DRUGS AND THERAPY Flashcards
(127 cards)
1
Q
Open label Definition advantage and disadvantage.
A
DEFINITION: Both the patient and research her know if they’re getting the drug or placebo.
. Advantage: Less ethical issues.
- In phase 1 in must be open-label because it is only looking at the safety of the drug.
- Well-informed
- Good if you can’t easily disguise the drug.
DISADVANTAGE:
- Risk of biases for example treating depression.
- Clinician might over interpret findings.
- Subjective and points compared to BP
2
Q
Single-blind Definition advantage and disadvantage.
A
DEFINITION:
- The participant is Blinded but not the clinician.
ADVANTAGE:
- Decrease subjectiveness
DISADVANTAGE:
- Clinician bias. Which is not good because you’re trying to minimise bias
3
Q
Double blind Definition advantage and disadvantage.
A
The participants and clinician both blinded.
ADVANTAGE:
- Decrease is bias. There is no subjectivity.
DISADVANTAGE:
- Anxiety in participants
- Adverse events could occur. For example a break in the trial can occur to decode to find out if it was the drug.
- Patients might need to know the drug they’re on if they have to go to hospital. And gets put on a new drug.
4
Q
Randomisation advantage and disadvantage.
A
ADVANTAGE:
Decrease bias and ensure consistency across the grips. For example not giving the drug to the sickest groups.
DISADVANTAGE:
- Difficult to set up
5
Q
Crossover design:Definition. Advantage. Disadvantage
A
DEFINITION:
- Swap control and treatment groups halfway through.
ADVANTAGE:
- Within patient control. Accounts for the baseline differences. And Less patience.
DISADVANTAGE:
- The first component might interfere with the second phase. If treatment in the first phase. Just but then taking them off reduced the efficacy
- Can take more time
6
Q
Parallel design Definition advantage and disadvantage.
A
DEFINITION: - Maintained for the whole period. (. Where there is only one Placebo and one intervention group happening.) ADVANTAGE: - Not going to have any interfering factors from the first phase vs the second phase like in a crossover. - Shorter DISADVANTAGE: - Not within patient control - Heterogeneity
7
Q
Comparator: Definition, advantage, and disadvantage.
A
DEFINITION:
- The drug is compared to a medicine on the market.
ADVANTAGE:
- Might have better efficacy.
. Might have similar efficacy better tolerated compared to the comparator.
- Wants to know if our drug is better?
DISADVANTAGE:
- One group may be disadvantaged if the drug is worse.
8
Q
Pharmaceutical Benefits Scheme? (PBS)
A
The drug must have greater efficacy or similar efficacy but better tolerated to make it more accessible to the public.
9
Q
What is the definition of a DRUG?
A
-Any chemical substance (other than a nutrient or essential dietary ingredient) that brings about a change in biological function
o Nautral products
o Synthetic chemicals
10
Q
What are the three different parts to a drug name?
A
- The chemical name
- The generic name (Salbutamol)
- The trade name (Ventolin ® )
11
Q
How do most drugs exert their effects?
A
-By binding to protein molecules
12
Q
What four different general types of targets can drugs exert their effects on?
A
- G protein coupled receptors.
- Ion channels
- Enzymes
- Transporters
13
Q
What are the three different strategies for finding new drugs?
A
- Analysis of pathophysiology.
- Analysis of mechanism of action of existing therapeutic drugs.
- Genomic approaches
14
Q
What does the analysis of mechanism of action of existing therapeutic drugs involve?
A
- Working backwards from the night action to the mechanism.
15
Q
What does the analysis of pathophysiology involved in general?
A
Understanding the pathways involved in disease determining the novel target
16
Q
In general what do generic approach is involved in determining a drug Target?
A
- Most drug targets are proteins so that means are encoded in the Genome. These jeans are mutated disease-modifying jeans or druggable genes.
17
Q
What is an example of a drug Target identified by pathophysiology?
A
- Depression with the target of a 5-ht Transporter and the drug fluoxetine.
- They found a decrease in serotonergic function in depression and that serotonin is a promoter of mood.
18
Q
What is the action of the drug fluoxetine?
A
Inhibiting the serotonin Transporter to stop the reuptake of serotonin.
19
Q
What is an example of a target identified by a drug effects?
A
- Diabetes with the drug Katp channels and the drug Sulfphonylureas
20
Q
How can we validate a drug Target?
A
Knockout the gene that makes the target out.
e.g. With ACE –> if knocked out, (KO with siRNA) the BP should theroetically go down
21
Q
What are the steps involved in identifying a new lead compound?
A
- Target selection
- Target validation
- Screen compounds
- Hit candidates (Lead discovery)
- Validate candidate (Lead discovery)
- Lead compounds (Lead discovery)
22
Q
What are 4 sources for new drugs?
A
- Screening for natural products:
- Plants, animals (venoms/toxins/secondary metabolites) (50% of drugs in clinical use) - Serendipity
- Rational Design (most new drugs today)
- Screening of chemical libraries
23
Q
What is an example of Serendipity in drug discovery?
A
- Sildenafil (Viagra ®)
- Was originally developed as dilator of coronary arteries —> CTs male patients reported sexual activity increase –> so marketing strategy was shifted to anti-impotence drug
24
Q
What are some examples of rational drug design?
A
- ACE enzyme inhibitors –>Captopril!
- Found from a peptide in pit viper venom which was INHIBITOR OF ANGIOTENSIN ii PRODUCTION
25
What is another form of rational design?
- Exploiting a side effect
- Sulphanilamide --> antibacterial with side effect of lowering blood glucose AND has diuretic activity
- Separated this out into two compounds which show either effect to have TWO DIFFERENT DRUGS
26
QSAR (Quantitative Structure Activity Relationships) - what is it?
- This uses pharmacophores to relate physical properties of series of compounds
- Pharmacophores contain chemical structure features that are essential for ACTIVITY at receptor
- Defines the structure necessary for drug binding
27
What does structure based design (part of rational drug design) involve?
-This uses the structure of the protein (receptor) of interest and X-ray crystallography/NMR/homology) to predict docking - You work BACKWARDS FROM TARGET
-Use the structure of the receptor target to deduce the chemical structure that would react with the receptor
of drug molecules
28
What does screening of chemical libraries involve?
- Involves COMBINATORIAL CHEMICAL LIBRARIES Large family of molecules of diverse structures
- Screening of 120 000 compounds to find a specific group of compounds
- They are large number of chemicals derived from: NAUTRAL SOURCES, RATIONAL DRUG DESGIN, CHEMICAL LIBRARIES
29
When screening compounds what is HTS (High Throughput Screening)?
- A target is incorporated into biochemical or cell based assays and exposed to LARGE numbers of compounds (robotics)
30
What is the process of HIT?
- Screening library --(primary screen)-->
- Primary HIT candidate (100-1000 hits) --(secondary screen)-->
- Validated HIT candidate (10 hit series)
31
What do we find in a primary screen?
- Activity against the target (affinity) --> only testing a SINGE concentration
32
What do we find from the Primary Hit candidate Step?
- If the therapeutic can bind to the target may not act as agonist or antagonist
- So this step shows that it can interact with the target of choice
33
What do we find in the secondary screen?
-Confirming the affinity/ potency/ selectivity --> MULTIPLE CONCENTRATIONS --> activity at panel of targets/repertoire
34
What can we conclude from a validated hit candidate?
- Inhibit/activate target
- Has the drug like properties (MW<500, clogP<5, aromatic ring)
- Has DEFINED novel structure
- NOT drugs
- NOT optimised for selectivity
- NOT optimised for humans (ADME, toxicity)
`
35
What does the clogP mean?
- Measure of the lipophilicity
| - We want a MODERATE level so it can be absorbed AND get out of the body
36
HIGHER CLOGP=
| -
More lipophilic
37
LOWER CLOGP=
Less lipophilic (hydrophilic)
38
What if the clogP is not where we want it?
-That’s okay! We can modify compound to REDUCE lipophilicity or REDUCE MW
39
What properties will the perfect drug contain?
- Orally bioavailable
- Little/no side effects
- Selective for target
- Not excreted too quickly
- Good balance of solubility distribution
- Good ADME
- Cheap --> synthesis and quality
40
What occurs in lead optimisation?
- Screens in animal models occur in this phase
- Must see if the drug has efficacy in animals
- Detailed drug metabolism and pharmacokinetic (ADME) analysis
- Safety pharmacology
- In vitro toxicity
41
Are animals used at every stage of drug discovery?
- YES
42
What does pharmacological profile involve?
- Screening assays ( In vitro profiling OR in vivo profiling)
- Radioligand binding
43
What does in vivo profiling invovle (as part of screening assays in pharmacological profiling)
- Do molecular and soil effects translate to predicted pharmacological action in WHOLE ANIMALS?
- Are there any off Target actions?
- Does in Vivo potency match with PK properties of the compound?
- What is the effect of repeated or long-term administration of the drug?
44
What does in vitro profiling involve as part of screening assays in pharmacological profiling?
- Do molecular and cellular effects translate to predicted pharmacological action in INTACT TISSUES?
- Are there any off Target actions?
- Does the potency of the compound at the molecular level tissue level and whole animal CORRELATE?
45
What is the translation from in vitro to in vivo in humans.?
In vitro (specific target) --> acute in vivo--> chronic in vivo--> Human.
46
Art of 10 compound how many do you lose when going from the animals the Human?
- 9 out of 10 compounds due to lack of efficacy.
47
What are the predictive values from preclinical animal to clinical human?
Very good
. Let's good
. Nice good or difficult.
48
What can be as a result of a good predictive value?
- Organ functons.
49
What can be a result of a less good predictive value from animal to human?
- Psychological/behavioural functions
- E.g. elevated plus maze (rodents) anxiolytic drugs (if they are anxious they won’t explore the maze)
- E.g. Forced swim test (mice) antidepressant drugs
50
What can be a result of a not good/ difficult predictive value from animal to human?
- Side effects
- Drug toxicity
- Not usually evaluating unpredicted activity
51
What is an example of a drug with POOR predictive value?
- RGN1412
- Human mAC --> CD28 superantagonist antibody (IMMUNOMODULARY DRUG)
- Intended to treat RHA (rheumatoid Arthritis)
- BUT severe inflammatory reactions in first human subjects
- Catastrophic organ failure 500x lower dose found safe in animals
- This was because it was tested in a different strain of monkey
52
What does knowledge of a drugs pharmacokinetic profile enable?
does knowledge of a drugs pharmacokinetic profile enable?
- Decisions about dosing how much? How often? By which route?
- Prevention of dose dependent adverse effects
- Prediction and avoidance of pharmacokinetic drug interactions
- Prediction of interpatient variability
THESE PROVIDE A BASIS FOR DRUG THERAPY
53
What is included in the pharmacokinetic phase?
A bsorption
D istribution
M etabolism
E xcretion
54
What factors influence how drugs move across the cell membrane (CM)?
- MW
- Charge
- The more lipophilic a drug is, the easier it is to cross the cell membrane (want moderate)
55
What is the ideal MW for drugs to move across the cell membrane?
- MW<500
56
What did a solute carrier transporters do? (as part of carrier mediated transport)
- These are NON selective e-->
- OAT and OCT (Anion and Cation)
- facilitative transporters OR secondary active transporters
- Expressed in LIVER and KIDNEY
- Can influence drug elimination
57
Which class of transporters are the P glycroproteins part of?
- ABC transporters (ATP binding cassette)
58
What mechanism does the transporter have for p glycoproteins?
-Transmembrane efflux pump influence the UPTAKE and EFFLUX of a range of drugs influence plasma and tissue ( [drug])
59
Where is the location of p glycoproteins?
- Epithelial cells with excretory roles:
o Renal and tubular brush border membranes
o Bile canaliculi
o Brain microvessels
o GIT
60
What happens if you inhibit p-glycoproteins?
- More drug will be absorbed because you want to be pushed out by the p glycoproteins efflux.
61
Drug Z is a substrate for p-glycoproteins. Predict the effect of INHIBITING p-glycoproteins in the GIT
- Increased absorption of Drug Z from GIT
62
If we inhibit p-glycoproteins, what will be the effect in the brain?
- Increased movement of drug INTO the brain
63
If we inhibit p-glycoproteins, what would be the effect in the kidneys?
- Decreased elimination (stopping the reabsorption of drugs from the kidney tubules)
64
Is it common for a drug to be evenly distributed around the body?
- NO
65
Where are very large drugs confined to in the body circulation?
- THe circulation
66
Where are very polar drugs confined to in the body compartments?
- THey are just excluded by cell membranes
67
Where are lipophillic drugs enriched in?
- The fat!
68
What are 3 factors that affect drug distribution?
1. How easily it moves out of the vasculature ( Movement of drug across cell membranes and Binding to plasma proteins)
2. How well drug is delivered to tissues (Blood flow in particular regions )
3. How well it binds to tissue components (Binding to extravascular sites (keeps drug out of plasma, might not get to active site) )
69
What three things does the degree of plasma binding depend on?
1. Free drug concentration []
2. Affinity of drug for binding sites
3. [plasma protein]
70
In most situations, is the [free drug]<< [protein]?
- YES so [DP] depends on [D] the fraction bound is CONSTANT!
71
EQUATION: for the degree of drug bound to plasma protein
D+P↔ DP
72
What does 95% DP mean?
- That 95% is bound to plasma proteins so if a drug has 95% PPB (Plasma Protein Binding)
- D (5%) means that 5% of the drug is FREE in the plamsa
73
What is a way to quantify drug distribution?
-VOLUME OF DISTRIBUTION
74
What is the volume of distribution of a drug that is a very large molecule and has a high degree of binding to plasma proteins, compared to the plasma volume?
- The volume is distributed in is about the same as the plasma volume.
75
What is the volume of distribution of a drug that is a very lipophillic molecule/drug moving easily out of the plasma compartment, compared to the plasma volume?
- The volume it is distributed in is way more than the plasma volume.
76
How can we estimate this Vd (volume of distribution)?
-By comparing the amount in the body (i.e. dose) to the plasma concentration (which is known)
77
Which areas of the body can't have the Vd predicted?
- CNS
- Liver
- Kidneys
78
What is Vd defined as?
- The volume into which a drug appears to be distributed with the concentration equal to that of plasma.
- It relates the plasma concentrations the total amount of drug in the body.
79
What is the equation for Vd?
V_d=(total amoount of drug in the body )/[plasma ] = (dose )/([plasma])
80
What are the units of Vd?
Volume/kg body weight
81
What are the units of Vd if there's no kilograms (of a person) in the question?
- We assume it is a 70 kg person. (. If L is by itself)
82
If the Plasma volume is normally distributed in 0.05 L/ kilogram then how many L of plasma will a 70 kg person have?
- Roughly 3.5 litres.
83
If the total exrtracellular volume is normally distributed in 0.2 L/ kilogram then how many L of plasma will a 70 kg person have?
- Roughly 14 litres.
84
If the total body water volume is normally distributed in 0.2 L/ kilogram then how many L of plasma will a 70 kg person have?
- Roughly 40 L.
85
If the plasma volume in a 70 kg person is approximately 3.5 l. Then where in the body compartments is this drug?
Retained in the vascular compartment (high MW, extensive protein binding)
86
If there is a drug that has a total extracellular volume of about 14 L in a 70 kg person then where in the body compartments is this drug distributed to?
- It is restricted to the extracellular fluid. (Low molecular weight but hydrophilic.
87
What is drug elimination defined as?
- The irreversible loss of drug from the body via metabolism or excretion.
88
In revising renal clearance what does the Glomerular filtration depend on?
- Depends on the concentration of free drug in the plasma and the GFR.
89
`. Improvising renal clearance what does the reabsorption depend on?
- It depends on the lipid solubility and the urine flow rate. If it's very lipid-soluble it will be absorbed.
90
What does the total amount eliminated by the kidneys equate to?
- Announce filtered + amount secreted- amount reabsorbed
91
Will there be a very low amount of a lipophillic drug eliminated in terms of renal clearance?
- YES
| - Low amount is eliminated
92
Will there be a high amount of renal clearance with the highly ionized drug?
- YES
93
Will there be any renal clearance for large biological molecules?
- No. They are too big to be filtered.
94
What occurs in phase 1 metabolism in liver?
- This is the main site of metabolism and the actions are catabolic.
- Redox reactions occur and in this we want to increase the polarity to make the drug more water soluble.
- These drugs are potentially saturable.
95
What occurs in phase 2 metabolism in only the liver?
- Anabolic reactions occur including conjugation.
| - The drug is combined with an endogenous molecule for example glycyl, acetyl, sulfate methyl group.
96
In phase 2 metabolism. Characteristics of the metabolite?
- It's pharmacologically inactive. This means that there is no potential for drug to drug interactions to occur.
- It is less lipid soluble so more water soluble.
- Excreted into URINE or BILE
97
Are the phase 1 and 2 reactions in level a sequential?
- NO
98
What occurs in an overdose of Panadol?
- Conjugation enzymes are saturated so most Panadol is being metabolised in phase 1
-then there is a toxic buildup of NAPQ1 this leads to hepatotoxicity.
-
99
What are the three types of phase I metabolising enzymes?
- Broad substrate specificity enzymes.
- Liver drug-metabolizing enzymes.
- Cytochrome p450 superfamily enzymes.
100
What do the broad substrate specificity enzymes do?
A particular enzyme catalyzes the metabolism of many different drugs.
- 1 drug may be metabolized by multiple enzymes (isozymes)
101
What is the general function of cytochrome p450 enzymes?
They catalyser oxidative metabolism of a range of xenobiotics.
102
What does cytochrome people 50 enzymes differ in?
- An amino acid sequence open for indices coding genes.
- Sensitivity to inhibitors.
- Substrate specificity
103
What is the enzyme reaction for Cytochrome P450 enzymes?
NEED: O2 (molecular), NADPH, NADPH-P450 reductase (flavoprotein)
FORMS: Hydroxylated product
104
How many CYP gene families are there?
- 74 but the three MAIN families are CYP1, CyP2 and CYP3
105
What are the two different types of drug interaction by the P450 enzymes?
Enzyme Inhibition
| Enzyme induction
106
What is involved in the enzyme inhibition drug interaction by P450 enzymes?
- Drugs metabolised by the same enzyme --> if they are administered together they will COMPETE for the metabolising enzyme
107
What is involved in the enzyme induction drug interaction by P450 enzymes?
- Some drugs can increase the activity/levels of enzymes that metabolise them --> e.g. alcohol, barbituates
108
What effect would CYP2D6 have on the effect of codeine?
- DECREASE the analgesic effect of codeine--> because most of the analgesic effect of codeine is due to it being converted to morphine --> less morphine = less response
109
Which glycoprotein plays an important role in enteropathic recycling?
- P glycoproteins
110
What occurs in enteropathic recycling?
- the drug can be conjugated in the intestine but there are microflora that will break down the conjugate so it can be reabsorbed into the blood and last for longer
111
What happens if you are taking a drug that has lots of enteropathic recycling and you have to go on antibiotics?
- Microflora are killed so no deconjugation and recycling --> so drug WILL NOT BE ACTIVE FOR LONG
112
What is a challenge with drug development from the body?
-Need to get the drug to the TARGET SITE at the APPROPRIATE [__] for the RIGHT AMOUNT OF TIME
113
What are the two different types of plasma drug concentration (protein bound) with drug administration?
- Constant infusion
| - Repeat dosing
114
What is the equation for concentration of drug plasma?
Cp= (Dose rate (DR))/(Clearance )
| Where clearance= CL (renal) + Cl (Liver) + Cl (other)
115
What does Clearance (Cl) mean?
- The units of plasma cleared of the drug per UNIT TIME (units= volume/time)
116
WHat does the Cl (renal) depend on?
- The [drug] in the urine
- Urine flow rate
- [free drug] in plasma
117
What does the CL (liver) depend on?
- Hepatic blood flow
- Intrinsic clearance
- [free drug ] in plasma
118
In repeat dosing, after how long are steady state concentrations reached?
- After three to five half lives
119
How can we quantify drug elimination?
- PLASMA HALF LIFE (t ½ )-->time taken for the amount of drug in the body to fall by half
120
What is the ½ life a determinant of?
- Dosing frequency
- Time to eliminate the drug (405 t ½ s)
- Time required to reach the steady state with REPEAT dosing (4-5 t ½ s)
121
Is t ½ CONSTANT for most drugs?
- YES
122
DOES THE DOSAGE INTERVAL AFFECT THE - Mean steady state concentration achieved?
- NO
123
DOES THE DOSAGE INTERVAL AFFECT THE - Rate at which the steady state concentration is achieved?
- NO (4x ½ lives)
124
What DOES the steady state level depend on?
- The dose of drug that we are giving
125
What is a maintenance dose?
- Dose you take to maintain steady state levels
126
What is the equation to determine the loading dose?
- LD=V_d×targⅇt[plasma] then follow up with the same maintenance dosing (clearance * target plasma concentration)
127
Because there is a time delay with a lot of drugs that are needed in emergency, how do we get around this delay to reach steady state in the body?
- Give a LOADING DOSE
- So GIVE a HIGH dose of the drug and then follow up with a maintenance dose
e. g. take 2 to start with then take 1 per day
