Pharmacokinetics Flashcards
1
Q
Whats pharmacodynamics?
A
The effects of the drug in the body
D–>R interactions processes specific to each class of drug
2
Q
Whats pharmacokinetics?
A
The effect of the body on the drug delivery to site of action
Generally the same for most drugs (ADME- Absorption, distribution, metabolism, excretion) irrespective of their therapeutic activity
3
Q
A
4
Q
In the following timetline, where does Pharmacokinetics and Pharmacodynamics come into play and what sort of effects do they have?
Adminitered dose –> Compound at site of action –> Therapeutic response
A
5
Q
What factors can affect pharmacokinetics?
A
- Age
- dietary factors
- Disease
- Genetic differences
- Other chemicals
6
Q
What factors can affect pharmacodynamics?
A
- Age
- gender
- disease
- Genetic predisposition
- Other chemicals
7
Q
What processes are helped to be understood by pharmacokinetics ?
A
- Time of onset of action
- Intensity and duration of effect
- Accumulation
- Inter-individual differences
Intra-individual differences - Drug interactions
- Inter-species differences
8
Q
What are the key pharmacokinetic processes, which of those are considered to be part of the elimination stage?
A
9
Q
What are the locations which drugs can go?
A
10
Q
What does this graph show…
A
- The relationship between the plasma concentration of the beta-adrenoreceptor antagonist propranolol and the reduction in exercise-induced tachycardia in different individuals
- There is a linear relationship and the two can be correlated together
- As plasma concentration increases the response also increases
- Key message: as the plasma concentration of the drug increases the response increases
- The concentration of the drug in the plasma is proportional to the therapeutic effect
11
Q
What are the different routes of drug administration?
When taken by each route, what part of the body does it have an effect on?
A
- Intravenous- General circulation
- Oral- Liver
- Intramuscular- Body tissues
- Inhaled- Lungs
12
Q
Whats First-pass metabolism?
A
The first pass effect is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally is greatly reduced before it reaches systemic circulation.
It is the fraction of drug lost during the process of absorption which is generally related to the liver and gut wall
13
Q
Our bodies need to be able to deal with this vast vareity of structures, how is it able to do this?
A
We have a large range of metabolic enzymes which can break down a variety of products
14
Q
How many low molecular weight compounds does coffee contain?
A
200
15
Q
What are the key pharmacokinetic processes?
A
- Absorption
- Distribution
- Metabolism
- Excretion
16
Q
What are the 3 potential routes which drugs can take in order to cross the membrane and state the types of compounds which can use each route?
A
17
Q
What are some factors affecting absorption?
How could each of these factors possibly affect absorption?
A
1. Lipid solubility
- Rapid from gut
- Slow from intra-muscular
2. Ionisation
- Poor for ionic drugs
- (from gut)
- pH partitioning
3. Formulation
- May limit rate of absorption
- May limit extent of absorption
4. Gastro-intestinal function
- May limit rate of delivery to site of absorption
- May limit time available for absorption
5. First-pass metabolism
- May limit extent of absorption
18
Q
What factors of pharmacokinetics does ionisation of drugs effect?
A
Absorption
Excretion
Metabolism
19
Q
Whats the extent of the ionisation of drugs?
What can be used to calculate it?
A
pKa of the drug and pH of the drug
Use the Henderson-Hasselbach equation
20
Q
Whats the Henserson-Hasselbach equation?
When is there 50% ionisation seen?
A
- H-H equation calculates what percentage of the drug is ionised or not
- If a drug has a pKa of 4 and a pH of 4, then 50% of drug is in ionised form and 50% of drug is in unionised form
21
Q
Tell me about conjugate acids and bases for acids and tell me their solubility, how pH effects them and if they can cross the membrane?
A
- Conjugate acid: weak acid as has COOH group, unionised
- Conjugate base: ionised
- pH can affect whether its ionised or unionised
22
Q
Tell me about conjugate acids and bases for bases and tell me their solubility, how pH effects them and if they can cross the membrane?
A
- weak base, conjugate acid form, ionised
- base, unionised
23
Q
Explain the following diagram
A
- determine if weak base or acid by looking at chemical structure
- for stomach pKa would be 3 as there’s a 1:1 ratio so therefore, pH=pKa
- moves across membrane to plasma, has different pH, so consequently the ratio of ionised to unionised form changes
- The same happens when it moves across the membrane to the urine
- Only the unionised form which is moving across the membrane
24
Q
Graph to show % absorption of acids and bases vs the pKa
A
25
What is absorption?
The process that takes place between the site of administration and the site of measurement (site of measurement is usually from plasma and its easily accessible)
26
For rapid and extensive absorption, what does the drug have to do?
The drug has to dissolve i.e. to produce a molecular solution
large particles do not produce a molecular solution to the gut lumen
Sustained release means you can take it less reguarly in day (may be better for people who forget to take it)
27
Which subject has the fastest gastric emptying and why?
Subject 1 has the fastest gastric emptying as the drug is getting to the intestine quicker, as you can see the shape is steeper than that seen in subject 2
28
Whats means by **conjugation?**
The combination, especially in the liver, of certain toxic substances formed in the intestine, drug or steroid hormone with glucuronic or sulphuric acid; a means by which the biologic activity of certain chemical substances is terminated and the substances ready for secretion.
29
In first pass metabolism, what's used in the gut wall?
esterases
Proteases
conjugation
30
In first-pass metabolism, whats used in the liver?
Oxidation
Hydrolysis
Conjugation
31
In first-pass metabolism, whats used in the gut lumen?
Esterases
Proteases
32
First-pass metabolism
Blue= metabolic
First pass= must go through liver before going into rest of circulation
33
How is bioavailability also represented?
F
34
Whats bioavailability?
Fraction of the dose passing from the site of administration into the general circulation **as the parent compound**
35
What are the common reasons for low bioavailiability?
* decomposition in the gut lumen
* First-pass metabolism in the gut wall
* First-pass metabolism in the liver
* Not absorbed from the gut lumen
* Tablet does not completely dissolve
36
How can we measure bioavailability?
Compare the plasma concentration **when the same dose** is given intravenously and orally
NB.
* If different doses used, then you have to factor this into the equation. But if the doses are the same for oral and intravenous then can use the equation
* In the exam; wont be expected to work out the area under the curve, this will be given to us to then used in the equation
37
Answer= 2 (absorption doesn’t take place once in stomach/ intestine)
38
What properties may prevent the drug Tubocurarine, from being absorbed?
Large molecule and charged. Quaternary ammonium ion that is charged. If drug is ionised it can’t be absorbed. Has to be unionised to be absorbed into the gut. Drug won’t be able to get through any pores or interact with androgenous transporters
39
Name the drugs which affect first-pass metabolism in the gut wall?
* Amines (tyramine)
* Terfenadine
* Levodopa
40
For the drugs affecting first-pass metabolism, name the enzyme these drugs affected and the inhibitors?
**As seen in the graph:** If tyramine levels get too high, they can affect normal cardiac functions. Increases blood pressure as it effects MAO. Pentolamine can be given to restore cardiac functions back to normal
41
With oral administration of drugs, what factors can be affected and what can this be due to?
**Absorption delay**
* due to gastric emptying
* Influenced by food
**Less lipid soluble/ more water-soluble drugs**
* absorbed slowly
**More lipid soluble drugs**
* Absorbed rapidly
**F= variable**
* First-pass metabolism
* too hydrophilic to be absorbed
* extremely lipid soluble compounds do not form a solution within the gut lumen
42
Name some factors of sub-lingual and recal administration?
* rapid absorption
* Blood drains into systemic circulation
* high bioavailability
43
Routes of administration
44
What is cocaine isolated from and what did it used to be used for?
Why is this not the case anymore?
Cocaine was isolated from Coca leaves in 1880 and used to be used for a local anesthetic
Due to its addictive properties, its use not is very restricted
45
How is cocaine given now?
Given topically in otolarynology (and ophthalmology)
46
Whats the non-therapeutic use of cocaine now?
Abuse due to its CNS effects
47
Why is cocaine not active orally?
Due to its first-pass metabolism
As the ester bonds get hydrolysed in first pass metabolism
48
What are the two routes of administration that cocaine can be taken to abuse it?
Buccal (relating to the mouth)
Nasal
49
Tell me about the buccal administration of cocaine?
* Limited and slow but avoids first-pass metabolism
* South american indians chew a mixture of coca leaves and lime (calcium oxide): the lime increases the buccal pH and lower ionisation of the basic drug molecule
50
Tell me about the nasal administration of cocaine?
* "snorting" cocaine avoids first-pass metabolism
* Inhaled- inhaling crack-cocaine avoids first-pass metabolism and gives a very high peak concentration
51
Whats distribution of a drug?
The rate and extent of movement of the parent drug from the blood into the tissues after administration and its return from the tissues into the blood during elimination
52
How do drugs bind to proteins?
As a reversible equilibrium
Drug + Protein \<----\> Drug-protein complex
53
Tell me the properties of when the drug binds to proteins
* In general, it is non-specific
* low affinity
* High capacity
* Saturable at high concentrations
* Not involved in drug mode of action
* Acts as a depot or reservoir of drug
54
Answer= B
Eventually will reach saturation as binding sites will fill up so a steeper incline is seem
55
Drug-protein interactions
56
When there are drug protein binding interactions, if the thing it binds to is another drug, why is this important?
Important only if the drug is highly protein bound
As the binding of a second drug can change the volume of distribution of a drug
**With endogenous compounds**
* IMPORTANT WHEN:
* endogenous compound is highly bound and
* endogenous compound is active or toxic e.g. bilirubin in neonates
* even though there’s only a 2% change, the proportional change is important: unbound drug has increased by 100% which could be harmful and produce a toxic effect
* if drug isn’t highly bound then it isn’t as much of an issue
57
Interactions affecting extent of drug distribution
* if proteins are highly bound in plasma it limits their ability to diffuse into tissue. Bound proteins can’t diffuse across membrane
* Acidic drugs bind to albumin e.g. warfarin
* Basic drugs bind to a1-acid glycoprotein e.g. propranolol
58
'V' or 'Vd' is the 'Volume of distribution' what is the equation for this?
59
Whats the definition of distribution?
The rate and extent of movement of the parent drug from the blood into the tissues after administration and its return from the tissues into the blood during elimination
60
What are the 5 main things that the blood brain barrier (BBB) is involved in?
1. Homeostatic mechanism allowing constant CNS environment
2. Brain is not exposed to polar components in the plasma
3. Acts as a barrier as far as drugs are concerned
4. Physiological bases
5. Area postrema
61
Tell me about the physiological bases of the BBB?
* **Small membrane pores**
* **Tight junctions between cells** (create a barrier to stop drugs moving from blood to brain)
* **Active transporters** (move nutrients required in brain, can also remove waste products from brain and can also act as acid transporters to remove lactate from brain)
* **IN-** essential nutrients
* **OUT-** waste products, acid transporters and P-glycoprotein (this has low specificity and can therefore move lots of types of drugs out of your brain)
62
Tell me about area postrema relating to the BBB?
Thisis a medullary structure in the brain that controls vomiting. its location in the brain allows it to play a vital role in the control of the autonomic functions by the CNS.
* Has no BBB so therefore responds to circulating chemicals
* **Emetic centre --\> Emesis** (chemicals can enter brain via emetic centre as no BBB)
63
Draw a graph representing different drug entre into the brain based on their solubility
water soluble drugs aren't very good at getting into the brain
64
What main compound does parkinson's disease effect and what are some of the affects it causes?
* decreases dopamine production from the substantia nigra
* Decreases dopaminergic activity in the nigrostriatal pathway
* BUT- dopamine will not cross the BBB
65
What compound can be converted into dopamine, why is this compound useful?
* **Levodopa** can be converted to dopamine (its structure has common features to AA)
* levodopa is an AA precursor of dopamine
* its commonly used in the drug treatment of parkinsons
* Features enable it to utilise the androgenous transporter pathways
66
Tell me about carbidopa
67
Tell me about the effects of administering Levodopa with carbidopa?
68
What two factors affect the rate of distribution of a drug?
**Rate-** Time taken between dosing and equilibrium of plasma: tissues
**Extent-** Ratio of drug in tissues compared to plasma at equilibrium
in the graph below an iv bolus has been administered
69
The different phases of drug distribution can be identified on a plasma concentration vs time graph...
What does phase 1 and phase 2 tell you?
Phase 1 tells you about **distribution**
Phase 2 tells you about **elimintation** (elimination is made up of metabolism and excretion)
70
The plasma concentration vs time graph fits what sort of model?
The graph fits a two-component model
71
The 'slope' of the distribution phase can provide information about the rate of drug distribution. What does it tell you?
* All initial gradients are different
* Distribution of pink fast, and that of green is slower
* Once past equilibrium point, the elimination slope of all 3 drugs is the same
72
The rate of distribution depends on what?
**Diffusion** rate of drug across the membranes
**Perfusion rate** of tissues that take up the drug
73
Consider the general profile of drugs that distribute to different tissues at different rates
74
The general profile of Thiopentone distribution
75
General profile of drug distribution
76
general profile of different drug perfusions
77
Now consider the profile of a drug that distributes to different tissues at different rates and how this relates to the time course of its physiological effects
78
Tell me some general facts about Thiopentone
* General anaesthetic
* Injected intravenously (iv)
* Rapid effect
* Short duration of action
79
The two factors affecting drug distribution are rate and extent.
Tell me about rate...
* Rate of partitioning into tissue
* Organ blood flow- affected by cardiac output
80
The two factors affecting drug distribution are rate and extent.
Tell me about extent...
* Plasma protein binding – affected by
- synthesis (liver disease = albumin decrease synthesis)
- synthesis (inflammatory disease = alpha-1 increase synthesis)
- excretion (renal failure & proteinuria = albumin decrease synthesis)
* tissue composition of body- could affect extent and distribution of drugs, as you get older you have more adipose tissue, if drug is lipophilic then it will do more into adipose tissue as it likes this type of tissue
81
In the process of elimination, removal of drugs from the body may involve what?
Metabolism (where the drug is transformed into a different molecule)
Excretion (the drug molecule is expelled in the body’s liquid, solid or gaseous waste)
82
Answer: 2 and 4
83
Whats elimination?
What does it involve and what are these things?
Removal of drug from the body
It involves;
1. Metabolism: where the drug is transformed into a different molecule
2. Excretion: the drug molecule is expelled in the body's liquid, solid or gaseous waste
84
Why do drugs need to be metabolised?
* Lipid solubility is a useful property of drugs because it allows movement across lipid membranes (esp. if given via oral route)
* BUT lipid-soluble molecules are not easily eliminated and that is where METABOLISM comes into play
* required for the elimination of lipid soluble drugs
* it allows a lipid-soluble drug to be converted to a water-soluble molecule
* water-soluble molecules are much more readily eliminated from the body e.g. in the urine
85
For the following...
1. Volatile
2. Wate soluble
3. Lipid soluble
How are the excreted for drugs and metabolites
86
What are the phases of drug metabolism?
The aim of these phases are to make lipid soluble drugs, water soluble for excretion
87
Whats the most common reaction in phase 1 metabolism?
Oxidation reactions
88
What atoms can oxidation take place at?
Carbon, nitrogen and sulphur atoms
89
What happens to the drug as soon as it is converted to the metabolite?
The drug molecule has been removed from the body
90
Whats determines the therapeutic effect?
In most cases the metabolite is inactive and therefore the rate of metabolism determines the duration of therapeutic effect
91
Oxidative reactions
92
What is drug metabolism a major source of?
a major source of patient to patient differences in the magnitude of response to drugs
93
What can drug metabolism be affected by?
can be affected by age (especially the very young and elderly), sex (only slightly), ethnic origins (for some metabolic pathways) and disease state
94
Tell me about half life and drug metabolism
enzymes are not (usually) saturated at therapeutic doses therefore the half-life is not affected by the dose administered
95
Are enzymes usually saturated during drug metabolism?
What does this mean can happen?
enzymes are not (usually) saturated
therefore the clearance and half-life of a drug is not affected when another drug, which is metabolised by the same enzyme, is given at the same time
96
What is the major enzyme involved in phase 1 metabolism?
Cytochrome P450
97
Tell me about the enzymes involved in phase 1 metabolism
What class do they belong to?
They are membrane bound enzymes- they're in most tissues especially the liver (as the liver is the main organ for metabolism)
They belong to a general class of enzymes called **monooxygenases**
98
What does cytochrome P450 bind?
What kind or protein is it?
What does it catalyse?
Cytochrome P450
* Binds drug substrate and O2/CO
* A **Haemoprotein** containing Fe
* Catalyses oxidation of drug
99
What is the cytochrome P450 (CYP) superfamily?
A family of related enzymes with differing substrate specificities
100
What are some genetically determined deficiencies of phase 1 metabolism?
Inducible by various compounds...
drugs- Phenobarbitone
environment- smoking
101
Name some compounds that phase 1 metabolism can be inhibited by
Cimetidine, quinine, grapefuit juice
102
Tell me some Non P450 oxidation reactions
103
Give me 2 examples of reduction reactions in phase 1 metabolism?
104
Give 2 examples of hydrolysis reactions in phase 1 metabolism
105
Drug extraction and metabolism (phase 1)
106
hydrolysis phase 1 metabolism
107
Whats the structure of **Procaine** and whats its use?
What is it similar to?
Procaine is used as a local anesthetic
It is similar to Procainamide
108
What is procaine acted upon by?
Its acted upon by **esterases, fast acting=** rapid hydrolysis and short duration of action
109
Whats the structure of Procainamide?
What is it used for?
What is it acted up by?
Procainamide is used as a anti-arrhythmic
It is acted upon by **amidases, slow acting=** slow hydrolysis and longer duration of action
110
Answer: **3** (number 1 describes phase 2)
111
Give some examples of groups that can be reduced?
Where does oxidation occur?
Less common than oxidation reactions and occur at unsaturated Carbon atoms, Nitrogen and Sulphur
112
Answer: 2
113
What type of reactions occur in phase 2 metabolism?
Conjugation reactions
114
What happens in conjugation reactions?
Formation of a covalent bond between the PHASE 1 metabolite and an endogenous substrate
115
For the following conjugation reactions, give the group and the product
116
When was Glucuronidation discovered?
By Jaffe in 1874
117
Tell me about Glucuronic acid
Its chemical formula and what it replaces?
What does it require?
* Glucuronic acid C6H9O6 replaces the H in -OH, -COOH, -NH2, -SO2NH-, -SH to give water soluble inactive products
* Requires activation of **carbohydrate (UDPGA)**
118
What is this?
Glucuronic acid
119
Tell me about **UDP-Glucuronyl transferase (UDPGT)**
* Several forms
* Microsomal in liver + gut + most other tissues
* Immature especially in premature babies
120
Whats sulphation?
A sulphate group –SO3- replaces the H in R-OH, ArOH, ArNH2, ArNHOH to give very water soluble inactive - usually - excretory products
121
What enzyme is used in the process of sulphation and what does it do?
**Sulpho-transferase**
* Cytosolic enzyme in liver + gut + most other tissues
* Found in nearly all species
122
Whats **Acetylation?**
Acetate CH3CO- replaces the H in -NH2, -SO2NH2, -NHNH2
* inactivates the functional group
* but no real increase in water solubility
123
What does Acetylation require?
Requires activation of the acetate (AcetylCoA)
124
Tell me the role of **N-acetyl transferase** in acetylation
What does this enzyme show?
* N-acetyl transferase **transfers the acetate to the drug**
* N-acetyl transferase shows a genetic polymorphism i.e. some people are fast acetylators whilst other are slow acetylators. Fast acetylators will metabolise certain drugs faster.
- Caucasians 50% fast acetylators
- Japanese 95% fast acetylators
125
What is a consequence of drug metabolism?
Once the drug has been metabolised it is a different compound and the activity due to the parent drug is removed
126
A consequence of drug metabolism is: Once the drug has been metabolised it is a different compound and the activity due to the parent drug is removed
Therefore the metabolite is a different compound and might have what properties...?
The metabolite is a different compound and may have:
* no activity (the usual case)
* similar pharmacological activity
* different pharmacological activity
* a toxicological action
127
Tell me some general properties of phase 1 metabolites?
* are usually inactive, but may show the types of change in activity give above
* frequently undergo phase 2 metabolism prior to excretion
128
Tell me some general properties of phase 2 metabolites?
* are nearly always inactive
* are usually much more water soluble and readily excreted
129
What are some variables affecting metabolism?
1. species
2. genetics
3. environment
4. age
5. disease
130
How does the species affect metabolism?
e.g. rats and mice cf humans
* higher cardiac output
* greater liver blood flow (rats and mice tend to have higher than humans)
* higher rates of metabolism
131
How does genetics affect metabolism?
Enzyme defects
132
How does pharmacogenetics affect metabolism?
Use the following enzymes as an example:
* Plasma pseudocholinesterase
* Aldehyde dehydrogenase
133
The following is an example of how environment affects metabolism
(aren't expected to memorise all this)
134
Explain this graph
Enzyme induction
* Clinical effects are slow to develop (~30 days) and after the drug (Phenobarbitone- NS suppressant used to control seizures) is removed it takes a while (~30 days) for the effect to end and levels to return back to ‘normal’.
* Reason: It takes time for the levels of enzyme to increase (inducer interacts with nuclear receptors to incr. mRNA transcription of Cytochrome P450 enzymes) = SLOW ONSET
* Increased levels of ENZYME last for a few days after removal of inducer (Phenobarbitone) before being removed by normal protein turnover = SLOW OFFSET
135
How does age affect metabolism?
**Elderly**
* Size of liver and blood flow decreases with age
* Reduced phase 1 metabolic reactions especially relevant when prescribing lipid soluble drugs (undergo extensive phase 1 metabolism)
**Young**
* Drug metabolizing enzymes are immature in the neonatal liver – glucuronidation
* First-pass metabolism is low
136
How does disease affect metabolism e.g. liver disease
**Liver disease**
* Anatomical changes that impair rapid uptake of lipid-soluble drugs
* Intracellular enzyme activity is reduced
137
Answer: 3
138
During excretion, how is the drug expelled?
The drug molecule is expelled in the bodies liquid, solid or gaseous waste
139
What are the routes of excretion?
Lungs
Kidneys
Bile
140
What drugs excreted via the lungs?
Volatile compounds only e.g. general anaesthetics, alcohol
141
What drugs are excreted via the kidneys?
* Low molecular weight (20 kDa) + water soluble (glomerular Filtration)
* Active secretion + filtration of unbound (tubular secretion)
* Reabsorption- affected by urine pH (reabsorption) and Pka of drug
142
What drugs are excreted via bile?
* High molecular weight (\>50 kDa)- esp. conjugates
* Biliary metabolites may be metabolised in gut lumen and reabsorbed- entero-hepatic circulation
143
What are the 3 processes involved in renal excretion?
1. Glomerular filtration
2. pH dependent reabsorption
3. renal tubular secretion
144
Tell me the following about **glomerular filtration**:
* What size molecules are filtered through?
* What does the glomerular filtrate contain?
* What can't be filtered and why?
* Small molecules are filtered through pores **7-8nm diameter**
* The glomerular filtrate contains 20% of the plasma volume delivered to the glomerulus and so 20% of all water-soluble, low-molecular-weight compounds.
* **Protein-bound drug is not filtered** (can’t get through pores of 7-8nm), but some dissociates when water is reabsorbed from the tubule, and the “new” free drug is filtered the next time it is carried back to the kidney
145
Tell me the following about pH dependent reabsorption
* What compounds are reabsorbed? Where from and returned to where?
* Where can weak acids be reabsorbed?
* Where are weak bases excreted?
* All **lipid soluble compounds** are reabsorbed from the **tubule** and returned to the circulation until they are metabolised to water-soluble products
* Urine has a normal pH of about 6 compared with plasma at pH 7.4
* Drug concentrates in the fluid in which it is most ionised (pH. partioning)
* **Weak acids** can be reabsorbed into the **plasma**
* **Weak bases** are excreted in the **urine**
146
What does NaHCO3 increase?
NaHCO3 increases urine pH (alkalinases) and enhances elimination of acids
147
What does NH4Cl reduce?
NH4Cl reduces urine pH (acidifies) and enhances elimination of bases
148
pH dependent reabsorption
149
pH dependent reabsorption for acids and bases
150
Tell me about renal tubular secretion?
* There are different transporters for acids and bases
* An active process that can strip a drug from protein binding sites
* Many drug conjugates are substrates for active secretion
151
When drugs are eliminated in bile, what are they mixed with?
they are mixed with **bile salts**
152
What drugs are eliminated in bile?
Large drugs or drug conjugates are eliminated in bile
\>32.5kDa mol.wt in rats
\>50kDa mol. wt in humans
153
What does elimination depend on?
Elimination depends on the release of bile from the gallbladder (which is not present in the rat)
154
Tell me about **entero-hepatic circulation**
* The drug may be reabsorbed from the intestine and carried back to the liver via the hepatic portal vein
* A drug conjugate may be hydrolysed in the intestine back to the drug or a hydroxy- metabolite and then carried back to the liver via the hepatic portal vein
155
What does entero-hepatic circulation of drugs help to maintain?
Concentrations in the systemic circulation
156
What determines the shape of the concentration-time curve intravenously?
Describe the graph
The rate and extent determine the shape
157
What determines the shape of the concentration-time curve orally?
Describe the graph
158
From the intravenous and oral concentration-time curves, what things can be quantified from this?
What does the area under the curve show?
What does the slope allow?
159
Absorption refers to...
1. How soluble the drug is
2. The processes that take place between the site of administration and the site of measurement
3. The time taken between dosing and reaching equilibrium of the drug in the plasma to tissue
4. The rate and extent of movement of the parent drug from the blood into the tissues after administration
Answer: 4
160
Bioavailability is the fraction of what in regards to absorption?
F is the fraction of an oral dose which reaches the systemic circulation as the parent compound
161
How is bioavailability calculated in terms of absorption?
F is calculated as the ratio of the AUCoral to the AUCIV (F=1 for an I.V. dose)
162
Whats the equation to calculate the bioavailability with oral administration?
163
Whats the equation to calculate bioavailability with intravenous administration?
164
Distribution refers to...?
1. How soluble the drug is
2. The processes that take place between the site of administration and the site of measurement
3. The time taken between dosing and reaching equilibrium of the drug in the plasma to tissue
4. The rate and extent of movement of the parent drug from the blood into the tissues after administration
Answer: 4
165
Distribution rate reminder...
166
In a two compartment biphasic model, data can be plotted on a log scale and can then be converted to a straight line, describe the phases seen on each of these curves
167
In a one compartment monophasic model, data can be pltted on a log scale and converted to a straight line, explain each of these graphs
168
Explain the distribution measured after an I.V. dose in monophasic model
169
Explain the distribution measured after an I.V. dose in biphasic model
170
What is the rate of distribution referred to as?
alpha
171
When the rate of distribution is referred to as alpba, what is alpha?
The initial rate of decrease in plasma concentrations after an I.V. boluse dose
172
Explain what each of these line represent on rate distributions...
What does Cp stand for?
* Cp is the **change in the [drug] in the plasma**
* The **extrapolated black** **line** hashed line represents just **elimination** if there was no distribution
* The **blue line** △Cp is the **difference** between the red line Cp (Distribution and Elimination) and the extrapolated black hashed line (Elimination)
* The **gradient of △Cp** is the **rate of distribution**
* This is called **⍺**
173
What is alpha...
* is the rate of distribution. It is the gradient of the blue line (△Cp).
* a characteristic for the drug, which depends on rate of uptake by tissues
174
Apprent volume of distribution
- **V or Vd** (don’t need to remember values in table just understand)
What is V?
V -is the dose divided by the plasma concentration of the drug (C0) after it has been distributed
175
For a one compartment model...
1. What is assumed?
2. At time 0...
3. Use C0 this represents... can be calculated by...
* Assumes the **drug distributes instantaneously** to all tissues
* At time 0 hours **full distribution** has already taken place
* Use C0 this represents the **plasma concentration after the drug has fully distributed** and can be calculated from the intercept of the extrapolated line (hashed line)
176
Draw the graph for a one compartment model for plasma concentration against time
Whats the equation for V?
177
Draw the graph for a two compartment model for plasma concentration against time
Whats the equation for V?
178
For a two compartment model...
1. At t=0
2. Using the actual plasma concentration at t=0 would not be representative of...
3. Use plasma concentration if... It can be calculated by...
* At t = 0 very **little or no distribution** will have occurred
* Using the actual plasma concentration at t = 0 would **not be representative of plasma concentration** after tissue distribution
* Use plasma concentration if **distribution was instantaneou**s, this can be calculated from **the y-intercept of the extrapolated (black hashed line)**
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What is V dependent on?
The physiochemical properties of the drug
180
What is V an indication of?
The extent of tissue uptake of the drug
A large/ extensive distribution gives a large V
181
What is V independent of?
Dose
182
What is V?
The volume of plasma in which the dose appears to have been dissolved
183
V is a non-physiological what?
dilution factor
184
V is the parameter which allows you to calculate?
The parameter which allows you to calculate the dose necessary to give a particular plasma concentration (therapeutic window- lecture 2)
185
V can be presented as...?
Can be presented as L/kg- based on the weight of the individual
e.g., if the weight of an individual is 70Kg and V is 70L it will be presented as 1L/Kg
186
Which statement(s) are correct when thinking about elimination?
1. Elimination is the removal of the drug from the body and may involve metabolism and excretion
2. Phase one metabolism includes oxidation, reduction and hydrolysis reactions
3. Phase two metabolism is where you form a covalent bond between the phase one metabolite and an endogenous substrate
4. Excretion is where the drug moleucle is expelled int he bodys liquid ,solid or gaseous waste
All of the above
187
Whats the elimination rate in terms of first-order kinetics
First-order kinetics: the rate of change in concentration is proportional to the concentration
188
What is the elimination rate constant?
What two unrelated variables does it depend on?
k
depends on:
1. clearance
2. apparent volume of distribution
189
Whats clearance in terms of the elimination variable?
irreversible
190
Whats apparent volume of distribution in terms of the elimination variable?
reversible
191
What is clearance?
The volume of blood cleared of drug per unit of time (Vol/time)
192
What does clearance depend on?
How good the body is at eliminated that drug (this will be determines by the prgans involved in elimination of the drug
193
Does each drug have a specific clearance value?
yes
194
Clearance is the parameter that best reflects the relationship between...
the blood and the organs of elimination
195
Clearance approaches liver blood flow for...
very rapidly metabolized drugs (1500 ml/min)
196
Clearance approach renal blood for...
for drugs secreted by the renal tubule (650 ml/min)
197
Clearance approaches glomerular filtration rate for...
for drugs eliminated by filtration (120-130 ml/min)
198
Plasma clearance of a drug will be very similar to what?
The blood flow for the organ via which it is eliminated
199
For mant drugs, how can the plasma clearance be calculated?
for many drugs equals the sum of metabolic clearance and renal clearance
200
Clearance can be calculated from plasma concentration data, what is the equation for this?
201
What the annotation for metabolic clearance?
CLM
202
Whats the rate of elimination?
**Rate of elimination- k (min-1)**
* is the terminal rate of decrease in plasma concentrations after either an oral or i.v. dose
* is a characteristic for the drug
203
What is metabolic clearance directly proportional to and inversly proportional to?
Directly proportional to the clearance (CL)
and
inversely proportional to the apparent volume of distribution (V) and the half-life
204
What is the equation for rate of elimination?
205
What do the components of this equation stand for...
206
In general, after one half life the concentration will be...
If C0 is 1 then Ct will be...
207
What is the eqaution for half life?
208
What does a short half life mean?
rapid elimination
209
What is half life independent of?
Concentration
210
Is the half life a specific value for each drug?
yes
211
How is a half life altered?
Is altered by changes in liver and/or kidney function (inducers/inhibitors/disease)
212
half life...
213
What is chronic administration?
What does it maintain?
* Continuous intravenous infusion (NOT A BOLUS)
* Maintain a constant/stable concentration at site of action
* Persistent therapeutic effect
214
Plasma (and tissue) concentrations increase until what?
Plasma (and tissue) concentrations increase until the rate of elimination is equal to the rate of input (or dosage) when a **“steady state” (Css)** is reached
215
Css is the steady state concentration when...
rate in= rate out
* **it takes 5 times the elimination half-life to reach Css**
216
Why is multiple dosing done?
To maintain a constant concentration in the blood, by repeating oral dosing
Average plasma concentration at steady state (Css)
What is the equation for Css in this case?
217
For multiple dosing, how can the Css of a drug be changed?
1. Changing the DOSE of drug
2. Chaing the DOSE INTERVAL
218
Multiple dosing- oral administration
How does interval change the Css?
219
Tell me about the chronic administration loading dose...
* For drugs with long half-lives, the delay in the time to steady-state concentrations may be unacceptable (Remember: time to reach Css is 5 times the half-life)
* The delay can be avoided by giving a large first dose (loading dose) which has the effect of “topping-up” the apparent volume of distribution
220
The equations to learn...
