Drug Disposition PED2001 Flashcards
1
Q
What are the 2 types of drug movement around the body
A
Bulk flow transfer in the blood; chemical nature if drug has no effect
Diffusional transfer; differs between drugs with different chemical properties
2
Q
What are the main factors affecting GI absorption
A
GI motility
Splanchnic blood flow
Particle size and formulation
Physicochemical factors
3
Q
Describe drug absorption from the intestines
A
By passive transfer
Rate determined by the ionisation and lipid solubility of drug molecules
4
Q
How does a migraine affect gastrointestinal motility
A
Causes gastric stasis and decreases drug absorption
5
Q
Describe systemic availability
A
The amount of drug that reaches the systemic circulation intact and the rate at which it happens
6
Q
What is a problem that occurs when using topically applied drugs
A
Variability in drug administration through skin = lack of precision regarding the real dose absorbed
7
Q
Why are new topical dosage forms important
A
Design emphasis on systemic input
8
Q
What is the energy source for a transdermal drugs
A
The difference in the drugs chemical potential between the reservoir and the systems exterior
9
Q
What ensures a consistent rather of delivery with transdermal drugs
A
Presence of excess drug in reservoir
10
Q
Why would a transdermal drug delivery be used
A
Patient compliance issues
Gastric irritation w oral therapy
Side effects with respective conventional dosage
11
Q
What are the factors that need to me considered when formulating oral drugs
A
Rate of disintegration on the tablet
The rate of dissolution on the drug particles in the intestinal fluid
12
Q
What physical factored affect pharmaceutical availability of oral drugs
A
Tablet compression and excipients
Other tablet excipients
The form of the drug
Particle size
13
Q
What does bioinequivalent mean
A
When 2 formulations of a drug with a significant difference in bioavailability
14
Q
What does therapeutic equivalence mean
A
When similar drugs have comparable efficacy and safety
15
Q
What determines the route of administration
A
Therapeutic objective
Properties of the drug
16
Q
How can the effect of injected local anaesthetic be prolonged
A
The formation contains adrenaline
Causes vasoconstriction = preventing the drug to be carried away by circulation
17
Q
What forms of drug will avoid 1st pass metabolism
A
Sunlingual, buccal, rectal and transdermal formulations
18
Q
How can you reduce the risk of gastric erosions
A
Delayed-release and slow release formulations
= less frequent administrations compared to conventional formulations
19
Q
What is the minimum criteria to be met for combination products in oral therapy
A
- The frequency of administration of the 2 drugs is the same
- Fixed doses in the product are therapeutically and optimally effective
20
Q
What is the potentials vantage of combination formulations
A
Improved compliance
Ease of administration
Synergistic or additive effects
Decreased adverse effects
21
Q
Give 3 examples of special drug delivery systems
A
Biologically erodable microspheres loaded w drugs
Pro-drugs
Antibody-drug conjugates
22
Q
Describe drug distribution
A
Process by which a drug reversible leaves the blood stream and enters the interstitium
23
Q
What factors does drug distribution rely on
A
Blood flow
Capillary permeability
The degree of drug binding to plasma and proteins
The relative hydrophobicity of the drug
24
Q
Why does blood flow to tissue capillaries vary
A
Consequence of unequal cardiac output to various organs
25
What determines capillary permeability
Capillary structure
Drying structure
26
What allows drugs to exchange freely between blood and liver interstitium
Large fenestrations
27
How do drugs pass the blood-brain barrier
Drugs must pass through the endothelial cells of the capillaries of CNS
Or actively transported
28
What drugs can and can’t penetrate the CNS
Can: lipid soluble
Can’t: ionised or polar drugs
29
How do hydrophilic and hydrophobic drugs cross membrane
Hydrophobic: readily across the membrane
Hydrophilic: through slit junctions
30
What is a major factor in the distribution of hydrophobic drugs
Blood flow to the area
31
What does it mean if a drug is trapped in the plasma compartment
Drug has a large MW or binds extensively to plasma proteins
Too large to move out through slit junctions of capillaries
32
What does it mean if the drug is trapped n the extracellular fluid
Drug has a low MW but if hydrophobic
Can move into interstitial fluid but unable to cross lipid membrane and enter intracellular fluid
33
What is the Vd if the drug is in the plasma compartment
Vd = plasma water
34
What is the Vd of a drug in the extracellular fluid
Vd = plasma water + extracellular fluid volume
35
What does it mean if the drug is trapped in total body water
The drug has a low MW and is hydrophobic
It can move through slit junctions and cross cell membranes into intracellular fluid
36
What is the Vd for a drug in total body water
Vd = plasma water + extracellular + intracellular volumes
37
What does it mean if a drug is bound
They’re pharmacologically inactive and are unable to reach target site to elicit a biological response
38
Describe the binding capacity of albumin
Has high capacity and low capacity
39
What types of drugs does albumin have the strongest affinity for
Anionic and hydrophobic drugs
40
What are the 2 classes of drugs w high affinity for albumin
Class I and Class II
41
What does it mean to be a class I drug
Dose of drug < binding capacity of albumin
Binding sites in excess of the available drug = fraction of frug bound is high
42
What does it mean to be a class II drugs
Dose of drug > number of albumin binding sites
= relatively high proportion of drug exists in free state
43
What is the clinical importance of drug displacement
The administration of class II drugs too displace class i drugs to increase their free state
44
What happens if the Vd is large
Then change in free drug conc is insignificant
45
What happens if the Vd is small
The newly displaces drug does not move into the tissue as much
= Increase in plasma drug conc more profound
46
What is enterohepatic circulation
When endogenous compounds are conjugated and excreted into the GI tract
Then they’re deconjugated and reabsorbed into systemic circulation
47
What is Phase I metabolism
A functional group is introduced normally producing a more polar and excretable molecule
48
What CYP450 is responsible for metabolising 50% of drugs
CYP3A4 - found most abundantly in liver and gut
49
What is phase II metabolism
Conjugate reactions which detoxify compounds and prepare them for excretion
50
When does a compound skip phase I metabolism and got straight to phase II
When there are subtle functional groups for conjugation already present on the molecule
51
Give 3 examples of phase II enzymes
UDP-glucuronosyltransferases UGTs
Sulfotransferases SULTs
Glutathione-S-transferases GSTs
N-acetyltransferases NATs
Methyltransferases
52
How can the loss in first pass metabolism be compensated for using oral drugs
Give a much higher dose
53
How does first pass metabolism affect an oral drugs bioavailability
Reduces it
54
What factors can affect first pass metabolism
Genetics variations between individuals in liver and GI
Variations between GI and liver blood flow
Gut microbiota
55
What is a prodrug
A drug that is administered as an inactive form and requires metabolism to become active
56
What are the benefits of pro drugs
Improves PK and decreases toxicity
57
Give an example of a prodrug
Codeine -> morphine
Metabolised by CYP2D6 demethylation
58
What are the main families of CYP450s that metabolise xenobiotics
1,2 and 3
59
Describe the prosthetic group of CYP450s
Haem containing Fe (III)
6th position os water in the absence of substrate binding
60
What is the cytochrome P450 reaction
DH + NADPH +O2 —> DOH + NADP + H2O
61
What are the 3 necessary components of a P450 reaction
CYP450 enzyme
NADPH-CYP450 reductase
Phosphatidylcholine
62
What is the purpose of NADPH in the CYP450 reaction
Supplies 2 protons and 2 electrons in electron transfer process
63
Describe the function of NADPH-CYP450 reductase
Accessory enzyme that interacts w CYP450 enzyme and transfer e- from NAPDH
64
What prosthetic group do NADPH-CYP450 reductases contain
Flavin adenine dinucleotide (FAD)
Flavin mononucleotide (FMN)
65
Describe the structure of CYP450s and the reductase on the enzyme
CYP450s membrane bound and the reductase fits between 2 monomers and is shared
66
What does an induction of CYP450s represent
Increase in the amount of mRNA and protein
67
What is the effect of CYP450 mediated reactions
Inactivate many drugs and increase their rate of reaction
68
How a CYP450 isoforms produced
Produced from different genes
69
Why are P450s important in drug metabolism
70-80% of all drugs subject to metabolism are P450 substrates
Almost 90% are metabolised by CYP3A4/2D6 and 2C9
70
What are the 3 ways to identify specific P450 isoforms responsible for metabolism of a drug
Correlation analysis using human liver microsome bank
Inhibition studies
Studies using purified or expressed enzymes
71
Describe CYP2D6
Substrates typically have a basic nitrogen and a hydrophobic region
Most substrates are either cardiovascular agents, antipsychotics or antidepressant
Common reaction: Hydroxylation
72
Name a substrate of CYP2D6
Antiarrhythmics
B-blockers
Antihypertensives
Neuroleptics
MAO inhibitors
Analgesics
73
Describe CYP2C9
Substrates tend to have areas of strong H-bonds
Target manny different fruity ones but especially NSAIDs
Subject to genetic SNPs
Induced by barbiturates and rifampicin
74
Name a substrate of CYP2C9
Ibuprofen
Naproxen
Warfarin
THC
75
Describe CYP3A4
Highly induced by glucocorticoids and rifampicin
Has considerable structural diversity in substrate
Binding site can accommodate large molecules -> hydrophobic interactions
Common reactions: N-dealkylation and aromatic hydroxylation
76
Name a CYP3A4 substrate
Lidocaine
Tamoxifen
Cocaine
Verapamil
77
What are the big 3 P450 isoforms
CYP3A4
CYP3C9
CYP2D6
78
What are the key substrates of CYP2C19
Omeprazole and clopidogrel
79
What factors determine metabolism by specific P450 isoforms
Topography of active site of enzyme
Degree of steric hindrance of access of Fe-O complex to possible metabolism site
Ease of e- of H+ abstraction from various carbons
80
Where is the CYP1A1 found and what is its role
Role: activation of polycyclic aromatic hydrocarbons
Found: mainly outside of the liver
81
What does CYP2E1 contribute too
Ethanol metabolism
82
What role does CYP1A2 have
Activate arylamine compunds to carcinogens
Role in caffeine metabolism
83
What is involved in non-P450 phase I metabolism oxidation reactions
Flavin-linked monooxygenases
Prostaglandin H-synthase-dependent co-oxidation
Amine oxidases
Oxidoreductases
84
What is involved in non-P450 phase I metabolism hydrolysis reactions
Esterases
Epoxide hydrolases
85
Describe FMOs
Smaller than P450s but have similarities
Require NADPH and O2
Overlap in substrate specificity w P450 -> yield distinct metabolites
86
What are the properties of FMO
Oxidise nucleophilic N, P or S centres
Contain FAD as a prosthetic group
All isoforms except FMO5 are non-inducible
87
What enzymes have peroxidase activity
Prostaglandin H-synthase
Myeloperoxidase
Lactoperoxidase
88
Describe PGHSs
Involve co-oxidation of:
arachidonic acid -> prostaglandin
xenobiotic -> oxidised metabolite
Has cyclooxygenase activity and peroxidase activity and co-oxidation of xenobiotic
89
What is the mechanism for COX activity in PGHSs
Arachidonic acid -> PGG2
Oxidation reaction
90
What is the mechanism for peroxidase activity in PGHSs
PGG2 -> PGH2
Reduction reaction
91
Describe prostaglandin H-synthase
O atom transferred not derived directly from O2
NADPH is not a cofactor
92
Describe MAOs
Mitochondrial enzyme which oxidises via FAD-dependent pathway
Main role: metabolism of neurotransmitters
93
What are the 2 forms of MAO
MAO A
MAO B
Have different substrate specificities
94
what is the reaction mechanism of MAO
RCH2NH2 + FAD -> RCH=NH + FADH2
RCH+NH +H20 -> RCHO + NH3
FADH2 + O2 -> FAD + H2O2
95
Describe oxidoreductases
Oxidising: NAD(P) dependent
Reducing: NAD(P)H dependent
Mainly cytosolic enzymes
96
Describe the reaction for alcohol and aldehyde dehydrogenase
Alcohol -> aldehyde
RCH02 + NAD+ -> RCHO +NADH +H+
Aldehyde -> carboxylic acid
RCHO + NAD+ -> RCOOH + NADH + H+
97
Describe the normal method of ethanol detoxification
Via alcohol dehydrogenase
NAD+ required as a co factor
Converts alcohols -> carbonyls
CYP2E! Uses excess ethanol as a substrate
98
Describe the role of carbonyl reductase
Catalyses the reduction of carbonyl compounds in the general form:
R-CHOH-R’ + NADPH <=> R-CO-R’ + NADPH + H+
99
Describe quinone oxidoreductase I
2 e- reductase that reduces quinones -> hydroquinones
No semiquinone intermediate = no singlet oxygen
100
Describe carboxylesterases
Catalyse the hydrolysis of a wide range of esters, thioesters and amides
Have 2 forms : CE1 and CE2
101
What is the preferred substrate of CE1
Small alcohol group, large acyl group
102
What is the preferred substrate of CE2
Large alcohol group and a small acyl group
103
Describe butyrylcholinesterase
Major contributor to hydrolysis of aspirin to salicylate in plasma
ChE or BChE
104
Describe hCE1 reactions
Cocaine -> benzoylecgonine
Heroin -> 6-acetyl morphine -> morphine
105
Describe epoxide hydrolases
Cleaves epoxides in the presence of water
2 forms: microsomal and cytosolic -> different substrate specificities
106
Describe paroxonase 1
Enzyme w arylestrase, lactonase and paroxonase activities
Role: degradation of oxidises lipids and protects LDL and HDL from lipid peroxidation
107
What happens in phase II metabolism
Conjugation reactions
Compounds have greater MW and are more water soluble
Less able to pass through cell membranes = easier to excrete
108
Describe glucuronidation
Carried out by UDP-GTs
UDP-glucuronic acid required as co-factor
109
What are the effects of glucuronidation
Promotes excretion and results in loss of biological activity Biological activity present in some glucuronides
Some glucuronides are reactive and bind irreversible to proteins
110
Describe the family of UGTs
2 distinct families: UGT1 and UGT2
Have different isoforms
111
Describe how UGT1 and UGT2 isoforms are produced
UGT1: products of the same gene
UGT2: products of separate genes
112
How are glucuronides conjugates eliminated
MW> 400: excreted in the bile
MW< 400: excreted in urine
113
Describe enterohepatic recirculation
Beta-glucuonidase produced by the micro flora removes the glucorinde portion of the metabolite
Original drug reformed and re-enters liver via portal vein
114
How does enterohepatic recirculation effect pharmacology of drug
Potentiates the activity = increases t1/2
115
Describe the glucuronidation reaction
UDP-glucuronic acid reacts w -OH, -COOH, -NH2 and -SH
116
How can UDP-GT be induced
Induction is modest compared to CYPs
Family 1: phenobarbitone and PAHs - not UDP-GT specific
Specific inducers operate through the antioxidant response element (ARE)
117
Describe sulfotransferases
Catalyse the transfer reaction of sulphate group from PAPS to an acceptor group
118
Why is sulfation useful
Sulfate esters are anionic = more soluble
Usually pharmacologically inactive
Lead tor edged availability of drugs
119
Why does sulfation tend to be important at low substrate concentrations
Sulfate availability is limited
PAPS is an expensive commodity
120
Why can sulfation be dangerous
Can result in activation to carcinogens
Some derivatives are pro-carcinogens and can spontaneously form reactive nitrenium compounds
121
Describe amino acid conjugation
Occurs in mitochondria
Proceeds by activation of carboxyl group to its Acetyl CoA derivative
Amide formation w amino group of conjugating amino acid follows
122
What carries out the initial reaction in amino acid conjugation
Mitochondrial xenobiotic medium chain fatty acid: CoA ligase (MACS)
123
Why are so few xenobiotics conjugated to amino acids
N-acetyl transferase is selective
Not all CoA thioesters formed by MACS are conjugated
124
Describe acetylation
Carried out by acetyltransferases
Acetyl CoA donates acetyl group
2 types of human transferases NAT1 and NAT2
125
Where is NAT1 and NAT2 expressed
NAT1: most tissues
NAT2: mainly liver and intestines
126
Which NAT is the most polymorphic
NAT2 - referred to as polymorphic NAT
NAT1 - referred to as monomorphic NAT
127
What substrates do NATs have
Isoniazid (NAT2) and sulfamethoxazole (NAT1)
Restricted number of substrates due to requirement for amino group
128
What are the effects of acetylation
Results in masking amine groups w acetylation group = decreased solubility
129
What is glutathione
Tripeptide important in maintaining reduced environment within the cell
Can be oxidised during glutathione peroxidase reaction = GS-SG
130
Describe GSTs
Mainly soluble;e enzyme that conjugates reduced glutathione to electrophilic compounds through nucleophilic cysteine thiol groups
131
What are the most important forms of GST subfamilies in humans
Alpha class
My class
Pi class
Theta class
132
What classes of GST are inducible
Alpha and mu
Inducers include: PAHs, barbiturates and antioxidants
133
Describe glutathione conjugation
Bonds through nucleophilic cysteine thiol group
Nucleophilic substitution of acetates, sulphate, nitrates and epoxides
Conjugates lose glutamic acid and glycine
Cysteine is N-acetylated to give stable mercapturic derivatives
134
Name a drug substrate of GST
Anti cancer drugs
Vasodilators
Analgesics
Diuretic
135
How does methylation and acetylation affect excretion
Do not improve solubility
Reduce pharmacological activity instead
136
What are the 3 different methyltransferase families
O-methyltrasnferases
N-methyltrasnferases
S-methyltrasnferases
137
What is the co-factor for methyltransferases
S-adenosylmethionine (SAM)
138
What is pharmacogenetics
The study of unusual responses to drugs and other foreign compounds that have a hereditary basis
139
What is a genetic polymorphism
A mutation that occurs at a frequency of at least 1 in every 100 chromosomes
Can be a base substitution, insertion or deletion
140
What is a single nucleotide polymorphism
Mutation that occurs 1 in every 1000 bases
Most do not have a functional effect
141
Describe a functional polymorphism
Has an effect on biological activity
142
What causes functional polymorphisms
Amino acid substitutions
Splice site change
Effect on txn factor binding
143
How does phenotyping analyse genetic polymorphisms
Measures enzyme activity directly by:
Giving a probe drug and measuring metabolites
Direct enzyme assay
144
How does genotyping analysis genetic polymorphisms
Look directly for presence of mutation in individuals DNA
Need to know gene responsible for defect and what mutation to screen for
145
Why can some patients experience adverse effects if they lack metabolising enzyme
Drug has a narrow therapeutic index
Drug is not metabolised by other enzymes
146
Name a few common loss of activity polymorphisms in CYP2D6
CYP2D6*3 allele - A deleted
CYP2D6*4 allele - substitution G -> A
CYP2D6*5 allele - entire gene is deleted
147
What copies of genes do poor metabolisers have
2 copies of loss of activity in any combination
148
Describe CYP2D6 ultra rapid metabolisers
Have an extra copy of the CYP2D6 gene adjacent to the wild type
Results in more enzyme and faster drug metabolism
149
What are the consequences of CYP2D6 polymorphisms
Have higher plasma concentrations of certain drugs
Risk of exaggerated effects and toxicity problems
Prodrugs can be ineffective
Poor response to treatment due to fast metabolism
150
describe NAT2
NAT2 acetylates a variety of xenobiotics
151
describe the NAT2 polymorphisms
People that lack NAT2 activity are called slow acetylators
Have 2 copies of the mutated gene
152
What are the clinical consequences of NAT2 for Isoniazid
Slow: more likely to show neurotoxicity and increased risk of hepatotoxicity
Fast: more likely to show lack of response to intermittent therapy
153
How does biotransformation is a major cause of toxicity
Direct biotransformation of parent drug to toxic metabolites
Metabolites which are subsequently metabolised to toxic metabolites
154
What can inadequate assessment of metabolism lead to
Adverse reactions in trial participants
Drug attrition rates
Drug recall even after approval
155
What is the purpose of reaction phenotyping
To identify the specific enzymes responsible for the metabolism of a specific drug
156
Why are primary hepatocytes the gold standard
Physiologically relevant model retaining in i i o like functions
Ability to asses whether compound passed through membrane
157
What are the cons of using primary hepatocytes
Limited by suitable liver sources
Immediate cryopreservation is important
Can lose functionality if cultured over a long period of time
158
Why are microsomes used in experiments
Can be derived from any organ
Cryopreserved without loss of function
Genotyped
159
How to calculate the amount of drug excreted
Amount excreted = amount filtered - amount reabsorbed + amount secreted
160
What does it mean if the drug is filtered in the nephron
Left untouched by the nephron
Amount excreted = amount filtered
161
What does it mean if the drug is filtered then reabsorbed by the nephron
Amount excreted < amount filtered
162
What does it mean if a drug is filtered and secreted by the nephron
Amount excreted > amount filtered
163
How to calculate total renal clearance
Cl by filtration + Cl by secretion - retention by reabsorption
164
When does the renal function not affect the elimination of an active compound
When the active drug is metabolised mainly to inactive metabolites
165
When does the renal function effect the elimination of an active compound
The active drug and/or metabolites excreted in the kidneys
166
What drugs do not enter the filtrate
Macromolecules e.g heparin
167
What happens to the clearance if the drug is bound to plasma proteins
Conc of drug in filtrate = free unbound drug
Clearance by filtration is reduced
168
How to calculate the rate of clearance
Filtration is directly proportional to GFR (120ml/min) and the fraction of unbound drug in plasma (Fu)
Clr = Fu x GFR
169
When can Clr = Fu x GFR be used
When a drug is principally cleared by filtration
Can be affected by secretion and reabsorption
170
What happens if Clr < Fu x GFR
Renal absorption is taking place
Clr is significantly affected by changes in urine flow
171
What is the principal factor in the passive tubular reabsorption of weak acids and bases
The pH of the renal tubular fluid
Ionisation and passive reabsorption dependent on pH in relation to pKa of drug
172
What happens to the reabsorption rate if a drug is ionised
Decreased
173
What happens to the reabsorption rate if a drug is unionised
Reabsorption will be higher
Unionised form can diffuse through the proximal tubule cell membrane
174
Name 2 independent non selective carrier systems
Acidic drugs and endogenous compounds
Organic bases
175
Describe drug-drug interactions in the proximal tubule
Drug 2 is a better substrate for effluent than drug 1
They compete for the pump when administered together
Drug 1 accumulates to toxic concentrations
176
Name an acid that is actively secreted into the renal tubule
Glucuronic acid conjugates
Uric acid
Salicylic acid
Penicillins
177
Name a base that is actively secreted into the renal tubule
Dopamine
Histamine
Morphine
Serotonin
Amiloride
178
What drugs cause hyperuricaemia
Diuretics and low dose aspirin
179
What is a first line therapy for gout
Allopurinol
180
How does age affect drug metabolising enzyme levels
Levels are low
Unable to clear the drugs as effectively
Can lead to toxic build up
181
Describe the changing levels of CYP1A2 from neonatal to toddler
Neonatal: undetectable
1–3 months: present at low levels
<1 year: approx 50% of adult value
3+ years: comparable to levels in adults
182
How can the difference in species affect metabolism
Phase I: different metabolites produced from same drug
Phase II: variation in conjugation of sulphate and glucuronic acid to substrates
Variation in proportion of phenol conjugated to glucuronide and sulfate
183
What other issues are there in using animals for metabolising experiments
Different strains show differences in metabolism due to genetic differences
184
Why are there difference in metabolism between rat species
Differences in expression patterns of CYP2A, CYP2B, CYP2C and CYP3A enzymes
185
What are the consequences of using rats to study metabolism
Each isoform has a different specificity so different metabolism patterns between sexes
186
What effect do growth hormones have on CYPS within rats
Specific effect on CYP2C enzymes in sex-related manner
Levels increase at puberty and up regulate expression of different CYPs
