
What does a Vd 0.6L/kg suggest?
The drug distributes to both ECF and ICF
26
What does a high Vd (e.g. 2L/kg) suggest?
The drug is likely accumulating at a particular tissue site
27
Give the approximate volumes of total body water and ECF normalised for weight
- Total body water: 0.6L/kg
| - ECF: 01-0.3L/kg
28
What are the units of decontamination/elimination?
Amount per unit time
29
What is elimination dependent on?
- 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)
30
Define total body clearance
- Volume of blood/plasma cleared of parent drug per unit time
- A constant relating the rate of elimination to the blood/plasma concentrateion
31
Give the equation for rate of elimination?
blood/plasma clearance x blood/plasma concentration
32
Give the equation for total body clearance
Cl(hepatic)+Cl(renal)+Cl(pulmonary)
33
How are elimination rate and clearance related?
- 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
34
How is total body clearance determined from a concentration time curve?
- After IV dosing: CL=dose/AUC
| - After oral dosing: Cl-(FxDose)/AUC where F = oral availability
35
Define bioavailability as it relates to drugs
Measure of extent of absorption from administration site to measurement site
- i.e. the fraction/percentage of the administered dose that reaches the plasma
36
How is bioavailability affected by administration method?
IV administration has greater bioavailability (assume 100%), oral much lower
- Need to normalise for differences in dose depending on administration method
37
Give the equation for bioavailability
F = (DoseIv/Doseoral)x(AUCoral/AUCIv)
38
Define half life of a drug
The time for the concentration of a drug to halve
39
Describe the decay curve where there is single, exponential decay of a drug
Linear, following a natural logarithmic transformation of the concentration
40
Give the equation for a linear half life
(0.693xVd)/Cl
41
Describe the non-compartmental pharmacokinetic model
- No specialist software required
- No assumptions on disposition of drug, administration method or location
- Can not use to simulate pharmacokinetics for different dosing regimens
42
Give the characteristics of compartmental models of pharmacokinetics
- Assumes disposition of drug into compartments
| - Way of predicting and extrapolating drug pharmacokinetics
43
Describe a one compartment model, with first order elimination following IV administration, with single exponential decay
- Weak acid, low Vd
- Vd = initial volume = dose
- Assumes drug is instantly distributed
44
Describe a one compartment model with first order absorption and elimination following PO, subcut or IM administration
- Drug must first be absorbed
| - Rise to peak plasma concentration (absorption phase) followed by elimination phase
45
Describe a 2 compartment model, with first order elimination and distribution following IV administration
- 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
What does a low K12 suggest?
- Instant distribution through compartment 1 (ECF and rapidly perfused tissues) and slow distribution through compartment 2 (poorly perfused tissues)
- IV administration
47
What are the 2 phases of distribution following bolus administration of a drug?
- Phase I: the drug partitions into tissues
| - Phase II: the drug is slowly cleared from tissues
48
What occurs in Phase I of distribution regarding plasma concentration and volume of distribution?
- Plasma concentration drops (Vi)
- Tissue concentration increases
- Therefore volume of distribution increases
49
What occurs in Phase II of distribution regarding plasma concentration and volume of distribution?
- Plasma concentration continues to fall but at a slower rate (Varea)
- Tissue concentration begins to fall following initial increase
- Volume of distribution plateaus
50
What is meant by first order kinetics?
- Absorption rate is proportional to the amount of drug present
- E.g. oral administration
- Diffusion type administrations
51
What is meant by zero-order kinetics?
- The rate of absorption of the drug is independent of the concentration of the drug
- Absorption rate from infusion administrations e.g. IV
52
What is the effect of saturation on absorption kinetics of a drug?
- Saturation of clearance
- Approach Km (clearance constant)
- Moving towards zero-order kinetics
- Longer half life and accumulation of a drug
53
Describe steady state kinetics
- 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
Give the equation for Average Concentration(ss)
- AUC/dosing interval
- (therapeutic dosexF)/Clxtau
tau = 2pi
55
What is the Average Concentration (ss) of a drug dependent on?
- Clearance only
| - Independent of distribution
56
What is a loading dose?
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
What is the purpose of a loading dose?
- Usually for drugs eliminated slowly (long systemic half life)
- Allows reaching of therapeutic dose and thus the steady state more quickly
58
Give the equation for a loading dose
(Therapeutic Css x Vss)/F
59
How is dosing frequency determined?
- 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
What are the potential clinical consequences of saturation of elimination of the mechanisms of a drug?
- Lengthen half life
- Elevated and prolonged exposure
- Therefore toxic or adverse effects more likely to occur
61
What is Km ?
Constant of a reaction and is essentially the affinity of the substrate complex
62
How can elimination of a drug become saturated?
- 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
How can clearance of a drug be predicted across species?
Allometry or in vitro enzyme kinetics in tissue derived from metabolising organs e.g. liver, gut, kidney
64
How can Vd of a drug be predicted?
From knowledge of drug plasma protein and tissue binding
65
What is the effect of body weight on metabolic rate?
```
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
How is mass specific blood flow to eliminating organs affected by weight?
- Decreases with weight according to allometic 1/5 power law
67
Compare the clearance of a drug in smaller to larger species based on blood flow alone
- Small mammals, faster heart rate therefore faster removal
| - Clearance expected to be greater for smaller species vs larger ones
68
How is in metabolic clearance assessed in vitro?
- 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
What is a limitation of in vitro assessment of clearance?
Shows clearance that would occur without physiological limitations e.g. hepatic blood flow
70
What is intrinsic clearance?
The enzyme-mediated clearance that would occur without physiological limitations
71
What factor is metabolic clearance of a drug meatbolised by the liver limited by?
The blood flow
72
How is hepatic blood clearance calculated?
- 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
How is blood clearance by the liver calculated?
Blood flow x metabolic clearance from the liver
74
What may affect drug plasma protein binding?
- 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
What happens to the concentration of a drug if displaced from PPBs?
- More free drug in blood
| - Leads to increased clearance and increased distribution
76
What is the total drug concentration of plasma?
It is the sum of the unbound and plasma protein bound drug
77
How is free drug concentration calculated?
A measure of the fraction unbound using dialysis methods
78
What happens to the free drug concentrations when the total drug concentration is decreased?
- 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
What happens to the free drug concentration when plasma proteins are decreased?
- 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
In what situations do drug binding interactions (e.g. administration of a displacing agent) have a meaning/significance?
- 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
Explain how rapid bolus injection may affect drug binding
- Lots of changes
| - If displacing agent given quickly, then free concentration may increase dramatically, redistribution takes place
82
Outline the advantages of controlled released (CR) drug delivery
- 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
What is the depot effect?
- Slow release of drug from a sequestered drug
84
What are the areas of a depot drug?
- 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
How is the rate of diffusion/release of a depot drug calculated?
Kx[Drug](dissolution boundary)
- Where K is drug diffusion/release constant
- [Drug] dissolution boundary = drug concentration at depot interface
86
Explain why depot drugs have zero-order kinetics
- Boundary losing material but being replaced by sequestered drug
- Concentration stays constant
87
Give examples of depot drugs
- Bovine boluses
- Spot-on anti-parasitics (e.g. fipronil, sequestered by sebaceous glands)
- PRID
88
Define therapeutics
The treatment of disease and the action of remedial agents
89
List the core components of rational therapeutics and the therapeutic plan
- Pharmacological and clinical rationale
- Selection of drugs
- Target (patho)physiological processes
- Disease, drug, patient, client, practice and personal considerations
90
What is the importance of correct therapeutic decision making?
- Welfare of animal
- Owner satisfaction
- Own satisfaction
- Drug resistance and loss of efficacy
91
What are some alternatives to therapy?
- Self resolution may be possible
- Prevention
- Culling
92
Outline how disease factors affect therapeutic decisions
- Diagnosis important - should be in pathophysiological terms
- Symptomatic treatment may be appropriate vs treatment of primary cause
- Impact of disease on drug
93
Why might it be appropriate to treat symptomatically rather than the cause?
- 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
How might disease affect drug pharmacokinetics?
- 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
Give an example of how disease status may reduce the efficacy of a drug
Potentiated sulphonamides are ineffective in purulent wounds
96
Outline how drug considerations affect therapeutic planning
- Licensing of drug for veterinary use
- Formulation (preparation can alter time of onset)
- Administration (frequency/method)
97
Outline some administrations factors that affect drug choice
- Route and frequency
- Owner choice
- Animal factors
- Route may be affected by disease
- Route may affect efficacy or safety
98
Give an example of altered efficacy as a consequence of administration route
Lignocaine only effective for ventricular dysrhythmias when administered IV
99
Outline some owner factors that may affect therapeutic choice
- Financial considerations (but is not valid excuse for drug choice)
- Owner compliance
100
Give some potential reasons for owner non-compliance
- Cost
- Previous relationship/experience
- False information
- Pet considerations
- Time/effort required
- Perception of resolution of disease
- Poor judgement of pain
- Therapeutic options
101
Outline some practice factors that may affect therapeutic decision making
- Corportate practices
- Drug buying power/deals
- Shelf stock and turnover
- Practice experience/policy
102
Define adverse event
Unintended or noxious response to a drug that occurs within a reasonable time frame following
103
Give some use patterns associated with adverse events
- Off label use
- Drugs with low therapeutic indices
- Inappropriate trivial use
- Lack of therapeutic goals
- Polypharmacy
- Young/old/altered PK
104
Give some types of adverse events
- Lack of efficacy
- Exaggerated normal response
- Hypersensitivity
- Toxic effects
- Idiosyncratic
105
Outline exaggerated normal responses to drugs
- 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
Outline hypersensitivity to drugs
- 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
Outline toxic effect of drugs
- Not related to pharmacological action
| - e.g. nephrotoxic effects gentamycin are unrelated to antimicrobial protein synthesis blocking effect
