Pharmacokinetics Flashcards
1
Q
What do pharmaceutical processes involve?
A
Getting the drug to the patient
2
Q
What do pharmacokinetic processes involve?
A
Getting the drug to the site of action
3
Q
What do pharmacodynamic processes involve?
A
Producing the correct pharmacological effect
4
Q
What do therapeutic processes involve?
A
Producing the correct therapeutic effect
5
Q
What are the four basic gator that determine drug pharmacokinetics?
A
Absorption
Distribution
Metabolism
Elimination
6
Q
What is absorption?
A
Process of movement of unchanged drug from the site of administration to the systemic circulation
7
Q
What are the seven routes of absorption?
A
Oral
Subcutaneous
Intramuscular
Sublingual
Rectal
Inhalation
Transdermal
8
Q
What does oral absorption involve?
A
Taking a drug orally so that it can pass through the intestinal tissue and into the circulatory system
9
Q
What does subcutaneous absorption involve? Why is this method advantageous? Why is this method disadvantageous?
A
Injecting the drug into the tissue layer between the skin and muscle
Only requires a small volume of the drug. It avoids first pass metabolism
Some drugs are not well absorbed with this route - those that are insoluble in water
10
Q
What does intramuscular absorption involve? Why is this method advantageous? Why is this method disadvantageous?
A
Injecting the drug into muscle
Fast, due to the great blood supply in muscle. Only requires a small volume of the drug. It avoids first pass metabolism
Some drugs are not well absorbed with this route - those that are insoluble in water
11
Q
What does sublingual absorption involve? Why is this method advantageous? Why is this method disadvantageous?
A
Administering drugs via the mouth
Avoids first pass metabolism as they will directly enter circulation
12
Q
What does rectal absorption involve? Why is this method advantageous? Why is this method disadvantageous?
A
Uses the rectum as a route of administration
Avoids first pass metabolism
Absorption is slow
13
Q
What does inhalation absorption involve? Why is this method advantageous?
A
Inhaling and breathing in the medication. Suited to volatile drugs.
Relatively rapid. Small amount of the drug is needed to have a huge effect . Less side effects
14
Q
What does transdermal absorption involve? Why is this method advantageous? Why is this method disadvantageous?
A
Delivers a drug into systemic circulation across the skin
Avoids first pass metabolism. Controlled release
Few substances well-absorbed
15
Q
Why is intravenous not required as an absorption?
A
Straight into blood stream
16
Q
What is Tmax?
A
Time to peak concentration.
The more the rapid the rate of absorption, the smaller the Tmax value.
17
Q
What is Cmax?
A
The peak concentration.
18
Q
What effect does increasing dose of a drug have on Cmax and Tmax?
A
Increasing the dose does not affect the time at which peak concentration is reached but does increase the peak concentration
19
Q
What is AUC?
A
The area under the drug concentration-time curve, which represents the amount of drug which reaches the systemic circulation
20
Q
What is the therapeutic range?
A
The range of concentration in which the drug is active
Below this range, there will be insufficient or no pharmacological action.
Above this range, toxicity will occur
21
Q
What is bioavailability of a drug?
A
The amount of drug which is available for action
22
Q
How can a drug have 100% bioavailability?
A
If it is given intravenously
23
Q
What affects a drugs ability to pass through physiological barriers?
A
Particle size
Lipid solubility
pH
Ionisation
24
Q
How does particle size affect a drugs ability to pass through physiological barriers?
A
Small particle size tend to diffuse more rapidly across cell membranes than those that are large
25
How does ionisation affect a drugs ability to pass through physiological barriers?
Those that don't ionise in aqueous environments tend to diffuse more rapidly across cell membranes than those that do
26
How does pH affect a drugs ability to pass through physiological barriers?
Most drugs are weak acids or bases, which means that their degree of ionisation depends on the pH of the environment
Both ionised and un-ionised forms will be present, with the ionised form of the drug being unable to pass across the membrane and the un-ionised form being able to pass across the membrane until equilibrium is reached and an equal concentration is on either side of the membrane.
An acidic drug will be more concentrated in the compartment with a high pH and a basic drug will be more concentrated in the compartment with a low pH.
27
How does lipid solubility affect a drugs ability to pass through physiological barriers?
Those that are lipid soluble diffuse more rapidly across cell membranes than those that are lipophobic
28
What is the lipid-water partition coefficient?
Measures a drugs ability to diffuse across a lipid barrier.
This is the ratio of the amount of drug which dissolves In the lipid and water phase when they are in contact
29
What are the four ways drugs can move across the cell membrane?
Passive diffusion
Active diffusion
Facilitated diffusion
Filtration
30
What is passive diffusion?
Method of diffusion that occurs along the concentration gradient, from a high to low concentration.
Requires no energy or carrier
Non-selective method that depends on lipid solubility and the degree of ionisation
31
What is active diffusion?
Method of diffusion that occurs against the concentration gradient
Requires a carrier and energy
Specific method that usually transports ions. To undergo active transport, drugs must resemble the naturally occurring compounds
32
What is facilitated diffusion?
Method of diffusion that occurs along the concentration gradient, from a high to low concentration.
Requires a carrier but no energy. The carrier is structurally specific to the molecule that they transport across the membrane
33
What is filtration?
Normally occurs through channels in the cell membrane
Transports molecules of a low molecule size and weight
Driving force of passage is the hydrostatic or the osmotic pressure differences across the membrane
34
What gastrointestinal factors effect absorption?
Gut motility - speed of gastric absorption will affect the speed at which the drug reaches the site of absorption
Food - enhance or impair rate of absorption
Illness - disease that affects GI system or liver function
35
What factors affect absorption?
Formulation
Ability to pass through physiological barriers
Gastrointestinal factors
First pass metabolism
36
What is first pass metabolism? What does it depend upon?
The concentration of a drug is greatly reduced before it reaches the systemic circulation, as the drug is already metabolised.
Acid and enzymes in the gut and liver
37
What is distribution?
Occur after a drug has been absorbed, where the drug is distributed to the tissues.
38
When is a drug active?
When a drug leaves the bloodstream and enter the intercellular spaces.
When it is unbound from the proteins in the plasma.
39
Is distribution reversible?
Yes, drugs can diffuse from the intercellular spaces back to the bloodstream
40
What do drugs bind to in order to enter tissues?
Proteins in the plasma
Example - albumin or alpha1-glycoprotein
41
When is a drug inactive?
When in the bloodstream and bound to a plasma protein
42
What change the amount of drug bound to the plasma protein?
Renal failure
Hypalbuminaemia
Pregnancy
Other drugs
Saturability of binding
43
If a drug is 96% protein bound, what percentage of the drug is free and available for action?
4%
44
If the amount of unbound drug changes from 4% to 6%, then how much will the level of free drugs have increased by?
50%
45
What is the volume of distribution (Vd)?
The volume of plasma that would be necessary to account for the total amount of drug in a patient's body, if the drug were present throughout the body at the same concentration as found in the plasma
46
What is the units for the Vd?
Litres per kg
47
What does a greater Vd value mean?
The drug has a greater ability of diffusing into and through membranes
48
What should the Vd value be/
42L
49
What should the Vd value if the drug stays in the extracellular fluid and cannot penetrate cells?
12L
50
What should the Vd value be If the drug is highly protein bound?
3L
51
What is clearance?
Defined as the theoretical volume from which a drug is completely removed of a period of time.
Measure of elimination
52
What is the units of clearance?
ml/min
53
What does renal clearance depend upon?
Concentration and urine flow rate
54
What does hepatic clearance depend upon?
Metabolism and billiard excretion
55
What is the half-life (t1/2)?
The time taken for the drug concentration in the blood to decline to half of the current value
56
What is half life dependent upon?
The volume of distribution
Rate of clearance
57
What happens if the half-life is prolonged? Why?
Toxicity of drug will increase.
Reduced clearance of the drug and large volume distribution.
58
How do we achieve a steady state concentration of a drug?
A loading dose, which is an initial higher dose to a drug which may be given at the beginning of a course before dropping down to a lower maintenance dose.
59
What is drug elimination?
The removal of an active drug and metabolites from the body
Determines the length of action of the drug
60
What is drug elimination dependent upon?
Body metabolism (occurs in liver)
Drug excretion (occurs in kidney)
61
What is drug excretion dependent upon?
Glomerular filtration
Passive tubular reabsorption
Active tubular reabsorption
62
What is glomerular filtration?
Process whereby a clear fluid is produced from the blood perfusing the glomerulus at the beginning of each nephron
All unbound drugs will be filtered at the glomerulus as long as their molecular size, charge or shape are not excessively large.
63
What is active tubular secretion?
When drugs are actively secreted into the proximal tube, within the nephron in the kidneys.
The molecules secreted are acidic and basic compounds as well as protein bound drugs
64
What is passive tubular secretion?
As the filtrate moves from the proximal tubule, any drugs present is concentrated.
Passive diffusion along the concentration gradient allow the drug to move back through the tubule into circulation.
Only un-ionised drugs are reabsorbed.
Affected by renal failure
65
Apart from the kidneys, what else is involved in excretion?
The biliary system
Drugs may be passively or actively secreted not the bile. Many drugs are then reabsorbed from the bile into the circulation. This is called enter-hepatic circulation. It continues until the drugs is metabolised in the liver or excreted by the kidneys.
66
What can metabolism of a drug in the liver lead to?
Conjugation of the drug, which means that is cannot be reabsorbed from the intestine
67
What is drug metabolism?
The biochemical modification of pharmaceutical substances by living organisms usually through the action of enzymes
Converts lipid soluble, non-polar compounds to lipid soluble, polar compounds so that they can be excreted - as only polar compounds can undergo excretion.
68
Where does metabolism take place?
Liver, Gi tract, kidneys and lungs - but mainly liver
69
What is the purpose of metabolism?
To increase water solubility of drugs to aid excretion
Deactivate compounds
70
What are prodrugs?
Drugs which are activated by metabolism.
The inactive form of prodrugs is absorbed into the bloodstream and during metabolism it is converted into tis active form
71
What is phase I of metabolism?
Converts drug into a more reactive species
Takes place through three reactions; oxidation, reduction and hydrolysis. These reactions result in the polar groups of drug molecules being exposed or introduced, thus increasing the polarity of the compound and providing an active site for phase II metabolism
72
What enzymes are involved in phase I of metabolism?
Cytochrome P-450 enzymes
73
What is the CYP3A4 enzyme?
Enzyme in the liver and gut, metabolises a wide range of drugs
Responsible for the pre-systemic metabolism of several drugs, which is when the drug is metabolised before it reaches the systemic circulation
74
What is the CYP2D6 enzyme?
Metabolises anti-depressents, antipsychotics and the conversion of codeine to morphine.
75
What is the CYP1A2 enzyme?
Enzyme induced by smoking and is important in the metabolism of theopylline
Therefore, smokers require a higher dose of theophylline a as they excrete it much quicker
76
What is phase II of metabolism?
Involves conjugation of the drug, which increases the water solubility of the drug and therefore its excretion.
Usually inactivates the drug
77
What factors affect metabolism?
Other drugs
Genetics
Hepatic blood flow
Liver disease
Age
Sex
Ethnicity
Pregnancy
Enzyme Induction
Enzyme Inhibition
78
How can genetics affect metabolism rates?
An individual may inherit a set of genes that slow or increase metabolism rates.
Gene mutations can also occur that result in deficiencies or absence of a particular metabolising enzyme, which can increase drug toxicity or enhanced metabolism
79
How does age affect metabolism rates?
Drug metabolising enzymes are often found deficient or reduced in the foetus or premature infant. Renal function is also deficient, which means that drug and metabolites can rapidly build up to toxic levels as excretion isn’t occurring as regularly.
80
How does race affect metabolism rates?
Racial differences in the genetic expression of cytochrome P-450 isoforms
81
How does pregnancy affect metabolism rates?
A female’s enzyme activity increases which means that they metabolise medicines more rapidly.
Hormonal changes can also effect drug metabolism
82
What is enzyme induction?
Increased synthesis and activity of a drug.
83
How can enzyme induction affect drug metabolism?
Increased synthesis and activity of a metabolising-drug, which decreases the drug effect
84
How can enzyme inhibitor affect drug metabolism?
Decreased activity of drugs, which increases the drug effect
85
Name the four ways that drugs can be delivered
Oral
Injection
Transdermal
Carrier based
86
What are carried based drug delivery systems?
A drug carrier is any substrates used in the process of drug delivery
They are used to improve bioavailability, effectiveness and safety of drugs
87
Name two common drug carriers
Monoclonal antibodies
Liposomes
88
What is the rate limiting step of tablets ?
Dissoloution, break down of the tablets
89
Why are some tablets coated?
In order to delay disintegration of the tablet until it reaches the small intestine
Prevent it from being broken down in the stomach by acid.
Allows the stomach to be protected from the drug
90
What are modified release tablets?
Prolong the release of the drug as they are related at a slower rate and contain more of the active drug
Allow the drugs to be maintained within the threapetuic range
Need for frequent dosing reduced, patients are more compliant with taking medication
91
What are the advantages of prodrugs?
Prolongation of duration of action
Avoidance of degradation in the gut
92
What are suspensions?
Dispersions of drug particles in a liquid phase
93
What are the two types of subcutaneous injections?
Dermojets - mass inoculation
Pellet implantations - drug implanted under skin as a solid pellet to provide uniform systemic effects
94
What are suppositories?
Small objects that you put in the rectum, once inside it melts and releases the drug
95
What are adverse drug reactions?
Any response to a drug which is unintended
96
What are acute ADRs?
When bronchiconstriction occurs within 60 minutes of the drug administration
97
What are sub-acute ADRs?
When a rash and serum sickness occurs within 24 hrs of drug delivery
98
What are latent ADRs?
When eczematous eruptions occur after two days of drug delivery
99
What are mild ADRs?
When the ADR is bothersome but requires no change in therapy
100
What are moderate ADRs?
When the ADR results in a change in therapy, additional treatment and hospitalisation
101
What are severe ADRs?
When an ADR becomes life-threatening
102
What are type A ADRs?
When ADR is due to a high dose and the response is normal but augmented
Reactions are reversible as we can reduce or stop drug delivery
Not life-threatening
103
What are the two types of type A ADRs?
Augmentation of the primary effect
Augmentation of the secondary effect
104
What are type B ADRs?
When ADR reaction is bizarre.
They cause serious illness or death
Unrelated to dose
Cannot be reversed
Can be caused be genetics or drug allergies
105
What are type C ADRs?
When ADR is related to the duration of treatment and dose.
106
What are type D ADRs?
When ADR occur a long time after treatment.
These effects include teratogenesis or carcinogenic
107
What is teratogenesis?
Process by which congenital malformations are produced in an embryo or foetus.
Caused by mothers treated with the drug isotretinonin during the first trimester of pregnancy
Drug is therefore avoided during pregnancy
108
What are type E ADRs?
When ADR occurs when a drug treatment is stopped suddenly following long term use.
To prevent these reactions, we can ease the dose of the drug over a long period of time
Can cause death
109
What are type F ADRs?
When ADR is due to a failure of therapy or drug interactions.
They are dose related
110
What makes individuals more susceptible to ADRs?
Age - children and elderly more susceptible
Multiple medications - leads to more drug interactions
Multiple co-morbid conditions - patient on more drugs
Inappropriate prescribing
Genetics
Sex - more common in females
111
Where can we report ADRs?
Yellow card scheme
112
What is a drug interaction?
When the pharmacological effect of two or more drugs given together is not just a direct function of their individual effects
113
What is an object drug?
A drug whose activity is affected by a drug interaction
114
What is a precipitant?
The agent which precipitates a drug interaction
115
What drugs are susceptible to interactions?
Those with a narrow therapeutic index, which means that a small change in blood levels can induce profound toxicity
Therefore, we monitor these drugs
116
What patients are susceptible to drug interactions?
Those who take a high number of medications
Elderly and young
Those who are undergoing complicated procedures and have multiple prescribing conditions
Those with chronic conditions
117
What are pharmacodynamic drug interactions?
When the pharmacodynamic actions of a drug are changed due to the presence of another drug either acting directly on the same receptor or indirectly on different receptors
118
What effects can pharmacodynamic drug interactions have?
Antagonistic - effect of two drugs is actually less than the sum of the effect of the two drugs taken separately
Additive - effect of two drugs is the same as the sum of the effect of the two drugs taken separately
Synergistic - effect of two drugs is actually less than the sum of the effect of the two drugs taken separately. This is because the two drugs have the same pharmacological effect and are acting on the same receptor at the same time
119
What are pharmacokinetic drug interactions?
Due to one drug altering the ADME of another drug.
A - absorption can be altered by the formation of insoluble complexes, altered pH, altered bacterial flora or altered GI motility.
D - distribution can be altered by protein-protein displacement or protein-binding displacement.
M - metabolism altered when drugs inhibition's the cytochrome system or induce the cytochrome system
E - excretion altered by changes in GFR and tubular secretion
120
What is protein-binding displacement?
Occurs when there is a reduction in the extent of plasma protein binding of a drug caused by the presence of another drug.
Results in increased bioavailability of the displaced drug, which is now pharmacologically active.
Two main proteins - albumin and alpha1-glycoprotein.
121
How do we deal with a drug interaction?
Alter dose timing
Alter dose
Monitor drug level
