TBL 7 - PHARMACODYNAMICS/PHARMACOKINETICS Flashcards
(119 cards)
1
Q
What is pharmacology?
A
The study of the actions of drugs and their metabolites in the body
2
Q
What does pharmaco and ology mean?
A
- Pharmaco - pertaining to drugs
- Ology: knowledge of
3
Q
What is pharmacokinetics?
A
Pharmacokinetics: what the body does to the drug
4
Q
What is pharmacodynamics?
A
Pharmacodynamics: what the drug does to the body
5
Q
What does pharmaco and kinetics mean?
A
- Pharmaco - pertaining to drugs
- Kinetics - movement
6
Q
What is pharmacokinetics the study of?
A
The study of the time course if drugs and their metabolites in the body.
7
Q
What is pharmacokinetics and what is ADME?
A
What the body does to the drug or administrations, absorption, distribution, metabolism and excretion.
8
Q
What is the 4 rights when a drug enters the body?
A
Before a drug can affect any of the systems in the body, drug has to enter body and be distributed around the body so eventually enough drug has reached the site of action where it has an effect e.g. the right drug in the right amount in the right place at the right time
9
Q
What is adminsteration?
A
Adminsteration: Delivery of drug to the body
10
Q
What is absorption?
A
Absorption: The movement of a drug across membranes
11
Q
What is distribution?
A
Distribution: Description of the compartments of the body entered by the drug
12
Q
What is metabolism?
A
Metabolism: Chemical alteration of the drug
13
Q
What is elimination?
A
Elimination: Transfer of the drug from inside the body to the outside
14
Q
What can pharmacokinetics describe (7 things)?
A
1) Absorption from the site of adminsteration
2) Delivery to the site of action
3) Elimination
4) Time to onset of effect
5) Duration of effect
7) Accumulation on repeat dosage
6) Drug interactions
15
Q
What does pharmacokinetics allow us to work out?
A
Pharmacokinetics can be predictive science that allows us to work out the required dose of a given drug by noting each of these aspects
16
Q
What are the types of routes of adminsteration (6 things)?
A
1) Oral (plus buccal and sub-lingual)
2) Rectal
3) Skin (topical)
4) Lungs (plus nose)
5) Eye, ear
6) Urethra
17
Q
What are different types of injection (6 things)?
A
- Intramuscular
- Subcutaneous
- Intradermal
- Intraperitoneal
- Intrathecal
- Intra-arterial
18
Q
What does an adminsteration by injection avoid?
A
Adminsteration by injection avoids passing through the GI tract
19
Q
What is first pass metabolism?
A
Drug given enterally (oral/rectal) route absorbed from intestine and pass to liver, so before drug been in body for very long time will be metabolised to different form which could be less effective. - FIRST PASS METABOLISM
20
Q
Where does drug get transported around the body?
A
Once the drug is in the body gets transported around the body in the blood.
21
Q
What can be a good indication of drug present in the body?
A
Concentration of drug in plasma could be a good indication of drug present in the body.
22
Q
What do drugs need to pass through to reach systemic circulation? And what is the exception
A
Drugs must cross membranes to reach systemic circulation exception given intravenously.
23
Q
What is the transition of drugs through membrane barriers determined by (4 things)?
A
1) Lipid solubility
2) Area available for absorption
3) Possible specific carriers
4) Amount that reaches target compromised by first pass metabolism
More lipid soluble drug, bigger surface area, drug can cross membrane barrier more easily
24
Q
What are the different oral forms and where does the drug enter?
A
Oral route most common, allows self-medication, forms = liquid, tablet, capsule, rectal adminsteration, drug enters the GI tract.
25
Why are drug given as sublingual?
Drug given under tongue so drug enters into blood vessels in that area, vasculated area.
26
Is he lungs a quick or slow route of drug adminsteration? And what does a large surface area allow for?
Lungs very quick route for drug adminsteration.
Narrow divide between inside of alveolus and blood capillary and large surface area available for exchange.
27
What is an advantage of a nasal route of entry?
Nasal: convenient point of entry easily accessed.
28
In regards to IM/SC what does drug pass through?
IM/SC - drug goes into areas near blood vessels so drug has pass through smooth muscle and endothelial lining in order to enter the plasma.
29
What does IV injection achieve and what type of environment is needed for IV adminsteration?
IV injection achieves rapid response as drug arrives immediately into the plasma. Demands sterile conditions and administered by trained personnel
30
What's an advantage of the oral route?
Safer/more convenient than injection
31
What's an advantage of Buccal/sublingual route of adminsteration?
Avoids presystemic metabolism
32
What an advantage of the rectal route of adminsteration?
Useful for patients who are vomiting/unconscious
33
What is an advantage of nasal route of adminsteration?
Useful absorption of some peptides (DDAVP)
34
What's an advantage of Intramuscular route of adminsteration?
Useful in emergencies
35
What's an advantage of Subcutaneous route of adminsteration?
Useful for insulin, heparin adminsteration
36
What is the problem with using Intrathecal route of adminsteration?
Directly into CNS, very high risk
37
What's an advantage of using Intravenous route of adminsteration?
Very useful in emergencies for most rapid/predictable reactions but too rapid an adminsteration is potentially dangerous, not easily reversed
38
What is the definition of bioavailability?
Used to define how well a drug is absorbed and reaches its site of action
Determined by comparison of oral and IV absorption
39
What is the bioavailability (F) equation?
F = amount of drug absorbed in systemic circulation following oral adminsteration/ amount of drug adsorbed when same dose administered IV
40
What is half-life (0.5)?
Time it takes for plasma drug concentration to fall to half its original value. Half-life is important as it give info on length of time that a drug will remain in the body
41
What is the clearance equation?
clearance = rate of elimination/plasma drug concentration
42
What is zero order kinetics?
Rate of elimination is constant and independent of drug conc.
43
What is half-life dependent on?
T 0.5 depends on amount of drug given and is longer when more drug is given
Few drugs behave this way
44
What order kinetics is at a high conc and a low conc?
At high conc the kinetics are zero order whilst at low conc first order.
45
What type of line represents zero order kinetics and what type of line represents first order kinetics?
First part representing zero order (straight line)
Second part where first order kinetics is demonstrated (exponential decay curve)
46
What happens to most drugs in the first order kinetics and what happens to the half-life?
Most drugs eliminated with first order kinetics
T 0.5 is constant
Rate of removal depends on how much drug is present
47
What is distribution and what is its main objection?
Distribution: The transfer of drug in and out of various tissues of the body.
Relates to therapeutic objective of maintaining an adequate conc of drug at the site of action.
48
In the distribution phase what is measured?
As its difficult to measure amount at the site of action, we measure the amount in blood.
49
What does no effect mean?
not enough drug - little or no effect
50
What does therapeutic window mean?
The right amount to be effective
51
What does toxic mean?
- Too much drug
- Too great an effect
52
Drugs usually reversibly distribute into various tissues of the body, depends on:
1) Perfusion rate of the tissue (blood flow through the tissues)
2) Physiochemical ability of the drug to cross membranes
3) Nature of the membranes
4) The extent to which the drug is bound.
53
What is distribution affected by?
Distribution affected by blood flow, greater flow rate, more drug pass through tissues - tissues that are well vascularised (=plenty of blood vessels) such as the liver, the kidney will receive more drug than other parts of the body
54
What is the impact of distribution trying to achieve?
Impact of distribution is either achieving steady state (For regular dosing) or a peak plasma conc followed by removal from body for drugs given as a single dose or after a course of medication.
55
What is distribution equilibrium?
Graph based on assumption that a drug is supplied until a steady state is achieved and essentially amount of drug entering the blood (or plasma) compartment is balanced by drug leaving the compartment. - Distribution equilibrium (steady state)
56
What is partition co-efficient (Kp)?
Uptake of a drug is defined by its partition co-efficient (Kp)
57
What is the equation of partition co-efficient (Kp)?
Kp = drug concentration in tissue/ drug concentration in blood
58
What happens when the value for Kp is big?
Bigger value of Kp longer it takes to achieve distribution equilibrium.
59
What type of molecules do cell membrane allow to pass through?
Membranes separating tissues from blood are lipid in nature so lipid molecules cross the membranes most readily.
60
What type of molecule do not pass through the cell membrane?
Ionised or polar molecules do not cross so readily.
61
What type of drug can cross cell membrane?
If drug more unionised then as its lipid-soluble it crosses the membrane.
62
What is one way to eliminate drugs?
One way to eliminate drugs is in urine - for which purpose drugs need to be able to dissolve in water.
If drugs more ionised - less lipid soluble and more water soluble.
63
Are basic drugs with a high pH able to cross cell membrane?
Basic drugs in a high pH (alkaline or basic environment) are lipid soluble and readily transported.
64
Are acidic drugs with low pH able to cross cell membrane?
Acidic drugs in low pH (Acidic environment) are lipid soluble and readily transported.
65
Are basic drugs with low pH able to cross cell membrane?
Basic drugs in low pH (acidic environment) are far less lipid soluble and not readily transported.
66
Are acidic drugs with high pH able to cross cell membrane?
Acidic drugs in high pH (basic or alkaline environment) are far less lipid soluble and not readily transported
67
What type of proteins can't cross membrane?
High MW proteins such as plasma proteins, can't cross membranes so any drug bound to them will not be available for distribution.
68
Is bound or unbound drug free to distribute into tissues?
Only unbound drug is free to distribute into tissues
69
What are the 2 process of distribution (Hint: R1/R2)?
R1: Delivery of drug to tissue on perfusion rate
R2: Passage of drug across membrane depends on physiochemical properties and nature of membrane.
Overall rate of distribution determined by R1/R2
70
What does the movement of drugs depend on?
Once dealt with pH effects and binding, movement of free drug depends on its ability to cross membranes and to be transported in the blood which reinforces how well the tissue is perfused with blood. Better vasculature i.e. more blood vessels flowing through, more readily drugs will get to the tissue
71
How do you measure volume of distribution?
Urine/blood sample used to measure drug levels in body - an indirect measure useful in giving some info about distribution
72
What is the volume of distribution (Vd) equation?
Vd = amount of drug in body / conc of drug in body
73
Where are lipid insoluble drugs confined to?
Lipid insoluble drugs are confined to plasma and interstitial fluids.
74
Where does lipid soluble drug accumulate and what does this accumulation lead to?
Lipid soluble drugs reach all compartments and may accumulate in fat
For drugs that accumulate outside the plasma compartment by being in fat or bound to tissues Vd may exceed body volume.
75
Where are majority of drugs excreted from?
Once drug has been absorbed, distributed, encountered its site of action it has to be removed from the body.
Majority of drugs are excreted via renal system
76
What does the drug need to be for it to enter the renal system?
In order to enter renal system drug have become less lipid soluble and more water soluble
Achieved by process of metabolism that takes place in liver
77
What is the main route of elimination and what does it pass out the body as?
Main route of elimination via renal system so drug needs to become water soluble to pass out of body in urine.
78
What does drug metabolism mean?
Drug metabolism can be defined as an enzyme mediated conversion of lipophilic compound into a more water soluble one.
79
How many phases are involved in drug metabolism?
- Involves 2 phases - phase I/phase II
80
What is the phase I of drug metabolism?
Phase I: Metabolism tends to make drugs more water soluble but its main purpose is to prepare the drug molecule for phase II
81
What type of reaction are involved in phase I of drug metabolism?
Phase I reactions include oxidation, reduction and hydrolysis
Reactions which uncover functional groups
82
How does the process of phase I start?
Phase I starts process of making drug more water soluble
83
What is a prodrug?
Prodrug: Any compound that is metabolised in body to yield a pharmacologically active compound but is itself devoid of such activity e.g. enalapril.
Also possible that metabolism may produce a toxic metabolite.
84
What type of reactions are found in phase II of drug metabolism?
Phase II reactions are conjugations whereby drug is coupled to a 2nd fairly large water soluble molecule (e.g. sugar or amino acid)
Reactions include addition by: Glucuronidation, methylation, sulphation, acetylation, glutathione
Phase II reactions termed conjugations where large water soluble molecule is simply joined on to the phase I metabolite to make it even more water soluble.
85
What is phase II of drug metabolism responsible for?
Phase II responsible for increase in water solubility.
86
How do you achieve the reactions in phase I/II?
To achieve these reactions, enzymes systems in place, key system is cytochrome p450 family located in the endoplasmic reticulum of the liver.
87
What is the large superfamily related to distinct enzymes?
Cytochrome p450 large superfamily of related but distinct enzymes
88
What are the great variation of cytochrome p450 (8 things)?
- Great deal of variation with: species difference, strain difference, disease, gender, enviro factors, diet, genetic determination of enzyme activity and age.
89
Where is the enzymes part of cytochrome p450 located?
System operates by particular enzymes that metabolise the drug molecules.
Enzymes part of cytochrome P450 family which are key process of drug metabolism. Located in smooth endoplasmic reticulum of the liver.
90
What is induction?
Induction: some factors will induce drug metabolising enzymes, will increase amount of enzyme present which means that drug is metabolised more quickly and its half-life will be less.
91
What is inhibition?
Inhibition: some factors will inhibit drug metabolism, less active enzymes is available so drug metabolised more slowly and the half-life of drug will increase.
92
What happens when more enzymes is present?
If more enzymes is present the drug is broken down more quickly.
93
What happens when less enzyme is present?
If less enzyme is present the drug will be broken down much more slowly.
94
What are the 3 properties of drugs
1) Affinity
2) Efficacy
3) Specificity
95
What is affinity?
- How well a drug binds to a receptor
- Electrostatic forces initially attract a drug to a receptor.
- If shape of drug corresponds to receptors binding site, will held there temporarily by weak bonds.
- Number of bonds and how well drug fits the binding site determines affinity of drug for this receptor.
- Greater number of bonds, more perfect it fit, stronger affinity.
- Drugs form weak attractions have low affinity
96
What is efficacy (3 things)?
- Strength of agonist at eliciting a response.
- 3 different molecules having very similar chemical structures can behave very differently:
1. One might be very potent agonist, meaning only a small amount elicits an effect (so possesses affinity and efficacy)
2. One might be a weak agonist, so requiring large amounts to elicit an effect (but still possesses affinity and efficacy)
3. The other antagonist blocks receptor (possesses affinity but NO efficacy)
97
What is specificity?
- How selective a ligand is.
- A ligand that exhibits a high degree of specificity will only bind to certain receptors.
- Specificity dependent on doses used.
98
How can binding of drugs to receptors be measured?
Binding of drugs to receptors can be measured using 3H, 14C or 125I labelled ligands bind with high affinity and specificity.
99
How can binding of drugs to receptors be measured?
Binding of drugs to receptors can be measured using 3H, 14C or 125I labelled ligands bind with high affinity and specificity.
100
What happens to tissue at high agonist concentration?
At high agonist concs, a maximum tissue response is observed, which will not increase any further even if higher agonist concs are used.
101
What type of responses do full agonists elicit?
Many full agonists can elicit maximal smooth muscle contraction responses when only occupying less than 1% of tissues receptors.
102
What are the 99% of receptors thought to be?
Around 99% receptors in tissue systems thought to be spare receptors. Since these reserve receptors are fully functional, might seem a wasteful arrangement.
103
What does receptor reserve contd allow for?
Allows for agonist economy as less agonist has to be released in order to produce a response.
104
What do high and low numbers of receptors allow for?
High numbers of receptors, probability of a small number of agonist molecules finding and binding to receptors is high, whereas if receptor numbers were low, then a large amount of agonist would have be released in order to increase the chances of agonist molecules finding the receptors.
105
Why is agonist economy useful?
Agonist economy is useful as otherwise it would take long time for the body to synthesise de novo or resynthesise the large amounts of agonist molecules that would be necessary to stimulate small number of receptors.
106
What are antagonists?
Antagonist are molecules that reduce the actions of agonists, that agonists being endogenous or drug molecules.
107
What do antagonist form?
Form ligand/receptor complex, but don’t form active cellular response.
108
What do antagonists block and what type of examples are there?
Antagonists block receptors referred to as blockers.
Many clinically useful drugs are antagonist e.g. b-blockers, histamine blockers (antihistamine)
109
What type of response do antagonist produce?
Antagonist producing a passive response.
110
What are the 6 mechanisms that produces antagonism?
Antagonism can be produced by several different mechanisms:
- Competitive
- Irreversible competitive
- Non-completive
- Pharmacokinetic
- Chemical
- Physiological (functional)
111
What type of binding does competitive antagonist have?
Competitive antagonists bind selectively to receptors, but do not elicit activation, instead they block receptors so interfering with agonist-receptor interactions.
112
Does competitive antagonist have affinity and efficacy?
Competitive antagonist have affinity for receptors, but NOT efficacy.
113
What does competitive antagonists compete with?
Bind reversibly with receptors.
Competitive antagonists will compete with agonists for occupancy of receptor.
114
What happens to the receptor occupancy in the presence of competitive antagonist?
In presence of competitive antagonist, receptor occupancy by agonist molecules will be reduced.
115
What is competitive antagonism referred to as?
- Competitive antagonism referred to as surmountable.
116
Why were Schild plots developed?
Schild plots were developed to identify reversible, competitive antagonism and to obtain an estimate of the affinity for antagonists for their receptors.
117
What is the pA2 an index of?
pA2 value for an antagonist is -log [antagonist] required to produce a two fold shift in the agonist dose-response curve. pA2 is an index of antagonist potency.
118
What does a large pA2 indicate?
The larger pA2, the more potent the antagonist.
119
What type of experiment is performed to collect data to construct Schild plot?
By performing an experiment, such as organ bath bioassay, it is possible to collect the necessary data to construct a Schild plot.
