SIU 1 GI tract And Metabolism Flashcards
(139 cards)
1
Q
What are cyclodextrins?
A
They are enzymatically modified starches
2
Q
What are the three types of cyclodextrin? And how many glucopyranose units are there for each one of them?
A
Alpha, beta and gamma
Alpha cyclodextrin has a ring of six units
Beta has seven
Gamma has eight
3
Q
What are the enzymes in stomach contribute to drug metabolism?
A
HCl Pepsin ( protease ) protein into small polypeptides (stable)
4
Q
Enzymes present in duodenum involved in metabolism
A
Trypsin, chymotrypsin, elastase, lipase, carboxypeptidase A B
5
Q
Enzyme that present in SI?
3
A
Cytochrome P450 enzymes, particularly CYP 3A4 in upper epithelial cells
High conc of villus tips of the upper and middle third of the intestine
Esterase and glucurinosyl transferase, transfer glucoronic acid to nucleophilic sites on drug
6
Q
Functions of the ANS
A
1) contraction and relaxation of SM in blood vessels and organ
2) regulation of glandular secretion ( endow and exocrine)
3) control of heart rate
4) metabolism
7
Q
Effect of sympathetic nerve on pupils
A
Adrenergic R- contraction of radial muscle- dilate pupils
8
Q
Which part of the body does cranial nerve controls?
A
Upper part
Eye, lacrimal gland, salivary gland, heart , lung, upper GI tract
9
Q
Which part of nerve controls Lower Gi tract?
A
Sacral
Nervi erigentes
Via pelvic ganglia
10
Q
How does sympathetic Nerve travel to target organ?
A
Preganglion projects to paravertebral sympathetic chain
Postganglion In sympathetic chain send long axonal projections that synapse on the target organ
11
Q
How does parasympathetic nerve travel to target organ?
A
Pregang send long axonal projection to parasympathetic ganglia (in or near the organ)
Postgang send short axonal projection which synapse on target organ
12
Q
What are the 2 types of cholinergic R?
A
Nicotinic
Muscarinic
13
Q
What type of receptor is nicotinic R?
A
Ligand gated ion channel
14
Q
What type of R is muscarinic R?
What are the 2 families?
A
G protein coupled R
EVEN and ODD
15
Q
Muscarine poisoning lead to parasympathic rxn SLUDGE, DUMBBELS
A
Salivation Lacrimation cry Urination Diarrhoea Gastric upset Emesis vomit
Diarrhoea Urination Miosis (pinpoint pupil) Bradycardia (slow HR) Brochoconstriction Emesis Lacrimation Salivation
16
Q
What’s is the pH partition hypothesis?
A
Drug accumulates on the side of the membrane where pH favours ionisation
17
Q
What’s the limitation of pH partition hypothesise?
A
Doesn’t take into account of
Type of epithelium
SA if absorption site
IONISED drug will be absorbed to a small extent
Active transport of drug
Residence time of drug delivery sites
Mass transfer of fluid
CHARGED drug may form ION PAIRS with oppositely charged spp.- ideal for absorption!
18
Q
What bond must be broken before drug enters the membrane?
How does it affect absorption?
A
H bond- the more H bonds there are, the more E needed to break bond- the higher the MP
The fewer the H bonds the easier the partition (CL rather than OH)
19
Q
Lipinski’s rule of 5 only works on what type of drug? And what type of absorption?
A
Oral Simple diffusion ( not involve biological transporters)
20
Q
What’s the Lipinski’s rule of 5?
A
MW<500
0< LogP <5
H bond donor (NH,OH)<5
H bond acceptor (N,O) <10
21
Q
What are the options for drug within solution category?
A
Elixirs- API in sweetened aqueous alcoholic vehicle
Syrups- Sucrose
Solution- aqueous
22
Q
What is a suspension?
A
Fine particle of drug that are insoluble
Enables larger dose to be given
Immediate dissolution and rapid absorption
Good for children
23
Q
What Are the 4 junctions involved in paracellular absorption?
A
1 tight junction (smallest) connection bw cell surface protein
2 adherence junction
Connection bw actin protein filament in the cytoskeleton
3 desmosome (most common) Fibrous protein, anchor keratin filaments in cytoskeleton together
4 gap junctions (aqua pores)
Intercellular hydrophilic pores. Allows direct cell to cell electrical conductance
24
Q
K - partition coefficient is largely affected by what which can be affected by what?
A
Lipophilicity of drug That can be affected by drug structure (with or w/o alky group attach) PH /ionisation Hydrogen bonding
25
How does surfactant affect on the diffusivity?
Reduced surface tension
| Greater diffusivity
26
An example for prodrug increases permeability
Bacampicillin is an inactive prodrug of ampicillin but more lipophilic
Increase absorption
Breakdown by esterase to reveal active drug ampicillin
27
Other strategies (beside prodrug) that increase permeability of drug
```
Lipidisation (covalently attach lipid to drug)
Penetration enhancer (partially solubilising the epithelial membrane to increase absorption )
```
28
Methods to improve absorption of drug (in drug design)
Prodrug -increase lipophilicity
P-GP inhibitor -prevent efflux pump
Mucoadhesive patches -drugs within mucoadhesive layer, bind to mucus hold the dosage form in place, increase residence time, insoluble coating ensures diffusions occur in one direction to epithelial membrane
Nanoparticulates -protect from acid
Cytoadhesion- targeting drugs to specific areas or cells in gi tract
29
What's the advantage of the third generation of g GP inhibitor?
1st&2nd inhibit CYP3A4 causing reduced drug tolerance
Third more specific!!for the transporter. E.g. Topotecan and g gp inhibitor elacridar
30
What is solubility of absolute
The max conc of a solute that can be attained in a given solvent (unit vol) under given condition
31
What are the steps involved in decision tree of salt selection?
1) crystallinity (crystalline salt can be prepared)
2) hygroscopicity (salt can't deliquesce at high humidity)
3) solubility
4) stability
5) polymorphism (final product)
If multiple polymorphs of salt
6) control (to produce desired form)
7) secondary/ final candidate
32
Describe the salt formation of drug
Solids phase :drug , counterion
Liquid phase : ionised drug, ionised counterion
Ionic interaction
- controlled microcrystalisation (vapour diffusion, vapour in eqm. 1) sitting 2) hanging drop
Drug salt
33
What's the pKa change of the weak acid and base required for salt formation?
3
34
Pros and cons of pharmaceutical salts?
```
Pros - enhance solubility
Increase dissolution rate
Easier synthesis and purification
Better taste
Improved photo stability
High bioavailability
Higher melting point
```
```
Cons- decreased % of drug
Increased hygroscopicity
Additional manufacturing steps
Increased toxicity
Decreased Chem stability
No change in solubility at different pH in Gi tract
Increase number of polymorphs
```
35
Define solution
Molecular dispersion formed by 2 or more components which form a one phase homogenous system
36
Define solvent
The component that determines the phase of the solution
| -largest proportion of system
37
What are pyranose
Carbohydrates that have a chemical structure that include a six membered ring consisting of five carbon atoms and one oxygen atom
38
Describe the structure of a cyclodextrin
Cylindrical-Hydrophilic outer surface
| Lipophilic nonpolar internal surface
39
Where can the lipophilic molecule binds to A cyclodextrin?
The lipophilic molecule can be accommodated wholly or partially in the Nonpolar cavity
The host and guest ratio usually one to one however one, two or three cyclodextrin molecule complexing with one or more drug is possible
40
What are the stages of cyclodextrin action
First, binding with poorly soluble drug
- form crystalline complex
- after five minute water dissolve- dissolution
- dissociations
- recrystallisation of cyclodextrin
41
Give an example of cyclodextrin in improving The solubility of drug
Beta- cyclodextrin improving the solubility of ibuprofen
42
What are the side effects of cyclodextrin?
Di-O-methyl beta-CD has strong affinity for cholesterol and is haemolytic however it is One of the best solubiliser
Overdose by increasing the solubility of progesterone -toxic
43
What is the surface activity of a surfactant?
The ability to reduce the surface tension at an interface without requiring large concentrations
The lower concentration required for a given effect, the better surface activity properties of a solute
44
Describe the molecular structure of a surfactant
Hydrophilic /polar head: unionic, ionic
| Lipophilic/ non polar chain
45
What are the physical properties of surfactants solution at dilute solution?
They act as normal solutes (and normal electrolytes)
The amphiphiles exist separately and have 'sub-colloidal' size
46
What are the properties of surfactant Solutions at concentrated solutions?
Aggregate into micelles over a narrow concentration range, over 50 monomers
Size of colloidal -protein/ bacteria size
47
Define critical micelle concentration CMC
The concentration of monomer at which micelles form
48
Define aggregation number of the micelle
The number of surfactant monomers that aggregate to form a micelle
49
What is the Kraft point? Describe what happens at either end of KP?
Temperature at which the solubility becomes equal to the CMC (for a soap/surfactant)
At T< Kraft point, CMC> sol. No micelles formation
At T< Kraft point, CMC< sol. Micelles--> self solubilisation
Un-associated surfactant has a limited solubility micells are highly soluble and can accommodate a large amount of the surfactant
50
What would happen if T< Kraft point
The CMC > solubility
| Micelles can't form
51
What would happen if T> Kraft point
Surfactant forms micelles, self- solubilisation
52
Define solubility in quantitative term
The maximum mass or volume of solute that will dissolve in a given mass or volume of solvent at a particular temperature
53
How to increase the solubility of a drug and how to reduce it?
Use of the salt form
Esterification
54
What are the other purposes of esterification?
Mask the taste
Protect from degradation in GI (Erythromycin propionate instead of erythromycin -less soluble and less readily degraded)
Facilitate absorption from GI Tract (erythromycin propionate more readily absorbed- lipophilic )
55
How does Salt form increase the solubility of drug?
By increasing interaction with the solvent increase Solubility
56
What reactions belong to phase 1 metabolism?
```
Oxidation,
Hydration
Hydrolysis
Isomerisation
Dethioacetylation
Reduction (rare)
```
57
Where are CYP450 found?
Endoplasmic reticulum aka microsomes
58
What are the other enzymes required in CYP450 reaction?
NADPH, O2, NADPH-cytochrome P450 reductase, lipid
59
Where are the more selective CYP oxygenases (oxidase system) found in cell? And what they oxidise?
In mitochondria
| Steroid
60
What's the most common type of oxidative rxn of an aromatic ring in phase 1 metabolism by CYP450?
Is the reaction specific?
Hydroxylation
Yes - stereoslective
Regiospecifc
61
What would happen in metabolism of a chiral drug?
```
Diff stereoisomers
Diff drugs
Metabolised by diff enzymes (in CYP450 fam)
To diff products
With diff kinetic
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62
What is cosolvency
For phenomenon where a solute is more soluble in a mixture of solvent then in one alone.
63
What is a cosolvent
(In combination) increases the solubility of solute
64
What are the purpose of cosolvency?
1) obtain aqueous based system in which the drug solubility is higher than the aqueous solubity
2) formulate higher conclusions of drug
3) improve stability of formulation
65
What are the requirement to be a cosolvent?
1. Organic compounds
2. Miscible with water
3. Better solvent than water for drug - H bond donor/acc
- small CH chain
4. Liquid -ethanol/ glycerol
5. Or highly soluble solids -urea
66
What is the effect of cosolvent on nonpolar semipolar and polar solute?
Increase the solubility of non and semipolar solute
Decrease the solubility of polar solute
As solute becomes more polar. Cosolvency becomes less efficient
67
How does polarity of solution affects its surface tension?
The less polar the solution. The smaller the surface tension!
(Fewer interaction between molecules within the solution)
(Longer CH chain, greater tendency of adsorbing surfactant mol at surface)
68
Define lundelius's rule
Any factor that tends to decrease solubility of the surfactant promotes surface activity
69
What is an emulgent?
Surfactant that are used to stabilise emulsions (each type of oil requires an emulgent of a particular HLB number)
70
What is phase inversion temperature (PIT) of an emulgent?
T at which it changes from being an O/W emulgent (HLB 8-16) o an W/O emulgent (3-7)
71
What are the treatment for peptic ulcer which belongs to H2 receptor antagonist?
Cimetidine- lots of interactions
Ranitidine
Famitidine
72
What are the advantages of pharmaceutical oral solutions?
1 easier to swallow (elderly, infants)
2 faster therapeutic response
3 homogenous system- no issues with dose variation due to phase separation (on storage, unlike emulsions, suspensions)
4 reduced irritation, immediate dilution by gastric contents (aspirin tablet can irritate gastric mucosa if localised in one area)
5 taste masking
73
What is the assumption on concentration of the suspension we made for sedimentation?
Dilute suspension < 2% w/v
Spherical particle uniform size
No P-P,P-medium interactions
74
Are there any problems associated with pharmaceutical oral solutions?
1. Problem with manufacture transport (leakage) and administration
2. Growth of microorganisms
3. Poorer stability of ingredients in aqueous solution than solid. Stability of excipients
4. Shorter half life than solid dosage form
5. Dose accuracy-patient using spoons
6. Taste
7. And suitable for drugs chemically unstable in water
8. Expensive to ship, bulky to carry
75
Methods for preparation of vehicle for oral solution?
Distillation, ion exchange or reverse osmosis
76
The solid residue of the vehicle of an oral solution must be under what concentration?
Solid residue obtained after evaporation <1 mg/100 ml
77
List 4 co solvents that are used in drug formulation for solution (increase sol.)
```
1 glycerol
2 alcohol e.g. Ethanol
3 propylene glycol - lipophilic
4 PEG :poly(ethylene glycol) -repeating units of ethylene oxide - hydrophilic
PEG200,400
```
78
What are the excipients used in pharmaceutical oral solutions?
1 buffer -control pH, acetates 1-2%, citrate 1-5%, phosphate 0.8-2%
2 sweeting agent -sucrose, glucose, aspartame (diabetes)
3 viscosity enhancing agent -non ionic: methylcellulose, PVP. ionic hydrophilic polymers: sodium alginate/ carboxymethylcellulose (anionic)
Or syrups (inherent viscosity)
79
What's the MIC of preservative?
Minimum inhibitory concentration required to inhibit microbial growth
80
What are the three factors that directly affect the efficacy of preservatives in oral solution?
1 the pH of formulation
2 the presence of micelle
3 the presence of hydrophilic polymers
81
Which form of preservative has antimicrobial property? IONISED or unionised?
Unionised form of acid
| E.g. Benzoic acid
82
What's the mechanism of preservative in cells?
Diffuse across membrane in unionsed form , into cytoplasm
Neutral pH in cytoplasm
Enable acidic preservative to dissociate
Acidification of cytoplasm
Inhibit growth
83
How does presence of micelles affect the preservative efficacy?
Preservative has lipophilic properties (cuz unionised form of acidic preservatives)
Partition into micelles
Reduced availability C of preservative in solution
Has to increase C of preservative, > = MIC
84
How does presence of hydrophilic polymers affect the preservative efficacy?
Preservatives undergoes chemical reaction with dissolved polymer
Has to increase C of preservatives
Cationic hydrophilic polymers should not be used with acidic preservatives ( electrostatic interaction)
85
What are the oral syrups components?
Purified water
Sucrose 60-80%
High conc of sucrose --> high viscosity, no sweetener/ viscosity modifying agents
--> reduced room for water , thus no addition of preservatives
Non sucrose bases : sorbitol solution 64%w/w
Flavours
Colours
86
At what alcohol concentration does elixirs not need for preservatives? I.e. Already have antimicrobial property
An example?
>12% v/v alcohol
| Theophylline elixir -20%
87
The cloud point applies to which type of surfactant?
Non ionic
88
What would happen if there is an increase in temperature for non ionic surfactant? (Cloud point)
Dehydration of POE chains
Decrease water solubility
Formation of very large micelles
Solution becomes cloudy
89
What's the reverse process of forming cloudy large micelles solution called? Mechanism? For non ionic
Cooling
Formation of small micelles
Clarification
90
Where are the histamine sources in body?
Tissue mast cells
ECL cells
CNS
Food: fish cheese salami
91
Physiological roles of histamine?
Beneficial inflammation
- supply plasma (antibodies and WBC) to tissues and organ
- flush and remove parasites from gut
Gastric acid
CNS-awakefulness
92
What are the pathophysiological roles of histamine?
Hypersensitive response:
Allergic rhinitis -hay fever
Urticaria -skin rush
Anaphylactic shock -food allergy
93
What are the 9 ideal properties of preservatives?
1 Broad spectrum of antimicrobial activity
2 Rapid kill
3 Chemically stable and effective at product pH
4 Good solubility in water (where microbes grow), low sol in oil
5 compatible with formulation/ packaging
6 physically undetectable
7 constitute very small proportion of drug
8 safe
9 cost effective
94
What's the purpose of preservatives?
Reduce the risk of microbial contamination throughout product shelf life NOT to mask a poor manufacturing process
95
What are the 5 factors affecting choice of preservative?
```
1 Intended application
2 No. and type micro-org present
3 Safety, stability and cost
4 Micro- environment
5 Properties of chemical agent
```
96
What are the most likely contaminating organisms for oral products?
Bacteria: Escherichia coli, Staphylcoccus Aureus, Pseudomonas aeruginosa, Clostridium sp.
Fungi: candida sp, other fungi
97
What are the rick factors of NAFLD?
1 obesity
2 type 2 MD (insulin R)
3 dyslipidemia (abnormal amount of lipids in blood)
4 metabolic syndrome
98
What are the syndromes of alcohol induced acute hepatitis?
| And at what point of drinking will the symptoms show?
Raised WCC- infection
Fever
Deterioration in clotting
Large rise in ALT - alanine transminase- liver enzymes in response to damage in hepatocytes
Comes on 5-10 days after cessation of drinking
99
What are the sign for CLD?
```
Jaundice
Bruising- lack of clotting factor
Spider naevi
Dupuytren's contractures- scar tissues
Palmer erytheme-red palm
Gynaecomastia- man boobs
Ascites
```
100
What is a lead compound?
Prototype chemical structure with desired biological activity
101
Is omeprazole a racemic product?
| If so, which is the chiral centre
Yes
| The S atom is tetrahedral
102
Which enantiomer of omeprazole has a better potency and PK profile? How does it relate to the patent of omeprazole
```
S- enantiomer
S enantiomer is launched after omeprazole patent expired.
Chiral switching
Extend the patent life time of a drug
Esomeprazole
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103
What's the reason for S enantiomer of omeprazole having a better performance?
Less hydroxylation by CYP450
Reduced clearance rate
No difference in MOA
104
What are the 2 main metab rxn for omeprazole?
```
Benzylic hydroxylation (S 46%)
O-dealkylation (R 94%)
Metabolism is stereoselective
```
105
Characteristics of bacteria?
No men enclosed organelles
Mircro m in size
Gram +be/ -ve
Mostly non pathogenic
106
What are the components a gram +be bacteria has?
Peptidoglycan
Teichoic acid- anchor to cell
Lipoteichoic acid- anchor to bacteria mem
Cytoplasmic mem
107
What are the components a gram -ve bacteria has?
```
Much thinner peptidoglycan
Lipopolysaccharide LPS- cause fever
Porin- allow sm mol in/ out
Outer mem
Periplasm
Cytoplasmic mem
```
108
Why are biofilms such a problem?
More R to antibiotics (1000x)
More R to biocides ;bleach)
More difficult to phagocytose (embedded in slime)
109
What microorganism can R sterilising process the most?
Porin
| Gram +ve spores
110
Describe the process of sporulation
```
1 asymmetrical cell division
2 formation of septum
3 engulfment of spore (internalised)
4 additional cost & proteins around spore
5 cell lysis
6 release of spores
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111
When does sporulation occur?
When nutrients run out n bac. Stops dividing
112
What type of bac. Is Clostridium difficile?
Obligate anaerobic - only fire without air
113
What are the properties of the spores of C. Difficile?
Can survive aerobic environment
| Spores larger than mother cells
114
What are the common preservative agents that are used in the UK?
Organic acid : Benzoic acid, Sorbic acid
| Parabens; ester of p-hydroxybenzoic acid : propyl paraben
115
What type of drug tends to be re-Absorber by the liver?
Lipophilic drugs
116
Why are lipophilic drugs more likely to undergo enterohepatic circulation?
Intestinal wall is consist of long chain of fatty acid
| Lipophilic drugs can re-enter the blood and go back to live by passive diffusion down concentration gradient
117
Lipophilic or hydrophilic drug in general, which one of those has a longer half life? What's the indication
Lipophilic
Greater toxicity
Side E
118
What are the two types of peptidase?
Endo and exo
Endo: cleave from outside of the chain
Exo: cleave from middle of the chain
119
Why do we have those exo and endo peptidase
Cleave for digestions and nutrition
120
What is the concentration of any drug in our body
A drug has an affinity of nanomolar nM
121
What is the concentration of GSH in our body?
1 mM
122
Why can't GSH get degraded by peptidase? Eg trypsin, chymotrypsin
Because GSH has gamma not alpha glutamine (stereochemistry
123
What's the MOA of El+ that can produce toxicity?
El+ react with nu- (on protein side chain)
Acylation of protein
Cytotoxicity
124
What is mutagenesis?
Cancer
125
What's the causation of mutagenesis (relate to structure of DNA
```
DNA and rna mol have many O2 and N atoms that are rich in LP
Nu-
React with El+
Acylation
Mutagenesis
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126
What is the result of acylation for lysine
NH group react with el+
| No longer be able to carry/ transport Vit B6
127
How does GC separation occur?
Different vapour pressure of compounds (rate of evap.)
128
Water octane ethanol
| Place in order of increasing vapour pressure
Water ethanol octane
129
What's the relation between H bond and vapour pressure
More H bonds (OH, phenol, COOH)
Harder to evaporate (break the bonds) not volatile
Lower vap pressure
130
How to improve volatility of compound with OH group?
```
React w Me3SiCl trimethylsily TMS
Base Et3N
Form silyl ester - high MW
fewer H bond
more volatile
```
131
How to improve resolution in GC?
```
Lower temperature
Longer contact time bw stationary (liquid) and mobile (gas) phase
Bigger separation of peaks
Longer retention time
Greater resolution
```
132
To increase peak separation in GC what factor should be changed? And in HPLC?
GC temperature ramp
| HPLC solvent ramp
133
What are the 3 ways of changing temp/ solvent?
Linear
Stepped
Convex/ concave
134
What are the 2 characteristics of internal standard for HPLC?
Same chromophores
| Similar chem structure
135
Give examples for organic modifiers that can be mixed with water to give a solvent
```
Methanol
Ethanol
Propanol
MeCN
ACN- acetonitrile
```
136
Explain what is SPE?
Solid phase extraction
Can be used to isolate analytes of interest from urine, blood, water
It uses the affinity of solutes in a liquid mobile phase and in solid stationary phase to separate a mixture into desired and undesired components
If the portion retained on the stationary phase includes the desired analyte they can be removed from stationary phase by rinsing it with an appropriate eluent
137
What can b cyclodextrin also be used for?
Controlled release of drugs
Neural ph along the GIT
Constant release
138
What does antioxidant do
Increase stability of drug. Oxidised in preference to drug protecting drug from decomposition
139
Example of Preservatives
Benzoic acid and salts
Sorbic acid and salts
Alkyl ester is parahydroxybenzoic acid
