Week 1: Concepts in Clinical Pharmacology Flashcards
1
Q
Dosing Instruction Abbreviations: BD
A
Twice Daily
2
Q
Dosing Instruction Abbreviations: NOCTE
A
At night
3
Q
Dosing Instruction Abbreviations: OD
A
Once a day
4
Q
Dosing Instruction Abbreviations: QDS
A
Four times a day
5
Q
Dosing Instruction Abbreviations: STAT
A
Single one off dose
6
Q
Dosing Instruction Abbreviations: TDS
A
Three times a day
7
Q
Pharmacokinetic Abbreviations: Cmax
A
Maximum concentration
8
Q
Pharmacokinetic Abbreviations: Cp
A
plasma concentration
9
Q
Pharmacokinetic Abbreviations: CpSS
A
Plasma concentration at steady state
10
Q
Pharmacokinetic Abbreviations: CYP
A
Cytochrome P450
11
Q
Pharmacokinetic Abbreviations: Tmax
A
Time to maximum concentration
12
Q
Pharmacokinetic Abbreviations: Vd
A
Volume of Distribution
13
Q
Administrative Route Abbreviations: IM
A
Intramuscular
14
Q
Administrative Route Abbreviations: IV
A
Intravenous
15
Q
Administrative Route Abbreviations: LD
A
Loading Dose
16
Q
Administrative Route Abbreviations: PO
A
Oral
17
Q
Administrative Route Abbreviations: PR
A
Per rectum
18
Q
Administrative Route Abbreviations: SC
A
Subcutaneous
19
Q
Administrative Route Abbreviations: SL
A
Sublingual
20
Q
As a clinician, you are given the Apparent Volume of Distribution for three drugs. These have been tested in a clinical trial in a male patient, 35 yrs old of normal build. The values are given below. What real fluid compartments do you think these drugs are distribute between?
Drug 1: 0.12 L/kg
Drug 2: 0.26 L/kg
Drug 3: 3.4 L/kg
A
- 12 L/kg is 8.4 L - mainly plasma (e.g. insulin)
- 26 L/kg is approx 18 L- extracellular (e.g. penicillin)
- 4 L/kg is approx 238 L- mainly intracellular (morphine)
The idea is to show how changes in Vd broadly correlate to fluid compartments and their related set of binding sites.
21
Q
Two female patients in their early twenties were being assessed for treatment with haloperidol for psychotic illness. Both patients were about 1.7m in height, but one patient weighed 46 kg, the other 92 kg.
Given the normal Vd for haloperidol is about 18L/kg, how would you expect this weight difference to affect its value?
How do you think this information would affect your initial dosing regime with haloperidol in these patients?
A
You may consider using a lower than normal dose to avoid the possibility of overdose in the underweight patient. In the obese patient you would probably start with normal doses and adjust from there.
The very high Vd for Haloperidol of 18L/Kg indicates that it is widely distributed throughout the rest of body tissues and it is comparatively lipid soluble. The patient with a weight of 92 kg is evidently more obese than the other patient. You would expect the value of Vd to increase due to its increased distribution in body adipose for this patient
For the patient with a weight of 46 kg she is underweight for her height is evidently less obese. You would then expect the value of Vd to decrease due to decreased volume of adipose tissue.
22
Q
What factors referenced to three major systems would you expect to affect Clearance and why?
A
HRH
Hepatic – If you have hepatic deficit you would expect lowered clearance due to the reduction in available Phase I and II enzymes for metabolism
Renal –Similarly if renal clearance is affected either by reduced filtration, active OATP and OCTP transport and reduced tubular secretion then clearance will be affected adversely
Heart/Cardiac Output – If cardiac output is reduced then the rate of blood flow to the liver and kidneys also drop again meaning clearance will be reduced.
23
Q
A 53 yr old man is admitted to hospital with a long history of alcohol abuse. He is severely jaundiced and has suspected renal failure. He is also underweight for his height.
Before you begin any drug therapy, what effect might you expect there to be on clearance of any drugs you might prescribe?
A
a. Alcohol abuse and jaundice point to liver failure. This would be expected to reduce clearance for many drugs therefore longer half life
b. Renal failure would also be expected to affect clearance half life
c. Reduced weight would also be expected to result in a lower volume of distribution for drugs partitioning in to body tissues
d. Therefore would have to take all this into account before starting therapy as each would affect doses of most drugs administered.
e. Problems with reduced clearance mean that systemic toxicity becomes more of a problem.
24
Q
Drug Elimination Half Life – t1/2
A
The terms for the volume of distribution and clearance are used by clinicians to calculate the overall figure summarising first order elimination kinetics the half-life.
This is approximately
t1/2≈ 0.7 x Vd/CL
25
Assuming linear elimination kinetics approximate the time taken to get to CpSS for drugs with the following half-lives.
i. 2.5 hrs
ii. 6 hrs
iii. 12 hrs
iv. 24 hrs
v. 36 hrs
times each by 4 to 5, the number of half live required to reach CpSS
26
If the elimination half life was very much shorter than the dosing interval, could you reach a reasonably stable CpSS by the oral route?
Penicillin has a half life of 30 minutes. It is usually given four time per day. Describe the changes in concentrations across 24 hours.
The time take to peak absorption is about 1 hour with penicillin but the idea here is to show that some drugs when given orally, will not reach a steady state due to their short half-life. This is not necessarily a therapeutic problem as they can still be highly efficacious over these relatively brief intervals.
27
4 main factors affecting pharmacokinetics of a drug
The main factors affecting entry and removal of the drug can be remembered
using the mnemonic acronym ADME.
* Absorption - Drug In
* Distribution
* Metabolism
* Excretion Drug Out - Elimination
28
What is meant by enteral delivery?
Many drugs are given orally which forms the major group for enteral delivery, that is drugs that are given via the GI tract. This category also includes the sub-lingual and rectal routes.
29
What is meant by parenteral delivery?
This includes all the other routes that are not the GI. These are especially important in acute medicine and are used to overcome the problems presented by GI absorption
30
List 3 parenteral delivery routes
```
Intravenous
Subcutaneous
Transdermal
Intramuscular
Intrathecal.
```
In addition, the routes across specialised epithelia come under this heading.
31
main passive factors affecting systemic entry of a drug
lipophilicity
molecular size
changes in pH
32
main active factors affecting systemic entry of a drug
Important active factors include presence of active transport systems; splachnic blood flow (reduced in shock and heart failure) and drug destruction by gut and/or bacterial enzymes.
33
What is first pass metabolism?
metabolism carried out by the gut and liver
As virtually all molecules absorbed by the gut will travel via the portal circulation to the liver, hepatic first pass metabolism can again significantly reduce the amount of available drug as measured by its extraction ratio.
Can occur in:
o The Gut Lumen
• Gastric acid, proteolytic enzymes, grapefruit juice
• E.g. Benzylpenicillin, insulin, ciclosporin
o The Gut Wall
• P-glycoprotein efflux pumps drugs out of the intestinal enterocytes
back into the lumen e.g. ciclosporin
o The Liver
• E.g. Propranolol is extensively metabolised
34
What is bioavailability?
Bioavailability refers to the relative amount of drug that reaches the systemic circulation once it has overcome all the barriers to its absorption. This fraction will depend on the route used.
This is calculated as (Amount of Drug Reaching Systemic Circulation) divided by (Total Amount of Drug Administered)
Clinically, this is calculated by looking at the Total Area Under the Curve or AUC that describes the drugs plasma concentration over time for both the numerator (top) and denominator (bottom) parts of the above equation.
35
True or false?
The oral route and its subsequent enteral passage will normally involve more barriers to systemic uptake than the intramuscular or subcutaneous route.
True. Therefore the oral route has limits to bioavailability - the relative amount of drug that reaches the systemic circulation once it has overcome all the barriers to its absorption.
36
What is the bioavailability of a drug administered through IV?
= 1 or 100%
Oral availability is usually defined by comparing the fraction (F) of drug that gets into the body after oral (po) versus IV administration. Therefore a drug administered through IV would have the same numerator and denominator.
This is calculated as (Amount of Drug Reaching Systemic Circulation) divided by (Total Amount of Drug Administered)
37
What letter is used to denote oral bioavailability?
F
F = AUC(oral) / AUC (IV)
38
Which two factors largely determine oral availability of a drug?
Oral availability defines how much drug gets 'on board' after oral ingestion. It is determined by 'absorption' and 'first pass' metabolism.
e.g. good drug absorption and low first pass metabolism will result in very high oral availability
Absorption refers to the ability of a drug to cross the gut wall into the portal vein.
First-pass metabolism describes presystemic drug elimination and can occur in the gut wall, portal vein or liver. The liver is usually the most important contributor.
39
How is the term absorption defined in terms of oral availability?
Absorption refers to the ability of a drug to cross the gut wall into the portal vein.
40
Do high rates of first pass metabolism result in high or low oral availability?
low
First pass metabolism can occur in the gut wall, portal vein (uncommon) and in the liver.
Note that high rates of metabolism at either site result in low oral availability.
41
What is meant by distribution in pharmokinetics?
Once a drug gets into the bloodstream it is first distributed around the body over large distances by bulk flow in the bloodstream and then over shorter
distances by diffusion. The concentration of a drug can vary greatly throughout the different tissues.
The distribution of a drug throughout all the body
tissues is determined by its physical and chemical (or physicochemical) properties.
42
Major factors affecting distribution of a drug throughout the body
- Lipophilicity/ Hydrophobicity
- The degree to which it binds to plasma protein
- The degree to which it binds to tissue proteins
- The mass or volume of tissue and density of binding sites within that tissue
43
How does Lipophilicity/ Hydrophobicity impact distribution of a drug throughout the body ?
-The more lipophilic a drug molecule is,
the greater it will partition out of the blood plasma into tissues with a higher lipid content (for example the brain or adipose tissue)
44
How does plasma protein binding impact distribution of a drug throughout the body ?
If binding to plasma proteins such as albumin is considerable, this will reduce its entry into other tissues and also the amount of drug freely available to exert a pharmacological effect.
45
How does tissue protein binding impact distribution of a drug throughout the body ?
The degree to which it binds to tissue proteins – e.g. muscle. This will have the effect of moving the drug from plasma and decreasing its plasma concentration. This can affect the amount of free drug available for pharmacological effect.
46
How do tissue properties impact distribution of a drug throughout the body ?
The mass or volume of tissue and density of binding sites within that tissue
o This can vary significantly from individual to individual. For a patient who is a body builder, their large muscle mass would, for example, affect digoxin binding as it has a very high affinity to Na/K ATPase.
o Digoxin is also highly lipophilic, so in an obese individual, digoxin would also be heavily bound, thus reducing its plasma concentration
o Conversely, in a supermodel with relatively reduced muscle and minimal adipose tissue, then more digoxin would stay in her plasma.
47
The major fluid compartments in order of drug movement are modelled as
Plasma
Extracellular Fluid
Intracellular Fluid
Passive movement of drug between these main fluid compartments will be primarily determined by lipophilicity, although some drugs are actively carried or transported across these fluid compartments.
48
What is the most important factor deterring which major fluid compartment a drug will move into?
lipophilicity
49
True or false?
Drugs with small Vd stay mainly in the central compartment bloodstream.
True.
Drugs with a large volume of distribution (Vd) spread to the tissues or adipose cells.
50
True or false?
Drugs with a small Vd have a high initial concentration and drugs with a large Vd have a low concentration.
True.
Vd determines the initial drug concentration in the plasma, after distribution
51
How does the Vd (volume of distribution) calculation differ for protein bound vs lipid soluble drugs.
If a drug cannot get out of the plasma compartment because it is not lipid soluble or is highly plasma protein bound, then Vd approximates to the real plasma volume of about 5L.
If a drug can diffuse out of the plasma compartment and pass into the other real fluid compartments because it is more lipid soluble or less highly bound, it will then have a reduced plasma concentration, as the drug leaves the relatively small plasma compartment. Then the apparent Vd approximates to a figure between the ECF and ICF values of 10-30L.
If the drug is highly lipid soluble and/or highly bound by tissue protein such as muscle, then you can get a very large proportion of drug removed from the fluid compartments into the tissue compartments. This means that the concentration in the plasma is drastically lowered and that the theoretical ‘apparent’ Vd can appear to be hundreds of litres.
52
What units are used to express volume of distribution
Litres or litres/kg
Sometimes you will see Vd written simply in litres i.e. 5 L, 27 L or 280 L.
It can also be expressed as litres/kg, where an average theoretical body weight of 70 kg is often used. In this case, the above values become: 0.07 L/kg; 0.385 L/kg; 4L/kg.
53
Define drug metabolism?
A process, largely carried out by the liver, in which drugs are primarily chemically changed to enhance their ionic charge, which in turn makes renal elimination or excretion a lot easier. These are Oxidation/Reduction or Phase I reactions, and Conjugation/Hydrolysis reactions or Phase II reactions.
54
List the two phases of drug metabolism
Oxidation/Reduction or Phase I reactions
Conjugation/Hydrolysis reactions or Phase II reactions.
55
Oxidation/Reduction or phase I metabolism is carried out by which enzymes?
Cytochrome P450
The Cytochrome P450s,or CYP450s for short, constitute a very large family of hepatic enzymes that primarily oxidise drugs and are located on the external
face of the ER in hepatocytes. These biotransformed drugs are then either eliminated directly, or further metabolised by Phase II enzymes.
56
What structures in the kidney are most important for drug elimination?
Renal transporters: organic anion and cation transporters (OAT & OCT)
57
Define clearance
Clearance is usually defined as the rate of elimination of a drug from the body. (sometimes this is presented as a sum of hepatic clearance and renal clearance)
Because we pretend that the whole body is one large fluid compartment that we can easily measure in plasma, Clearance is defined as: ‘The Volume of Plasma that is completely cleared of the drug per unit time’.
58
True or false?
Plasma concentration (Cp) is directly proportional to the dose rate, and inversely proportional to the clearance (CL).
True. The steady state concentration (Cpss) is thus determined by the maintenance dose rate and the clearance.
59
What two factors determine the steady state concentration?
The steady state concentration (Cpss) is thus determined by the maintenance dose rate and the clearance.
Plasma concentration (Cp) is directly proportional to the dose rate, and inversely proportional to the clearance (CL).
60
Clearance factors can be remembered using the acronym HRH. What does this stand for?
Heart - Cardiovascular and Circulatory factors affecting blood flow to main organs of elimination
Renal - Factors affecting Renal Elimination
Hepatic - Factors affecting Hepatic Elimination
61
How is half life calculated?
t(½) = 0.7 Vd/clearance
Therefore, half life is affected by all the other factors that affect Vd and CL
62
definition of half-life
‘The amount of time over which the concentration a drug in plasma
decreases to one half of that concentration value it had when it was first
measured’.
63
What is meant by linear or first order kinetics
the metabolism and rental clearance of a drug is dependent on the concentration of the molecules
This is why the plots you see of half-life with plasma concentration vs. time go down in a curved fashion - the rate slows as the concentration drops. This is what first order and linear kinetics refer to.
64
The half-life (t1/2) is a dependent variable, dependent on what two factors?
the 2 independent variables Cl and Vd.
65
What four factors determine whether a drug is kept in the ideal window between minimum effectiveness and minimum toxic concentration?
Vd, Cl, t1/2, dose size and dose interval.
66
Non-Linear or zero-order or ‘saturated’ kinetics
the kinetics are no longer concentration dependent and are said to be saturated as they cannot work any faster.
67
Are first order or zero order kinetics more likely to occur at very high concentrations of drug?
zero order kinetics - the enzymes are said to be saturated as they cannot work any faster.
68
List a few important drugs with zero order "saturated" kinetics
Relatively few drugs exhibit saturated kinetics over therapeutic doses. There are a number of important drugs taken by very large numbers of patients, including high dose aspirin, phenytoin, verapamil, fluoxetine (Prozac).
Nontherapeutic drugs with non-linear kinetics include alcohol and MDMA (ecstasy).
69
How many half lives does it take to reach a Steady State Concentration in Plasma?
4-5 half lives of the drug.
So for example, if a drug has a half-life of 2 hrs, then the time taken to reach steady state will be 8-10 hours.
NB This only applies for a drug with linear or non-saturated kinetics over the therapeutic dose range!
70
Define pharmacodynamics
Pharmacodynamics is concerned with describing how drug molecules bind to a range of biological receptor molecules. Once bound at their specific sites on the receptor molecule, they then exert a measurable
effect on some aspect of cellular function.
What the drug does to the body
71
The four principle classes of receptor site in pharmacodynamics are:
Receptors
Enzymes
Carriers or Transporters
Ion channels
```
Examples:
• Cell Surface Receptors
• Nuclear Receptors
• Enzyme Inhibitors
• Ion Channel Blockers
• Transport Inhibitors
• Inhibitors of Signal Transduction Proteins
```
72
Define agonists vs. antagonists
When an agonists bind to its receptor it stabilises it whilst
bound, in the Active conformation.
When antagonists bind to the receptor these stabilise it whilst bound, in the inactive conformation.
73
How do we determine when a drug is a partial agonist?
When drugs act as a mixture of both the above, they are said to act as Partial Agonists or Partial Antagonists. The overall action of this activity class drugs is dependent on the proportion of which the drug stabilises the receptor in the Active: Inactive conformation.
For example, if the proportion of Active: Inactive sites was 80%:20%, then this drug would be acting as a strong partial agonist and a weak partial antagonist. If this was reversed to Active:Inactive sites of 20%:80% then the drug would be acting as a weak partial agonist and a strong partial antagonist.
74
Pharmacodynamic Terminology: Affinity
This defines to the tendency of a drug to bind to a specific receptor type
The terms often used to define this are Kd for agonists and Ki for antagonists, these symbols are used to indicate the concentration at which half the available receptor are bound.
Kd = equilibrium dissociation constant, a measure of affinity.
75
Pharmacodynamic Terminology: Efficacy
This defines the maximal effect of a drug when bound to a receptor. This is expressed in percentage terms of the response, when no increase in drug concentration brings about any further increase i.e. when the response is
saturated and the response becomes non-linear
76
Pharmacodynamic Terminology: Agonist potency
This is straightforward to define for agonists, and is defined by the drug concentration at which 50% of the maximal response is obtained.
This is referred to as the EC50. NB because the potential for non-linearity of response following binding at a receptor, the EC50 is often not equal to the Kd.
77
Pharmacodynamic Terminology: Antagonist potency
the concentration of drug that reduces maximal activation of a receptor by 50%.
78
Pharmacodynamic Terminology: Competitive antagonist
In competitive antagonism, agonist efficacy can be restored by simply increasing agonist concentration to increase the competition for receptor sites. You then simply see a shift in the dose response curve rightwards. So in this case, EC50 changes but the maximal effect value for that agonist stays the same.
79
Pharmacodynamic Terminology: Non-Competitive antagonist
In non-competitive antagonism, the antagonist can bind in two ways
1. At the same site for the agonist binding irreversibly or unbinding very slowly.
2. At a separate site to the agonist either reversibly or irreversibly.
In this case, no matter how much the agonist is added, maximal effect will be depressed proportional to the degree of antagonist binding to the receptor.
However, because the agonist does not have to compete to occupy its binding site, the EC50 remains the same.
80
In pharmacodynamics, what is the shape of the linear graphs the log graph of effect vs concentration?
What is the shape of the linear graph is called a rectangular hyperbola. The shape of the log graph is called a sigmoid curve.
81
In pharmacodynamics, on a log graph of effect vs concentration, would increasing potency be represented by a shift left or right?
Higher potency is a leftward shift. You need less of the drug to reach drug concentration at which 50% of the maximal response is obtained.
82
In pharmacodynamics, on a log graph of effect vs concentration, which way does the graph shift due to changed in potency? efficacy?
Higher potency is a leftward shift.
Efficacy would shift the graph up or down. For e.g. less efficacious drugs have a lower Emax, shifting the graph down. Note: potency stays the same when efficacy moves.
83
How might drug distribution impact drug drug interactions?
The distribution phase can be affected by competition between drugs at protein/lipid binding sites. For the most part, with drugs exhibiting linear kinetics and a reasonable Therapeutic Window, these effects are offset by an increased clearance. If the drug has non-linear pharmacokinetics and/or a narrow therapeutic window, such as that seen for phenytoin, then this can lead to serious toxicity.
84
How might metabolism impact drug-drug interactions?
induction and inhibition of the CYP 450 enzymes
- induction leads to a more rapid elimination, i.e. decreased t1/2 and increased CL of
the therapeutic substrate
- inhibition leads to a slower elimination, i.e. longer half life and slower clearance. Inhibition of CYP450s can occur through both competitive and noncompetitive
inhibition
85
The 3 primary mechanisms affecting drug excretion
- changes in protein binding -> Decreased protein binding increases the amount of free unbound drug which accelerates its removal.
- inhibition of tubular secretion -> Inhibition of tubular secretion will result in increased plasma levels of drug.
- changes in urine flow/pH.
86
Three types of Pharmacodynamic Drug-Drug Interactions
- those deliberately used to enhance therapeutic outcome
| - those that result in either a reduction in therapeutic outcome or an ADR
87
Drug groups commonly contributing to drug-drug interactions (DDIs) include these five major classes.
Anticonvulsants: especially phenytoin and carbamazepine
Anticoagulants: especially warfarin
Antidepressants: especially mono-amine oxidases
Antibiotics: especially quinolones, macrolides and rifampicin
Antiarrhythmics: especially amiodarone
88
True or false?
Hepatic and cardiovascular disease in the absence of renal deficit can lead to a reduced Glomerular Filtration Rate (GFR).
True.
Further reduction of GFR in patients, such as that seen with NSAIDs and ACE inhibitors can lead to acute kidney injury and these drugs are then considered as nephrotoxic.
89
Importance of Hypoalbuninaemia in pharmacology
Many drugs are appreciably bound to albumin. If
circulating albumin levels are low as seen in liver failure, malnutrition or nephrotic syndrome, free drug plasma levels will be higher. This disease interaction is distinct from the displacement due to competition between
drugs for albumin binding sites in otherwise healthy individuals. In the case of these diseases, drug clearance is likely to be already affected and hypoalbuninaemia is an additional factor adversely affecting pharmacokinetics.
90
What is the importance of grapefruit and cranberry juice in pharmacology?
Grapefruit and Cranberry Juice inhibit Phase I CYP450 isoenzymes. This can result in significantly reduced clearance of a number of important drugs,
including statins and warfarin.
91
Once in the systemic circulation, many drugs are bound to circulating proteins. Give four examples of such proteins and the type of drugs they bind.
```
o Albumin (acidic drugs)
o Globulins (hormones)
o Lipoproteins (basic drugs)
o Acid glycoproteins (basic drugs)
```
92
Changes in protein binding can occur, causing changes in drug distribution. These are only important if which 3 criteria are met:
1. High protein binding
2. Low Vd
3. Has a narrow therapeutic ratio
93
Changes in protein binding can occur, causing changes in drug distribution. Major factors affecting protein binding include:
oHypoalbuminaemia
oPregnancy
oRenal failure
oDisplacement by other drugs
94
How is Vd calculated?
Vd = Dose/[Drug]t0
[Drug]t0= maximum plasma concentration
Hypothetical measure, but useful in
understanding dosing regimens e.g. 100mg
gentamicin dose, peak plasma concentration
5mg/l, then the Vd will be 20 litres.
95
What are prodrugs?
Prodrugs: pharmacologically inactive compound
metabolised to an active one, e.g.: L-Dopa is metabolised to a more active metabolite
to improve distribution (crosses blood-brain barrier)
96
Main demographic characteristics that influence drug metabolism
```
oRace (Development of pharmacogenetics)
oAge (reduced in aged patients & children)
oSex (women slower ethanol metabilisers)
oSpecies (drug development)
oClinical or physiological condition
```
97
3 processes determine the renal excretion of drugs
o Glomerular Filtration
o Passive tubular reabsorption
o Active tubular secretion
Give an example of drug for each.
unbound drugs - e.g. gentamicin are proportional to GFR
Penicillin is actively secreted
aspirin is affected by urine flow rate and pH
98
Are toxic levels more likely to be reached in zero order or first order kinetics?
zero order
99
CYP 3A Inhibitors
```
• Anti-fungals
o Ketoconazole
o Fluconazole
o Itraconazole
• Cimetidine
• Macrolides
o Erythromycin
• Grapefruit juice
```
100
CYP 3A Inducers
* Carbamazepine
* Phenytoin
* Rifampicin
* Ritonavir
* St. John’s Wort
101
```
Which enzyme is responsible for Metabolism of:
o Calcium channel blockers
o Benzodiazepines
o HIV protease inhibitors
o Most statins
o Cyclosporin
o Most non-sedating antihistamines
```
Cytochrome P450 3A
102
CYP 2D6 metabolises which kinds of drugs?
Codeine
Beta-Blockers
Tricyclics
103
CYP 2D6 Inhibitors
Fluoxetine
Paroxetine
Haloperidol
Quinidine
104
CYP 2C9 metabolises which kinds of drugs?
Most NSAIDs (incl. COX2)
S-warfarin
Phenytoin
Tolbutamide
105
CYP 2C9 inhibitors
Fluconazole
106
CYP 2C9 inducors
Carbamazepine
| Ethanol
107
CYP 2C19 metabolises
Diazepam
Phenytoin
Omeprazole
108
CYP 2C19 inhibitors
Ketoconazole, Omeprazole
Isoniazid, Fluoxetine,
Ritonavir
109
CYP 2C19 inducors
Rifampicin
110
Drug Selectivity
* The more selective a drug for its target:
* less chance it will interact with different targets
* therefore have less undesirable side effects.
* eg. Penicillin target
* enzyme involved in bacterial cell wall biosynthesis
* mammalian cells do not have a cell wall
* so penicillin has few side effects.
111
Drug Specificity
• Targeting drugs against specific receptor
subtypes often allows drugs to be targeted
against specific organ
• eg adrenergic receptors:
o heart β1 receptors
o lungs β2 receptors
o More specific a drug acts less action on other
organ.
112
Describe the relationship between Kd and affinity
Kd = equilibrium
dissociation constant,
a measure of affinity
smaller Kd indicates greater affinity
113
CYP 450 General Inducers
```
• P – Phenytoin
• C – Carbamazepine
• B – Barbituates
• R – Rifampicin
• A – Alcohol (chronic use)
• S – Sulphonylureas & St
John’s Wort
```
Not expected to memorize lists, but just to illustrate that there are many!
May be useful as a reference in group work.
114
CYP 450 General Inhibitors
```
• O – Omperazole
• D – Disulfiram
• E – Erythromycin
• V – Valproate
• I – Isoniazid
• C – Cimetidine +
Ciprofloxacin
• E – Ethanol (Acutely)
• S – Sulphonamides
```
Not expected to memorize lists, but just to illustrate that there are many!
May be useful as a reference in group work.
115
What is an adverse drug reaction?
An unwanted or harmful reaction
which occurs after administration
of a drug or drugs and is suspected
or known to be due to the drug(s)
116
What are the different types of adverse drug reactions?
```
A - augmented effect
B - Bizarre
C - chronic
D - delayed
E - end of treatment
```
117
High Risk for ADRs
• Ignorant, inappropriate or reckless prescribing
• Polypharmacy
• Patients at the extremes of age
o altered PK profile (renal and hepatic)
o co-morbidities
• Multiple medical problems
• Use of drugs with narrow therapeutic indexes
o↑risk of toxicity
• Drugs are being used near their minimum effective
concentration - increased risk of treatment failure if metabolism increased
118
Man stopped drinking and driving. Noted to have difficulty staying
in his lane. His blood alcohol concentration was 95 mg/dL. (Limit 80 mg/dL). Also taking co-codamol tablets. Claims that a drug interaction is responsible for his raised blood alcohol.
Is his excuse valid or should he be convicted?
No!
Pharmacokinetics: Codeine slows gastric emptying, so less alcohol
is Absorbed. Should have lower blood alcohol concentration.
Pharmacodynamics:
Codeine interacts with alcohol, increasing CNS effects
119
A women dropped her baby. In the ER, ECG showed QTc Interval Prolongation. What possible drugs could have caused this?
```
Torsade de pointes Usual Suspects
• Anticonvulsants
• Antibiotics
• Anticoagulants
• Antidepressants/ Antipsychotics
• Antiarrhythmics
```
120
Causes of Variability in Drug Response related to the biological system
1. Body weight and size
2. Age and Sex
3. Genetics – pharmacogenetics
4. Condition of health
5. Placebo effect
121
Causes of Variability in Drug Response related to the conditions of administration
1. Dose, formulation, route of administration.
2. Resulting from repeated administration of drug:
drug resistance; drug tolerance-tachyphylaxis; drug
allergy
1. Drug interactions:
- chemical or physical;
- GI absorption;
- protein binding/distribution;
- metabolism (stimulation/inhibition);
- excretion (pH/transport processes);
- receptor (potentiation/antagonism);
- changes in pH or electrolytes.
