drug metabolism Flashcards
1
Q
in order for a drug to work what needs to be achieved
A
an adequate concentration in tissues
2
Q
what name is given to administration via the skin
A
topical administration
3
Q
what name is given to administration into the body
A
systemic administration
4
Q
what are the 2 types of systemic administration and what route do they take
A
- enteral administration - GI tract route
- parenteral administration - non GI tract route
5
Q
give the 3 forms of enteral administration
A
- oral
- rectal
- sublingual
6
Q
give the 5 forms of parenteral administration
A
- injection
- bolus injection
- I.V.
- inhalation
- cutaneous
7
Q
how does a drug reach the target organ
A
it must cross the cell membrane from GI tract to blood plasma
8
Q
what are the 3 sites of absorption
A
- stomach
- small intestine
- large intestine (colon)
9
Q
why is the small intestine the the main site of absorption
A
- large surface area due to microvilli
- high blood flow
- bile helps solubilise some drugs
10
Q
what is the mechanism of diffusion for non-polar chemicals (transcellular)
A
passive diffusion
11
Q
what is the mechanism of diffusion for polar chemicals (transcellular)
A
facillitated diffusion
12
Q
what is the mechanism of diffusion for polar chemicals with no concentration gradient (transcellular)
A
active transport
13
Q
what type of drugs enter the blood capillary via paracellular absorption
A
non-lipophilic drugs
14
Q
how does food interat with the effect of tetracycline
A
it can bind to calcium in milk, forming an insoluble complex that cannot be absorbed by the GI tract therefore, reducing the drugs bioavailability making it less effective
15
Q
what do anticholinergics do
A
slows down stomach emptying time, delyaing the drugs passage to the intestine
16
Q
what do laxatives do?
A
increase gut motility, reducing the contact time of the drug with the absorption site
17
Q
what do cardiovascular drugs do?
A
reduce blood flow to GI tract, decreasing the rate and efficiency of absorption
18
Q
what happens when a drug interacts with an antacid
A
drugs may bind to antacids reducing their absorption
19
Q
give 2 ion exchange resins
A
- cholestyramine - used to lower cholesterol
- charcoalw
20
Q
what effect does cholestyramine have on other drugs
A
it can absorb other drugs prevent their effect
21
Q
what is charcoal used for
A
used in poinsoning cases to absorb toxins and prevent their absorption
22
Q
give 5 factors that affect passage of drug through the cell membrane
A
- water soluility
- lipid solubility
- degree of ionisation
- active transport
- molecular weight
23
Q
what does the partition coefficient measure
A
distribution of unionised molecules
24
Q
what does it mean is Log p>0
A
- drug is more lipophilic
- rapidly absorbed via the cell membrane (transcellular route)
25
what does it mean is Log p<0
- drug is more hydrophilic
- slowly absorbed between cells (paracellular route)
26
what does it mean if pH>pKa in acidic conditions in a weak acidic drug
more unionised so better absorption
27
what does it mean if pH>pKa in basic conditions in a weak acidic drug
more ionised so less absorption
28
what does it mean if pH>pKa in basic conditions in a weak basic drug
more unionised so well absorbed
29
what are the 3 main proteins that drugs bind to
1. albumin
2. b-globulin
3. acid glycoprotein
30
what drugs does albumin bind to
- acidic drugs
- most abundant plasma region
31
what drugs does b-globulin bind to
- some basic drugs
- e.g. hormones/steroids
32
what drugs does acid glycoprotein bind to
- binds to some basic drugs
- levels increase during inflammation
33
what are the effects of proteins binding to drugs
1. reduced excretion
2. reduced pharmacological effect
3. potential displacement of other drugs already bound
34
what does the amount drug bound depend on
1. drug concentration
2. affinity for the protein
3. protein concentration
4. competition
35
what administration route is best for a high affinity drug and why
I.V. injection - single dose, drug can diffuse out of the plasma
36
define drug metabolsim
the enzyme catalysed conversion of a drug into a chemically distinct product (metabolite)
37
why do drug need to be metabolised to a metabolite
most drugs are non-polar (lipophilic) and require conversion to a polar chemical (hydrophilic for excretion
38
where is the main site of metabolism
liver
39
how many phases of metabolism are there and what do they do
1. phase i - functionalisation, small chemical modifcations e.g. oxidation
2. phase ii - conjugation, addition of large charged groups to increase water solubility and excretion
40
what is the consequence of phase i reactions
- small decrease in lipophilicity
- slight increase in excretion
41
what is the consequence of phase ii reactions
- large decrease in lipophilicity
- increase in excretion
42
give 4 reaction types in phase i
1. oxidation by cytochrome P450
2. non-P450 oxidation
3. reduction
4. hyrdolysis
43
where is CYP450 found
- smooth endoplasmic recticulum of liver cells
44
what does CYP450 require
- molecular oxygen and NADPH as co-factors
- cytochrome P450 reductase
45
give the 12 different oxidation reactions of CYP450
1. aliphatic hydroxylation
2. aromatic hydroxylation
3. epoxidation
4. N-dealkylation
5. O-dealkylation
6. S-dealkylation
7. oxidative deamination
8. N-oxidation
9. S-oxidation
10. alcohol oxidation
11. dehydrogenation
12. dehalogenation
46
what is the prosthetic group in all P450s
ferriprotoporphyrin IX
47
where does oxidation occur
in the heme group
48
explain the P450 cycle
1. drugs bind to the active site
2. molecular oxygen (O2) interacts with the iron the heme group
3. one oxygen atom is used to form water and the other is incorporated into the drug to form the oxidised product
4. drug leaves the active site
49
give an example of a molecule that goes through aliphatic hydroxylation
- tolbutamide
- hypoglycaemic agent used to treat diabetes
50
give an example of a molecule that goes through aromatic hydroxylation
- salicylic acid
- treatment for psoriasis
51
give an example of a molecule that goes through epoyxidation
- carbamazepine
- anticonvulsant used to treat epilepsy
52
give an example of a molecule that goes through O-dealkylation
- phenacetin
- analgesic related to aldehyde paracetamol
53
give an example of a molecule that goes through N-dealkylation
diazepam, treatment for anxiety
54
give an example of a molecule that goes through deamination
- amphetamine
- indirectly acting sympathomimetic
55
give an example of a molecule that goes through N-oxidation
clozapine
antipsychotic used for schizophrenia
56
how is alcohol oxidation mediated and where does it occur
- alcohol dehydrogenase
- primary and secondary alcohols
57
what mediates N-, S-oxidation reactions
flavin monooxygenase
58
where is FMO found and what is its necessary co factor
- in liver microsomes smooth E.R
- NADPH
59
what are the 2 types of monoamine oxidase
MAO-A and MAO-B
60
where is MAO-A found
- found in the liver
- pulmonary vascular endothelial
- GI tract
- placenta
61
where is MAO-B found
- blood platlets
62
what is the role of MAO
- inactivates endogenous neurotramitters
63
give 2 inhibitors of MAO
- caffeine
- antidepressants
64
give an example of a molecule that goes through metabolisation via MAO
- sumatriptan
- treatment in headaches
65
what does aldehyde oxidation
aldehydes into carboxylic acid
66
give an example of a molecule that goes through xanthine oxidation
6-mercaptopurine
anti-tumour drug
67
give an example of a molecule that goes through azo reduction
- prontosil (inactive) to sulphanilamide (active)
68
give an example of a molecule that goes through nitro reduction
clonazepam
used to prevent seizures
69
give an example of a molecule that goes through sulfoxide reduction
sulindac
non-steroidal anti-inflammatory drug
70
give an example of a molecule that goes through quinone and epoxide reduction
vitamin K
71
give an example of a molecule that goes through amine hydrolysis
procainamide
anti-arrythmic
72
where does hydrolysis occur
plasma tissue
73
give an example of a molecule that goes through lactone hydrolysis
activation of lavastatin
choleterol lowering drug
73
give an example of a molecule that goes through ester hydrolyis
activation of morphine
74
give an example of a molecule that goes through alkaline phosphate hydrolysis
activation of phenytoin - antiepileptic
75
what is a phase ii reaction
reaction catalysed by a transferase enzyme that transfer a polar group from a donor to the phase i metabolite
76
what are the 2 exceptions in phase ii reactions
acetylation and methylation in which polar groups are masked
77
where does glucuronidation occur
in the liver
78
what is he donor molecule for glucuronidation and what does it do
uridine diphosphate glucuronic acid (UDPGA) - transfers the glucuronyl group to nucleophillic O, N or S
78
what is glucuronidation catalysed by
UDP-glucuronoyltransferase
78
give an example of a molecule that goes through O-glucuronidation
salicylic acid
79
give an example of a molecule that goes through N-glucronidation
sulphanilamide
79
what enzyme catalyses sulphation
sulphaeotransferase
79
what is the donor molecule for sulphation
3'phosphoadenosine-5'phosphosulfate (PAPS)
80
sulphation and glucuronidation compete for some pathways, who predominates
sulphation predominates at low substrate concentrations, glucuronidation predominates at higher concentration
81
give an example of a molecule that goes through sulphation
paracetamol
82
where does glycine conjugation occur
in the mitochondria
83
which enzyme catalyses glycine conjugation
N-acyl transferase
84
give an example of a molecule that goes through glycine conjugation
salicylic acid
85
what enzyme catalyses glutathione conjugation
glutathione S-transferase
86
give an example of a molecule that goes through glutathione conjugation
paracetamol
87
what enzyme catalysis acetylation
N-acetyl-tranferase (NAT)
88
what is the donor for acetylation
acetylene coA
89
what is the risk with acetylation
- decreases water solubility
- no increase in excretion
- can precipitate out into kidney tubules leading to renal toxicity
90
give an example of a molecule that goes through acetylation
sulfanilimide
91
what is the enzyme that catalyses methylation
methyltranferase
92
what is the donor molecule for methylation
S-adenosyl methionine (SAM)
93
what enzyme catalyses O-methylation
catechol-O-methyltransferase (COMT)
94
what enzyme catalyses S-methylation
thiopurine-S-methyltransferase (TPMT)
95
give an example of a molecule that goes through S-mthylation
6-mercaptopurine
96
give an example of a molecule that goes through O-methylation
L-DOPA - parkinsons disease treatment
97
what is the phase ii metabolism reactions for functional group OH
- glucuronidation
- sulphation
- methylation
98
what is the phase ii metabolism reactions for functional group COOH
- glucuronidation
- glycine conjugation
99
what is the phase ii metabolism reactions for functional group NH2
- acetylation
- glucuronidation
-sulpahation
100
give 5 causes of variabilty in drug metabolsim
1. drug-drug interaction
2. drug-diet interaction
3. genetic variation
4. underlying disease
5. environment/lifestyle
101
what is enzyme inhibition?
when a drug blocks the active site of a metabolising enzyme, reducing its ability to metabolise other drugs
102
what is a non-competitive inhibitor
the inhibitor binds to a site other than the active site - altering enzyme activity
103
what is a competitive inhibitor
drugs that compete for the same binding site on an enzyme
104
what is irreversicle inhibition
inhibitor (drug) forms a permamnent bond with the enzyme deactivating it
105
what is enzyme induction
when a drug stimulates the production of enzymes, this leads to increased metabolsim of the drug reducing efficacy
106
why is it bad to eat grapefruit when you are on certain medication?
it contains a compound called furanocoumarin which acts as an inhibitor of CYP3A4 (enzyme responsible for drug metabolism
107
what is irinotecan
a pro-drug used in colorectal cancer treatment
108
what is the phase i metabolism of irrontecan
conversion of irinotecan to its active SN-38 variant via carboxylesterase
109
what is the phase ii metabolism of irrontecan
glucuronidation of SN-38 to its inactive form by UGT1A1 - build up of active SN-38 can be toxic
110
give 4 examples of toxic phase i metabolites
1. epoxides
2. hydroxyl amines
3. quinoneimines
4. free radicals
111
how is paracetamol overdoes toxic
normally paracetamol can be metabolised by either glucuronidation or sulfation, in overdose situations these pathways become saturated leading to increased production of NAPQI (highly toxic) which binds to the liver causing hepatitis
112
explain isoniazid hepatoxcitiy
the phase ii metabolism is acetylation - converts isoniazid into inactive metabolites
- NAT responsible for metabolism has variations in its genes leading to different acetylation rates - slow acetylation means active isoniazid persists longer in the body
113
what is a type A ADR
- on target
- exaggeration o drugs normal pharmacological effect
- dose deendent
114
what is a type B ADR
- off-target
- novel unexpected responses
- may only be discovered after a drug is available for general use
115
what is a type C ADR
- continuing
- presists for long time after withdrawal
116
what is a type D ADR
- delayed
- become apparent sometime after the use of the medicine
117
what is a type E ADR
- end of use
- associated with withdrawal of medicine
118
