Theme 1 - General Principles of Drug action Flashcards
1
Q
What is pharmacology?
A
What the drug does to the body. What the body does in response to the drug.
- How does the body system respond, change it’s body cellular or molecular to respond to that particular chemical added.
2
Q
What is PharmacoDYNAMICS?
A
the effects of a drug on the body
- Molecular interactions by which drugs exert their effects
- Influence of drug concentration on the magnitude of response
(We would expect to ingest more drug and in turn get more effect. However, in reality, more drug will lead to either no more therapeutic effect or a toxic effect)
3
Q
What does the study of PharmacoDYNAMICS allow us to do?
A
Determine the appropriate dose range for patients
Compare the effectiveness and safety of one drug to another
4
Q
What is PharmacoKINETICS?
What are the stages?
A
what the body does to a drug
- process which tells us how often a patient needs medicine in terms with their metabolsim
- Absorption: From site of administration into the blood
- Distribution: Drug can reversibly leave the bloodstream and distribute into
the interstitial and intracellular fluids of tissues - Metabolism: Body inactivates the drug through enzymatic modification
- Excretion: Drug is eliminated from the body in urine, bile or faeces
5
Q
What does the study of PharmacoKINETICS allow us to do?
A
Design and optimise treatment regimens for individuals
e.g. deciding on the route of administration, frequency of drug administration, duration of treatment
6
Q
Pathway of a drug to enter the bloodstream from the mouth
A
Mouth -> stomach -> intestines (absorbed through intestinal wall) -> Liver (metabolised) -> through liver portal vein into the blood
Blood goes through kidneys and gets filtered, so the drug will get filtered out
7
Q
From what sources are drugs produced?
A
natural, synthetic and biologically engineered
8
Q
By what method does the the drug interact with the targets?
A
- Shape (lock & key)
- Charge distribution: Specific charge across the drug, outside the drug, matches the drug on the target – allowing an introductions
(determines the type of bonds that hold the drug to the target)
9
Q
What type of bonds can form upon drug interactions with the target?
A
(From weakest to strongest)
Van der Waals: electrons shift, one side has a greater charge than the next
Hydrogen: H positively bond to negative O or N atoms
Ionic: Negativly charged atoms are attracted to positively charged atoms
Covalent: Two bonded atoms share electrons
10
Q
Which drugs act via their physico-chemical properties?
A
Antidotes, antacids, laxatives
11
Q
What are the 4 targets for drug action?
A
Receptors: targets for endogenous transmitters
Enzymes: biological catalysts which facilitate biochemical reactions
Ion channels: pores which span membranes to allow the selective passage of ions
Carrier molecules: transport ions and small organic molecules across cell membranes
12
Q
How do drugs act at Receptors?
A
Agonists activate the receptor
Antagonists block the action of agonists
13
Q
How do drugs act at Ion channels?
A
Either block or modulate the opening/closing
Drugs may increase the frequency of opening, changing the transmission potential or capacity of the ion channel (how much of that ionic conduction can occur)
14
Q
How do drugs act at upon Enzymes?
A
Either inhibit or act as a false substrate
there to control biochemical reactions; as a drug target we can inhibit or act as a false substrate to the enzyme – stopping it from getting to its end point in a biochemical pathway
15
Q
How do drugs act at upon Carriers?
A
Either transported in the place of the endogenous substrate or inhibit transport
16
Q
What are the two Receptor binding sites?
A
Orthosteric: natural binding site
Allosteric: different binding site – normally a seperate (drug) binding site
17
Q
How does Benzodiazepines act on a GABAa receptor?
A
Drug will bind to the ion channel, change the chloride conductance in the ion channel (normally membrane potential for chloride is negative charged)
↑ Amount of chloride going in = ↑ permeability = hyperpolarization of the cell = ↓excitability of the cell
Benzodiazepine does not have any effect by itself, it works with GABA to ↑ its effect – drug enhancing what normally happens at that ion channel. Greater hyperpolarization within the cell
18
Q
Normal enzymatic process for inflammation or immune activation
A
Phospholipids in membrane go crazy, start to break down and
Phospholipids –> Arachidonic acid via Phospholipase A2 –> Prostaglandins via Cyclooxygenase
(Prostaglandins causes the problems associated with immune or inflammatory condition/action)
NSAIDs can interact with the key enzyme, Cyclooxygenase, stopping it from catalysing A.A into P –> alleviating the inflamations as we are not getting the prone inflammatory mediators being produced at the end of the cascade
19
Q
Define Agonists & Antagonists
A
Agonist activates receptor
(ligand that combines with receptors to elicit a cellular response)
Antagonist blocks the action of agonist
20
Q
Why do receptor subtypes elicit different cellular effects?
A
due to different specificities for what activates or inhibits them and different signal transduction mechanisms
21
Q
Normally, how does a drug elicit a response from a receptor?
A
Drug molecule will bound to allosteric or ollosteric binding site, which is separate from the main structure of the receptor
= Conformational change, something happens structurly to the receptor – change in conformation = signal transduction
22
Q
4 Main types of receptors
A
Ligand gated ion channels (Ionotropic)
G-protein coupled receptors
Enzyme (kinase) linked receptors
Nuclear (Intracellular) receptors
23
Q
Two types of Ionotropic receptors + how do they work?
A
- Ligand-gated: channel linked receptors that require an agonist to open the channel
- Voltage-gated: not channel linked but requires a chanmge in electrecial charge across membrane to opne/close
24
Q
What is the stucture of ionotropic receptors? + How does it help in its function
A
Pentomeric - 5 sections to ion channel
channels have an inward kink halfway down, which usually keeps it in a closed state. When agonist binds to extracellular binding space = conformational space so kink moves apart. Negativlty charged inside to cation selective
Multiple binding sites on the ion cannels, so multiple can bind at the same time
25
How are G-protein coupled receptors able to deal with different types of signal transduction?
as they have two different mechanisms:
1. Bind to an ion channel, effect the opening state. Instead of binding to ion channel directly, the g protein activates it
3. G protein receptors interact with enzyme based product, producing secondary messengers bringing about a molecular change
26
What is the structure of G-protein coupled receptors?
Single polypeptide chain with 7 trans-membrane helices
3 subunits:
α, β, ɣ
27
What allows specifity?
Through molecular variation in α subunits
28
What do these α subunits dicate?
What are the different α subunits?
alpha unit you have, dictates what secondary messengers get activated or inhibited
1. Gs (stimulatory):
Activates adenylyl cyclase
Activates Ca2+ channels
2. Gi (inhibitory):
Inhibits adenylyl cyclase Activates K+ channels
3. Gq:
Activates phospholipase C
4. Go: Doesnt interact with specific secondary messengers, instead makes β & ɣ subunits do all the work
29
What part of the G-protein coupled receptors has catalytic energy?
How does this protein receptor tranduce signals?
α has the catalytic activity, it has GDP attached to it --> part of the protein that can do signal transduction
1. Drug binds to receptor, conformation change in transmembrane
helix
2. Occupied receptor changes shape and and binds with Gs protein
3. Alpha subunit, Gs protein, changes shape and joins exchanging
GDP for GTP
4. Activates the alpha subunit, which dissociates and binds to
activate Adenylel cyclase
5. SM activated = further messengers activate
30
What is the structure of Enzyme (kinase) linked receptors?
What causes variation?
How does it function?
Large extracellular ligand-binding domain connected to intracellular domain by single membrane-spanning helix.
Variation is caused by type of kinase in structure
Ligand binding dimerisation (combinding of two single transmembrane helices) autophosphorylation Activation of multiple pathways
31
What are the 2 classes of Nuclear Receptors?
& What are the different types of dimers?
1. located in cytoplasm, form homodimers, ligands are endocrine (steroids, hormones)
2. present in nucleus, form heterodimers, ligands are lipids (fatty acids)
```
Homo = increase signalling from the particular receptor
Hetro = bind to another nuclear receptor and start signalling off another gene transcription event = increase the physiological effect because it is diversifying in terms of binding to another receptor
```
32
How does a Nuclear Receptor function?
Binding to hormone response elements initiates gene transcription changes (positive/negative).
Importance of whether these receptors form homodimers or hetrodimers adds to importance on receptor functions
Homo: increase signalling from the particular receptor
Hetro: bind to another nuclear receptor and start signalling off another gene transcription event = increase the physiological effect because it is diversifying in terms of binding to another receptor
33
Class I nuclear receptor signal transduction
1. Drug crosses over (must be lipid soluble)
2. Bind to nuclear receptor, conformation and change
3. Drug receptor gets translocated into nucelus
4. Drug receptor unwinds chromatin, allowing gene transcription to occur = produce new mRNA, new protein and new effects
34
Describe the mechanism of action of an Agonist
the binding and the physiological effects are two different events at different times – independent to each other.
35
What is the importance of dosage of druga?
Too much drug = poisonous
| Too little drug = no effect
36
Define Dose-response curve
measuring concentration against physical effect in the body
Dose is what you give them e.g. 5mg tablet
Concentration: concentration of that drug in the plasma having a therapeutic effect
37
Describe the normal Dose-response curve and the LOG scale Dose-response curve
```
hyperbolic curve (left): ↑ concentration = ↑ effect in the body
until you reach a maximal where all the receptors are occupied with the drug so you cannot have any more effect on that system
```
LOG scale curve: as it’s easier to do - changes hyperbolic curve to sigmoidal curve
```
Shows us:
the threshold of range (area where nothing happens)
linear response (area where we see the therapeutic response)
Maximal response (point where we will not get an effect)
```
38
What are the two types of Dose-response relationships? + What is the importance?
Grades: response of an isolated system
- measures grades increase against agonist concetration
Quantal: drug doses - population based effects
(Percentage response in a population when you increase the drug dose)
Important when working out safety measure such as:
Side effects
Toxicity profiles
39
What is the importance of a Dose-repsonse curve?
```
Allows to work out:
Emax
EC50/ED50
Efficacy
Potency
```
40
What is Emax?
Emax = maximal response --> Measuring EFFICACY
41
What is EC50/ED50?
- estimation of concentration/dose required to produce 50% of maximal response (amount of drug needed to produce a given effect)
concentration that we need for 50% response --> Measuring POTENCY
–efficient for knowing how effective a drug can be
42
What is POTENCY? hence what is a potent drug?
How impactful the drug can be:
Furthur to left = more potent
Furthur to right = less potent
Potent drug: binds well, strong effect (may not have to bind to many receptors for effect) and has a quick effect
(Need less of the drug to get the same response)
43
What is efficacy
the ability of an agonist, once bound, to activate the receptor
44
What is Affinity?
the strength with which an agonist/drug binds to a receptor
- how easily the drug falls off
45
Receptor occupance theory
At any given point, a receptor can be rested and activated – there must be an equilibrium
If there is no drug, the inactive state will predominate
If we add a drug, depending on the drug ability to interact with the receptor, we will get a change in the state – pushing the equilibrium over = activated receptor
46
What is Bmax?
What is non specific binding?
How do you measure specific binding?
maximum number of binding sites i.e. Receptor saturation
drug molecules binding to unexpected receptors
Total – Non specific = Specific
47
What is Kd?
equilibrium dissociation constant: Concentration of ligand at which 50% of the available receptors are occupied
Lower the Kd/Lower EC50 = Greater affinity & Greater Potency
Lower the KD, graph to LHS, lower the concetration to bind to 50% of receptors which means the drug has a high affinity as you don’t need a lot to bind to the receptors
48
When are Kd and EC50 equal?
However, why is this usually not the case?
Where there is a linear relationship between receptor occupation and biological effect
Spare receptors: Receptors usually amplify signal duration & intensity, hence only a fraction of total receptors may need to be occupied to elicit a maximal response from a cell --> maximum response can be achieved with only a small fraction of all the receptors occupied
49
What is a full agonist?
What is a partial agonist?
Full: (high efficacy) - AR* very likely
Produce a maximum response while occupying only a small % of receptors available
Partial: (low efficacy) - AR* less likely (just don't turn the receptors on in the same way)
can not produce a maximal response in the system even
when occupying all the available receptors
50
Why are Partial agonists important?
Given as a therapeutic option, trying to alleviate some of the side effects - so used in an inhibitory way – competes with the full agonist
51
What is special about Constitutivly active receptors?
Constitutivly active receptors don't need to bind to an agonist to turn on
52
What are inverse agonists?
Competitive antagonists that have higher affinity for the AR (inactive) state than for AR* (active) state
53
What is an Allosteric Modulator?
What are the two types?
Drug that is binding, and is positively or negatively increasing the potential for that receptor to respond to its normal endogenous signaling molecule
Positive: Not active alone but increase affinity and/or efficacy of endogenous agonist
Negative: Not active alone but decrease affinity and/or efficacy of endogenous agonists
54
How does Desensitisation of receptors occur?
Effect of the drug reduces with continual/repeated administration
55
How do Pure antagonists function?
do not by themselves cause any action by binding to the receptor & hence need an agonist with them
56
What are the 3 classes of antagonists?
1. Chemical: Binding of two agents to render active drug, inactive
2. Physiological: Two agents with opposite effects cancel each other out
3. Pharmacological: Binds to receptor and blocks the normal action of an agonist on receptor responses
57
How does a nonreceptor antagonist function?
does not bind to the same receptor as an agonist
Two types:
Chemical antagonists: inactivate an agonist before it has the opportunity to act (e.g., by chemical neutralization)
Physiologic antagonists: cause a physiologic effect opposite to that induced by the agonist.
58
What is the difference between a competitive and a non competitive antagonist?
Competitive: binds to the same site as the agonist but does not activate it - blocking (RHS shift on dose-response curve as more agonist needed to get same response)
Non-competitive binds to allosteric site - preventing activation of the receptor
59
What are the three types of pharmacological antagonism?
1. Competitive: binds to orthosteric site and prevents agonist but can be overcome with increase agonist concentration
(RHS shift on agonist-response curve)
2. Non-competitive (Irreversible): Binds to orthosteric site and forms irreversible covalent bonds with receptor
(RHS shift on agonist-response curve & reduced maximal)
3. Non-competitive: (Allosteric site)
effects Signal transduction - downstream responses are blocked
(Slope & maximum reduce of dose response curve)
60
In the presence of a Competitive antagonist, what happens to the dose-response curve?
RHS shift
Same form
Same maximal repsonse
As antagonism can be overcome by an increased concentration of agonist
61
Schild plot:
What is it used for?
What is the use of the cruve?
Work out:
How strong an antagonist is
How capable an antagonist is inhibiting a receptor system and comparing it to other antagonists
Where the straight line intercepts 0 = concentration of antagonists needed to reduce effects of agonists by 50%
62
Schild plot:
What is it used for?
What is the use of the cruve?
Work out:
How strong an antagonist is
How capable an antagonist is inhibiting a receptor system and comparing it to other antagonists
Where the straight line intercepts 0 = concentration of antagonists needed to reduce effects of agonists by 50%
63
pA2 values
activity of a receptor antagonist in simple number
pA2 = - log Kb
64
2. The Irreversible AntagonisT
Slide 19
65
How do irreversible antagonists effect agonist curves?
Do not have the same form
Have a reduced maximal response
Because:
Binds irreversibly
= Antagonism which CANNOT be overcome by an increased concentration of agonist
66
Irreversible Antagonism
Slide 21
67
What other products also act as irreversible antagonists?
Weak partial agonists
Difficult to differentiate between partial agonists and antagonists(+agonist)
68
Non-Competitive Antagonist
Slide 24
69
What is the Therapeutic Window/Index (TI)?
Determines the risk/benefit ratio - gives us a measure of the risk safety of the drug
70
How can we quantify antagonism?
using the schild equation and schild plot
71
Define Pharmacokinetics
The mathematics of the processes (ADME) which govern the amount of drug in the body and the way this changes with time
72
Why do we need to be able to calculate pharmacokinetics parameters?
dose given = correct plasma concentration
in all patients - regardless of disease state, capacity to eliminate, route of administration, age and other drug therapy
73
What is ADME?
Absorption: the movement of drug across membranes
Distribution: where the drug goes within the body
Metabolism: how the drug is broken down
Excretion: how the drug is removed from the body
74
What is the A in ADME?
Absorption - means that the drug will be distributed into the systemic circulation
Passive & Active diffusion are used
75
How are drugs administrated via the Oral route?
What are absorbed well?
Stomach: low pH, weak acids
Small Intestine: pH 6-7.4
absorption of exogenous compounds
weak acids and bases are well absorbed
76
What is the general correlation between pH of a drug and enviroment?
acidic drugs are absorbed well in an acidic enviroment, vice versa with alkalinic
77
What are the advantages and disadvantages of oral administration?
ADVANTAGES
- safe
- convenient
- economical
DISADVANTAGES
- irritant drugs cause sickness
- not possible in vomiting patients
- some drugs destroyed by gut acid/flora
- intestinal absorption can be erratic
78
Factors affecting GI absorption?
Gut motility: ↓ motility = ↓ absorpton
pH: poor absorption of strong acids & bases
Size & formulation
Physico-chemical interactions: potential for the drugs to bind to other things as well
79
Define bioavailability
the proportion of the administered dose which enters the (blood) systemic circulation
- 20mg may be injected, but not all of it gets to the blood
80
Define first-pass mechanism?
- Break down/metabolism of the drug as it goes towards the systemic circulation
Occurs in both intestine and liver before drug reaches systemic circulation
81
Parameter of absorption AUC is used for?
Limitations?
Estimating bioavaibility = AREA UNDERNEATH CURVE
iv dose F = 1
extra-vascular dose e.g. oral F = <1 – because its gone through some form of metabolism
```
Does not consider inter and intra individual variations in;
- enzyme activity
- Gastric pH
- Intestinal motility
Does not consider rate of absorption
```
82
What is Cmax & Tmax?
Cmax: Maximum concentration of compound after administration
Tmax: Time at which Cmax is reached
83
Sublingual administration
Where?
Advantages
Tablet taken underneath the tongue, which metabolises
- Uses venous drainage from the moutht o the Sup.VenaC
- Fast/rapid response
- Avoids 1st pass metabolism
84
Rectal/Vaginal route
Advantages
Bypasses GI/hepatic first pass effects
Rich blood supply = rapid absorption (but depends on drug & formulation)
Useful when drug causes nausea and vomiting, or if the patient is already vomiting
85
Intravenous Injection (into IV)
Advantages & disadvantages
Advantages:
Rapid action - predicatble
IV infusion for ill patients
```
Disadvantages:
difficult /painful
risk of infection
cost and safety
immediate adverse effects
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86
Subcutaneous injection - what is the advantage?
Faster blood (systemic) effect than oral administration or local effect (e.g. LA)
87
Important methods by which drugs are absorbed? (cross cell membranes)
- passive diffusion through lipid
- diffusion through aqueous channel
- carrier mediated transport
88
What factors affect passive diffusion?
Lipid solubility
Ionisation:
- ionised drugs have low lipid solubility
- Many drugs are weak acids/bases ... exist as both ionised & unionised
- ratio of ionised : un-ionised determined by pH
89
What is pKa?
What happens when solution pH = pKa
pKa = measure of the strength of an acid/base, with respect to the pH of a solution
When pH of solution=pKa of drug, 50/50 split = 50% of drug is ionised
90
Ionisation of a drug when moved from high to low pH.
slide 22 bp6
Basic drug form a high pH to a lower pH = ionized basic drug ... Ionized and won’t go through membrane
91
Ionisation of a drug when moved from low to high pH
Acidic drug in an acidic environment in stomach. If we increase the pH of the stomach, the drug will become ionized – getting stuck
92
Ionisation equation
% Ionisation = pH of solution – pKa
93
What is the D in ADME?
Distrubution
Equilibrium between the plasma and the tissues, which reaches equilibrium where the body thinks ”Do we need to process it anymore”, if not it is excreted
94
What is drug distribution?
reversible transfer of drug from one location to another within the body
- to the tissue as the concentration in the blood increases, and from the tissues into the blood when the blood concentration decreases.
95
What are the factors affecting distribution?
Membrane permeability:
Blood perfusion
Lipid solubility
Plasma protein binding
Tissue binding
96
How does Plasma protein binding affect distributionn?
Drugs with high molecular weight and/or high degree of binding to plasma proteins will stay in the blood rather than distribute into tissues/organs
97
What does the amount of protein bound drug depend on?
the concentration of free drug
its affinity for the binding sites
the concentration of protein.
98
What can extensive protein binding lead to?
Slow drug action & elimination
99
How does tissue binding occur?
either due to their composition – lipid soluble drugs will accumulate in fat
via binding to cellular components (proteins, pigments, minerals)
100
Volume of distribution
quantify the distribution of a medication between plasma and the rest of the body after oral or parenteral dose
[Comparing body drug amount to plasma concentraiton - how large would your body have to be for a given amount of drug to yield a concentration equal to that seen in the plasma?'
Drugs confined to plasma compartment = small VD
Drugs accumulate outside the Plasma = Large VD
VD = amount of drug given / plasma concentration at 0 time
101
What is the importance of volume of distribution?
used to calculate drug dose
102
What does plasma concentration of a drug dictate?
the ability of a drug to reach its target organ in an effective concentration, therefore defines doseH
103
How does Vd affect plasma distribution?
Low Vd - Confined to the plasma high plasma concentration
High Vd - Accumulated in peripheral tissues low plasma concentration
104
What is Enterohepatic recirculation (HER)?
the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile
105
What is the pathway of most drugs?
DRUG gut liver (gets changed) bile duct gut
106
Why may some diagrams have two metabolism peaks?
Double peak of concentration in the body: Goes through metabolism process again before hitting the tissues
107
What must occur for the drug to be eliminated?
Metabolism: converting a drug from a lipophilic state to hydrophillic - enzymatic modication of drugs
108
Drug metabolism - Phases
Phase one – activates the drug by increasing the pharmacological activity of that product by adding functional groups (making that drug receptive as in making it hydrophilic in nature)
Phase Two – adding on and conjugating that will make that drug as a whole unit hydrophilic
109
Phase 1 reactions
Catalysed by?
What occurs during this?
Consists of: oxidation, reduction or hydroylsis
Catalysed by: CYPs - cytochromes P450
- Increases hydrophillic
- Increases pharmacological activity
110
What are CYPs? Where are they located?
Phase 1 enzymes
Heme based enzymes - iron allows it to oxidise
Liver: hepatocytes
Intestine: enterocytes
111
CYP reactions
CYP causes redox reactions
Depending on wehre the redox reactions occur, isomers can occur - making them help/act differently
112
Are there any drugs that are not metabolised by CYP enymes in Phase 1?
Ethonol
113
Phase 2 reactions
Catalysed by?
What occurs during this?
Phase 2 is an enzyme dependant reaction which makes drugs therapeutically inactive and cause them to become hydrophillic
114
Renal excreation
Three major processes?
What is the difference in rate of excreation?
1. Glomerular filtration
2. Tubular reabsorption
3. Tubular secretion
Variation in rate at which drugs are excreated
Metabolites are cleared faster than parent compounds
115
How are water soluble drugs/metabolites excreated?
Unchanged through the kidneys
116
In Glomerular filtration, what does the rate of entry rely on?
Free drug conc. in plasma
| Molecular Weight
117
What is the most effective mechanism for secretion?
Active Tubular Secretion --> transfer of materials from peritubular capillaries to the renal tubular lumen;
118
How are Lipid soluble drugs excreated?
filtered in glomeruli
- -> reabsorbed on the distal portion of nephron
- -> metabolism to more polar compounds
- -> excretion in urine
119
In Active Tubular Secretion, how are drug molecules transferred to tubular lumen?
By two carrier systems which can activly transport against an electrochemical gradient
120
What two systems is the Tubular Secretion process comprised off?
Two seperate systems:
1. Acids
2. Bases
121
With tubular reabsorption, when does drug concentration increase?
↑ as water is reabsorbed
122
Tubular reabsorption mechanism
SLIDE 27 BP7
123
What is tubular reabsorption dependant on?
1. Drug lipid solubility (i.e. pKa)
| 2. pH of tubular fluid.
124
What happens to an acidic drug if the fluid becomes more alkaline?
ionises --> becoming less lipid soluble ... reabsorption diminishes so excreation ↑
125
What happens to an basic drug if the fluid becomes more alkaline?
un-ionised --> reabsorption increases
126
pH partition
tendency for acids to accumulate in basic fluid compartments, and bases to accumulate in acidic compartments
127
For different substances, what are the mechanisms of elimination?
Gases: exhalation
Water-soluble compounds: urine and/or bile
Lipid-soluble: undergo metabolism to more water-soluble metabolites that are then excreted in the urine and/or bile
128
What is Elimination parameter: clearance (CL)?
measure of the ability of the eliminating organs to remove a compound from the body
129
How do you work out CL?
Total body CL = sum of all organ CL processes
(i.e. Total CL = Hepatic CL + Renal CL + all other CL)
CL = Ke x Vd
[Ke: how quickly drug is eliminated from the body
Vd: volume of drug, where it will go (Volume distribution of the drug)]
130
What is Elimination parameter: elimination rate constant (ke)?
SLIDE 32 BP7
131
What is Elimination parameter: half-life?
Time it takes for concentration of a compound to reach 50% of its current value
132
What are the two important mechanisms by which drug interactions occur?
Induction and Inhibition
133
What is Induction of Drug metabolising enzymes?
↑ synthesis of enzymes in PHASE 1&2 = ↑ metabolisim of drug
134
What is Inhibition of Drug metabolising enzymes?
Inhibition that results in a reduced rate of metabolism and increased pharmacological effect
135
What are adverse drug reactions?
an unwanted or harmful reaction which occurs after administration of a dose inten ded for therapeutic effect
136
What measures can be taken if an adverse drug reaction occurs?
Reduction of the dose or withfrawal of the drug
137
What is the difference between ADRs & side effects?
SE: are reactions that we expect to see at the given therapeutic dosage level.
ADR|: higher severity of reaction - putting into a life threatening situation - completly abnormal given the concentration range administrated
138
What suggests a cause & effect relationship between drug administration and ADRs?
Reaction:
- stops when drug stops
- starts when drug retarts
- corresponds to the know pharmacology of the drug
Time sequence: most occur within a normal therpeutic window (some take months)
139
Define Side effects
something that we expect to happen (unavoidable) and are mild, due to the pharmacology of the drug and happen in a dose dependent way
140
Define secondary adverse effect
indirect side effect, the original drug has caused something in the body to happen which has caused an increase risk of some other effect
141
What are risk factors for ADRs?
- Age
- Sex: females are more susceptible due to pharmokinetic factors & hormonal influences
- Medical history: ADR to one drug = ↑ chance of another ADR
- Disease
- Current medication: Drug interactions
- Ethnicity
142
How does Age act as a risk factor for ADR?
Filtration rate:
Newborns - 6 months: have a low glomerulus filtration rate
(From 20 to) Elderly: filtration rate decreases
Metabolism:
Young: low conjugating enzyme, so do not have conjugating profile that we need to get drugs out of the body – so cannot give child certain drugs
Eldery: Lower phase 1 metabolic expression
Lower metabolism = potential of longer effect, half life, and side effects to occur
143
How does Ethnicity act as a risk factor for ADR?
slide 11 bp 8
144
What are the different clasifications of ADRs?
```
Type:
A. Augmented pharmacological effect
B. Bizzare Effects
C. Chronic effects
D. Delayed effects
E. End of treatment effects
```
145
What is the Type A classification of ADRs?
Augmented pharmacological effect -
Heightened response on what you expected from the pharmacology of that drug – it is extreme in response and terms of concentration of the drug but is still related to the pharmacology
146
What are Muscarinic antagonists ?
parasympatholytic - agonist at the parasympathetic system
147
What is the problem with the effec that muscarinic antagonists have?
A lot of cross over and non-selectivity occurs. Drug could be given for one therapeutic indication, but it can lead to adverse reactions (a reaction that we didn’t intend to target it)
148
What is the Type B classification of ADRs?
Bizzare Effects
| - Adverse effects that are unpredictable from the pharmacology of the drug
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What is the Type C classification of ADRs?
Chronic Effects
| - Occur as a result of chronic treatment of the drug
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What is the Type D classification of ADRs?
Delayed effects
-Delayed, effects occur remote from treatment or in child of treated patient
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What is the Type E classification of ADRs?
End of treatment effects
- occur as a result of stopping the treatment (withdrawal effects)
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What important Adverse drug interactions occur?
DRUG DRUG INTERACTIONS - drug being administrated isnt the only one causing ADRs maybe another drug is interacting with the drug being administrated
- Drug interactions can increase and decrease both sides, aka more or less metabolism
