Drug Action Flashcards
(131 cards)
1
Q
What is the “therapeutic index” of a drug?
A
A comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes side effects and toxicity
2
Q
What are the 3 parts of the therapeutic index of a drug?
A
- Therapeutic window
- Side effects
- Toxicity
3
Q
What units is the range for the therapeutic window in the therapeutic index of a drug?
A
Nanomoles
4
Q
What units is the range for side effects in the therapeutic index of a drug?
A
Micromoles
5
Q
What units is the range for toxicity in the therapeutic index of a drug?
A
Micromoles
6
Q
What is the therapeutic window of a drug?
A
The range between average minimum effective dose and average maximum tolerated dose without side effects/toxicity
7
Q
What are the current recommendations regarding aspirin?
A
Anyone over 50 should take daily as a prophylactic dose to prevent blood clot formation
8
Q
What are the therapeutic uses of aspirin? (4)
A
- Anti inflammatory
- Antipyretic
- Analgesic
- Anti thrombotic (anti-platelet aggregation)
9
Q
What is the main toxic effect of aspirin?
A
GI bleeding by causing gastric ulceration
10
Q
What are the ways drugs can cause side effects?
A
1) Very selective but too widespread distribution of drug action in body on unwanted organs
2) Insufficiently selective - drug increases, other targets affected
3) Prolonged drug use= permanent/long term structure and function changes
4) Lack of knowledge of disease process
5) Patient variability
6) Drug interactions
11
Q
Which of the causes of drug side effects are aspirin’s side effects caused by and why?
A
- Narrow therapeutic window, very selective (only inhibits COX)
- But too widespread distribution of drug action - inhibits COX in too many organs
- Target site underlies many processes e.g in stomach
12
Q
What are the therapeutic effects of morphine?
A
Analgesic
13
Q
What are the toxic affects of morphine? (4)
A
- Death: respiratory depressant
- Addictive
- Constipation
- Vomiting
14
Q
Which of the causes of drug side effects are morphine’s side effects caused by?
A
Narrow therapeutic window, and not very selective - hitting other drug targets even in window
15
Q
How does morphine cause addiction?
A
Patient develops tolerance very quickly, more needed for same analgesic effect
16
Q
How does morphine cause constipation? (2)
A
- Stops peristalsis in gut
- Reduced motility
17
Q
How can morphine kill someone?
A
Depresses respiration by stopping diaphragm contracting
18
Q
What does antipyretic mean?
A
Fever reduction
19
Q
What adverse reaction was fenclofenac withdrawn for?
A
Epidermal necrosis
20
Q
What was the original use of fenclofenac?
A
NSAID
21
Q
What was the original use of indoprofen?
A
NSAID
22
Q
What adverse reaction was indoprofen withdrawn for?
A
GI toxicity
23
Q
What was the original use of triazolam?
A
Hypnotic anti-depressant
24
Q
What adverse reactions was triazolam withdrawn for? (2)
A
- Psychotic reactions
- Haemolytic anaemia
25
What was the original use of centoxin?
Antibiotic
26
What adverse reaction was centoxin withdrawn for?
Increased mortality
27
What was the original use of vioxx?
COX2 inhibitor
28
What adverse reaction was vioxx withdrawn for?
Increased mortality
29
What is pharmacovigilance?
Monitoring medical drug effects after licensed for use
30
What is the purpose of pharmacovigilance?
To identify and evaluate previously unreported adverse reactions
31
What system of pharmacovigilance exists in the UK?
- Yellow card system from MHRA (Medicines and Healthcare Products Regulatory Agency)
32
What does the Yellow card system from MHRA (Medicines and Healthcare Products Regulatory Agency) allow?
Patients to self report drug side effects and aid future drug use
33
What is a large component of drug expense?
Development cost
34
What are the molecular targets for drug action? (6)
- Ion channels
- Transporters
- Membrane receptors
- Intracellular enzymes
- Nucleic acids
- Miscellaneous
35
How is a receptor a molecular target for drug action? (2)
- Plasma membrane proteins embedded in membrane induce pharmalogical response in cell through binding of neurotransmitter/hormone
- Transduce signal from drug
36
How are enzymes molecular targets for drug action?
Activate/switch off action
37
How are transporters molecular targets for drug action?
Carry molecule across membrane (out to in or in to out)
38
How are ion channels targets for drug action?
Open/close
39
How are nucleic acids targets for drug action?
Affect gene transcription
40
Give examples of drugs that target nucleic acids
Steroids
41
What are miscellaneous targets for drug action?
- Lipids
| - Metal ions
42
Give an example of a metal ion target for drug action
Lithium used in bipolar disorder
43
Give 3 examples of drugs that inhibit enzymes
- Cyclooxygenase inhibitors
- HMG-coA Reductase Inhibitors
- Angiotensin converting enzyme (ACE) inhibitors
44
What are HMG CoA reductase inhibitors used to treat?
Hypercholesterolemia
45
How do HMG CoA reductase inhibitors treat hypercholesterolemia? (2)
- Inhibit HMG-coA Reductase in liver
| - Reduces cholesterol that moves around body with liver transport proteins
46
Give 2 examples of HMG-coA reductase inhibitors
- Atorvastatin (Lipitor)
| - Pravastatin (Pravachol)
47
What are angiotensin converting enzyme (ACE) inhibitors used to treat? (3)
- High blood pressure
- Heart failure
- Chronic renal insufficiency
48
Give 2 example of ACE inhibitors
- Captopril (Capoten)
| - Ramipril (Altace)
49
How do angiotensin converting enzyme (ACE) inhibitors work? (2)
- ACE normally produces angiotensin 2 from angiotensin 1 in vascular bed
- Vasoconstriction: blood pressure goes up
- Stop angiotensin 2 production, relieve blood pressure
50
Name the major enzyme drug target that NSAIDS work on?
Cyclooxygenases (COX) enzymes
51
What are the types of COX ? (3)
- Cox 1 (Constitutive)
- Cox 2 (Inducible)
- Cox 3 (recently discovered)
52
What is COX 1? (3)
- Constitutive
- A "housekeeping" enzyme in homeostasis
- Found in all cells
53
What are the main effects of COX 1? (4)
- Blood clotting (platelets)
- Temperature response to infection (brain)
- GI mucosa protection (stomach, upper and lower bowel)
- Renal blood blow protection
54
What is COX 2 inducible by? (2)
- Injury
| - Inflammation
55
What can COX 2 exacerbate?
- Pain
- Inflammation
- Fever
56
Where is COX 2 constitutive?
- Brain
| - Kidney
57
What does it mean for an enzyme to be constitutive? (2)
- Produced in constant amounts without regard to the physiological demand or the concentration of the substrate
- Continuously synthesised because role in maintaining cell processes/structure is indispensable
58
What is the difference between COX-1 and COX-2 in terms of product production?
COX-1 = low level but COX-2 high, can cause pathology
59
What does inhibition of COX 2 allow and what condition is this useful for?
Inflammation inhibition
| Arthiritus
60
What do COX enzymes act on to produce eicosanoids?
Arachidonic acid - fatty acid in the phospholipid bilayer
61
What is an eicosanoid?
Products derived from C20 fatty acids e.g arachidonic acid with between 3-5 double bonds
62
What two classes of eicosanoid are produced from arachidonic acid?
- Prostanoids
| - Leukotrienes
63
What is the class of eicosanoid produced by COX enzymes and what are its subtypes?
Prostanoids = further subdivided into:
- Prostaglandins
- Thromboxane
64
What class of eicosanoid do COX enzymes not produce?
Leukotrienes
65
How do prostanoids differ from leukotrienes?
Pathway of production = prostanoids from COX pathway, leukotrienes from 5-lipoxygenase pathway
66
What are leukotrienes? (3)
- Potent pro-inflammatory mediators
- Produced by mast cells and leukocytes (in asthma attack)
- Responsible for bronchoconstriction in asthma
67
How do COX enzymes produce prostanoids? (3)
- Hydrolyse arachidonic acid to PGG2 (cyclic endoperoxides)
- Reduced to PGH2
- Acted on by enzymes to produce prostanoids
68
What does the amount of prostaglandins to thromboxane produced by COX enzymes depend on?
Location in body
69
What does the amount of prostaglandins to thromboxane produced by COX enzymes depend on?
Location in body
70
What are the prostaglandins does COX help produce? (4)
- PGE2
- PGF 2 alpha
- PGD2
- PGI2 (prostacyclin)
71
Where is PGE2 found?
Inflammatory periphery sites
72
Where is PGF2 alpha found and what can it cause there?
In brain - temperature response to infection (fever)
73
Where is thromboxane made/found?
Blood
74
What does thromboxane (Tx) A2 do? (2)
- Vasoconstrictor: reduces blood loss through leaky vessel wall
- Stimulates platelets to aggregate: form blood clot
75
What does PGI2 (prostacyclin) do? (2)
- Acts as vasodilator: encourages blood flow
| - Inhibits platelet aggregation = inhibits clot formation
76
What is the relationship between the effects of thromboxane and prostacyclin?
Opposing - maintains cardiovascular homeostasis
77
What do NSAIDS inhibit?
Cox enzymes
78
Inhibition of which prostagladin production causes inhibition of blood clot formation?
Prostacyclin
79
Why do NSAIDS inhibiting cox enzymes cause inhibition of blood clot formation even though they inhibit both prostacyclin and thromboxane formation? (3)
- At first NSAID has little to no effect as inhibiting both prostacyclin and thromboxane
- Prostacyclin concentrations recover much faster than thromboxane levels
- Effect of prostacyclin predominates as regenerated
80
What does NSAID stand for?
Non steroidal anti inflammatory drug
81
Name 2 main example of NSAIDS
- Aspirin
| - Ibuprofen
82
What effect does aspirin have on COX enzymes?
Irreversible covalent inactivation of COX-1 and COX-2 through acetylation
83
What makes aspirin a unique NSAID? (2)
- Its effects last until new enzyme is synthesised
| - New platelets/enzymes need to be made for drug sensitivity again/before effects of drug wears off
84
What effect do ibroprofen and paracetamol have on COX enzymes?
Competitive reversible inhibitors of COX-1 and COX-2
85
What do ibroprofen and paracetamol reduce? (3)
- Pain
- Inflammation
- Temperature
86
How does aspirin cause gastric ulceration? (4)
- COX enzymes protect GI mucosa e.g by aiding mucus secretion from cells
- Protective film preventing stomach muscle exposed to acid
- COX inhibition = no defence when acid breaks down stomach wall
- Lesions/gastric ulceration
87
What are anti-metabolites? What 3 ways do they affect specific cell metabolites?
```
A substance that:
- Competes with
- Replaces
- Inhibits
A specific metabolite of a cell and so interferes with the cell’s normal metabolic functioning
```
88
How do anti-metabolites interfere with DNA synthesis metabolic pathways?
- Act as substitute for metabolite (endogenous compound)
- Attaches to enzyme (drug target)
- Interferes with metabolism of enzyme
89
What 2 ways do anti-metabolites interfere with DNA synthesis enzyme metabolism?
- Enzyme inhibition (usually competitive)
| - Converted into alternative substrate by enzyme and "lethal synthesis"
90
How can anti-metabolites act as substitutes for metabolites in DNA synthesis metabolite pathways? (4)
- Only have a small change in structure of normal metabolite
- Mimics endogenous compound so taken up by cell but with added agent
- Similar enough to be capable of attaching to enzyme/be incorporated into DNA
- But different enough to interfere with normal function e.g division
91
How do anti-metabolites act as a type of cancer drug?
Block/subvert DNA synthesis metabolic pathways by interfering with enzymes necessary for them
92
Give 3 examples of anti-metabolites (3)
- Sulphanilamide
- Methotrexate
- Trimethoprim
93
What type of drug is sulphanilamide?
A bacteriostatic antibiotic
94
How does sulphanilamide act as an antimetabolite antibiotic?
- Structural analogues of PABA
- Metabolised by dihydropteroate synthetase instead, folate not made
- Pathway to DNA synthesis stopped
95
How do bacteria make folate?
From PABA via action of dihydropteroate synthetase
96
What does PABA stand for?
Para-aminobenzoic acid
97
What is selective toxicity?
Drug ability to target sites specific to microorganism responsible for infection without impact on host by exploiting difference between human and microbe cells
98
What 2 ways can drugs be selectively toxic?
- Targeting site unique to microorganism
| - Targeting site more essential to micoorganism survival than host
99
How does the action of sulfonamide the principle of selective toxicity? (4)
- Folate in humans = from food
- Diffuses/transported into human cells
- In bacteria=cannot cross cell wall by diffusion/active transport, must be intracelluarly synthesised from PABA
- Disrupting this process=bad
100
Describe the pathway from folate to DNA (3)
1) Folate reduced to tetrahydrofolate
2) Tetrahydrofolate to thymidilate
3) Thymidilate important in DNA synthesis
101
Which enzyme catalyses the formation of tetrahydrofolate from folate?
Dihydrofolate reductase
102
What is one of the most widely used antimetabolites in cancer chemotherapy?
-Methotrexate
103
How does methotrexate work as an anti cancer antimetabolite?
- Competitively inhibits dihydrofolate reducase and stops tetrahydrofolate synthesis
- Stops DNA synthesis and so cancer proliferation
104
What is trimethoprim?
Antibiotic used mainly in bladder infection treatment
105
How does trimethoprim work as an antibiotic? (3)
- Binds to dihydrofolate reductase
- Inhibits folate reduction to tetrahydrofolate
- Inhibits bacterial DNA synthesis
106
How is trimethoprim selectively toxic?
Its affinity for bacterial dihydrofolate reductase is many 1000x greater than affinity for human dihydrofolate reductase
107
How are ion channels molecular targets for drug action? (2)
- Drugs enter channel in open state and bind to extracellular pore opening recognition site to block it
- Drug diffuse across cell membrane and bind to intracellullar recognition site (on inside of channel) when channel inactivated, and prolong its inactivation
108
What are the types of agents that bind to ion channels extracellularly?
- Na+ channel blockers
| - Ca2+ channel blockers
109
Give an example extracellular Na+ channel blockers
TTX (tetrodotoxin) - neurotoxin found in puffer fish
110
How does TTX bind to the Na+ ion channel? (3)
- Interaction of positively charged guanidino group on TTX
- With peptide COO- side group on glutamate residues on mouth of channel
- TTX much larger than Na+ ion - binding site extremely tight
111
How does TTX binding to the Na+ ion channel cause toxic effects?
- Prevents depolarisation in nerve cells
- Prevents action potential propagation in nerve cells
- Blocks conduction of nerve impulses
112
What is LD50?
Dose that will kill 50% population
113
What is the LD50 of TTX in a man?
5μg (microgram)/kg
114
What is the lethal dose of TTX in a man?
1-2mg
115
What are drugs that are extracellular Ca2+ channel blockers used to treat? (2)
- Angina
| - Hypertension
116
Give an example of the types of drugs that are intracellular Na+ channel blockers
Local anaesthetics e.g lidocaine
117
What are transporters?
Proteins embedded in plasma membrane allowing membrane-impermeable molecules to enter cells
118
How are transporters used in nerve terminals?
Every neurotransmitter has a specific pump in region to move transmitter away from synaptic cleft back into nerve terminal/surrounding glial cells
119
Transporters for what substances are targeted by drugs? (4)
- Amino acids
- Glucose
- Ions
- Neurotransmitters
120
Give 3 examples of drugs that target transporters
- Cocaine
| - Floxetine (Prozac)
121
How does cocaine target transporters? (2)
- Non selective reuptake inhibitor of neuroadrenaline transporter
- So uptake 1 = blocked
122
What is uptake 1 of neuroadrenaline?
Neuroadrenaline uptake at presynaptic nerve terminal to remove it from synapse
123
How does floxetine (Prozac) target transporters? (2)
- Selective serotonin reuptake inhibitor (SSRI)
| - Stops serotonin transporter uptaking serotonin back into nerve terminal from synaptic cleft
124
What acid is aspirin?
Acetylsalicylic acid
125
Describe the metabolism of aspirin
- Rapidly hydrolysed = salicylic acid
| - Partial glycine conjugation = salicyluric acid
126
What is the rate of aspirin metabolism in the body like?
Rapid
127
Why does aspirin have a more prolonged action in the body even though it is rapidly metabolised? (2)
- Some metabolites = biologically active
| - Irreversibly inactivates COX, takes time for new enzymes to be made
128
What is the action of aspirin in the body like?
Prolonged
129
Give the structure of aspirin
(see notes)
130
Give the structure of salicyclic acid
(see notes)
131
Give the structure of salicyluric acid
(see notes)
