Drug Solubility, Metabolism, Resistance - Brent Copp Flashcards

Question

What form of chlorpromazine (weak base) exists in the intestine?

Answer 1

The non ionised form predominantly exists in the intestine

Answer 2

The drug molecule will be complicated by internal salt formation. At midrange pH they will have very poor solubility like in amino acids. At low pH, cationic species and at high pH, anionic species have better solubilities. These variations in solubilities alter the therapeutic effectiveness of the peptide and influence design of dosage forms

Answer 3

Disintegration of drug product into small particles and release of drug Dissolution of rug relies on particle size of drug product and physicochemical properties of drug - e.g. Ionisation Sometimes neither disintegration nor dissolution are complete. Leading to reduced bioavailability

Answer 4

+ absorption factors are avoided + achieves desired concentration obtained with accuracy and immediacy - has its own required properties like water solubility and precipitation blood constituents - it is a more invasive route for the patient than the oral route

Answer 5

Using lipski's rule of 5 Calculating the solubility at various pH, predicting pKa Assess its membrane permeability using caco-2 or MDCK

Answer 6

The intrinsic lipophilicity- affinity of a whole molecule for a lipophilic substance

Answer 7

By drug distribution in a biphasic system, either liquid liquid (partition coefficient) Or solid liquid (Rf on reversed phase HPLC)

Answer 8

N-octanol. The aqueous phase is either water or a phosphate buffer. A higher value of log P indicates compound will readily diffuse into membranes and fatty tissue i.e, hydrophobic Low value of log P indicates that the compound is reluctant to enter the lipid membrane i.e. hydrophilic

Answer 9

Monolayers of cells are used to estimate rug absorption rates This can be used in an HTS environment to rank the compounds by oral absorption profile Yields apparent permeability If transport from basolayer all side to apical side is higher than A to B then this implies presence of efflux pumps which can be confirmed by re assay in the presence of inhibitors

Answer 10

It is automatic Chemicals are in solution/ buffer Can detect where the drug goes over a period of time Use HPLC or other analytical techniques to see whether molecules pass through Can start at the bottom to measure how much goes up the cell

Answer 11

A layer of cells

Answer 12

Salt formation Incorporation of water solubilising groups into structure Disruption of molecular planarity and symmetry Drug delivery systems Formulation - not covered in this course

Answer 13

Improves solubility of acidic and basic drugs as the salts dissociate in water to produce hydrated ions. E.g. Acidic drugs are often paired with metal ions or amine salts. Sodium or potassium salts are very common E.g. Fusidic acid diethanolamine which is an antibacterial eyedrop for conjunctivitis. Has a mid strength carboxylic acid which is more acidic than normal. So it can be paired with an amine salt

Answer 14

Organic or mineral acids E.g. HCl salts are very common Lactate and tartrate salts common too. E.g. Chlorpromazine embonate which is bigger on its own as an alkaloid, but tasteless with a salt

Answer 15

Crystalline polymorphism. Where different crystalline forms of the same drug have different packing forms which later their solubility Particle size. Decreasing size of crystals increases solubility. Below a variable minimal size, solubility will decrease. Common ion effect where increased concentration on right hand side of equilibrium leads to left hand shift in equilibrium to lower solubility product. Some drug HCl salts actually precipitate in the stomach due to common ion effect

Answer 16

Some dissociate in small intestine to liberate component acid and base E.g. Erythromycin stearate Others act as drug depots e.g. Penicillin G procaine IM

Answer 17

Incorporation of polar groups in the structure of a compound will normally result in a more water soluble analoge

Answer 18

Acidic or basic groups particularly useful because these groups can be used for salt formation resulting in a wider range of dosage forms E.g. Doxylamine which is an antihistamine and hypnotic. The alkyl amine group is more solbule.

Answer 19

To make sure it still retains its biological effect and to check the changes are desireable

Answer 20

According to yalkowskys general solubilisation equation, the solute in water is dependent on the ability of the solute to interact with water and the crystallinity of the solute So disrupting the planarity and symmetry decreases efficiency of crystal packing resulting in decreased melting point and increased solubility

Answer 21

Removal of aromaticity Increasing dihedral angle (by adding methyl groups which cause steric clash) E.g. Integrin dual antagonists for the treatment of acute ischaemic disease

Answer 22

Drug delivery systems not only enhance drug solubility They also Protect drug from premature degradation Function as a sustained release system Increases targeting of drug to diseased tissue

Answer 23

Liposomes Micelles Polymer or antibody drug conjugates

Answer 24

Phospholipids which lower the surface tension of water Contain both hydrophilic and hydrophobic groups and dissolve in both polar and non polar solvents Frequently used to prepare solutions of compounds that are in solbule or sparingly soluble in water

Answer 25

When the CMC is exceeded, surfactants will preferentially form micelles. The shape of the micelle depends on the concentration of the surfactant. At concentrations just above CMC, the micelles are spherical. As concentrations increases, micelle changes to cylindrical, lokinar and other forms

Answer 26

Drug incorporation into micelles or liposomes can solubilise water in soluble drugs. Non polar compounds accumulate in the hydrophobic core whee water in soluble compounds are orientated within their polar groups towards the surface

Answer 27

Spontaneously formed spherical bilayer aggregates of phospholipids. They are surrounding an internal core of water E.g. Phosphatidylcholine, a lethicin

Answer 28

Family of cyclic oligosaccharides which are structurally characterised by glucose units in classical chair conformation linked by α1-4 bonds. The most common are α, β, γ, and σ

Answer 29

Form inclusion complexes with drugs They have an outer hydrophilic surface Inner hydrophobic surface And form a 1:1 host guest ratio though other ratios are also possible

Answer 30

Di-O-methyl β CD had a strong affinity for cholesterol and is haemolytic 2-hydroxypropyl-β-CD is a very useful solubilise and increases the solubility of progesterone by 88 x in a 1.5% solution

Answer 31

A drug e,g, cytotoxic agent, is fused onto an antibody via a linker. The antibody is specific for a tumour associated antigen which has restricted expression on normal cells The cytotoxic agent is designed to kill target cells when it is internalised and released The linker is cut by enzymes in the anticancer cell which releases the cytotoxic agent

Answer 32

There is sometimes not enough difference between surface anticancer cells and normal cells -> reduced selectivity -> lots of side effects

Answer 33

``` ADC is in plasma Binds to receptor of tumour cell ADC-receptor complex is internalised. I.e. It is pulled inside the cell Cytotoxic agent is released Tumour cell undergoes apoptosis ```

Answer 34

Enhanced drug solubity Rates of hydrolysis and oxidation may be reduced thus improving stability of some rugs Function as sustained release system Increased targeting of drug to diseased tissue

Answer 35

Absorption and hence activity is dependent on being released from micelle and liposome Surfactants can irritate mucous membrane and be haemolytically active Some compounds may decompose more rapidly when incorporated into a micelle

Answer 36

``` Drugs Food constituents Food additives Agrochemicals Pollutants Industrial chemicals ```

Answer 37

Alexander Ure observed conversion of benzoic acid to hip uric acid. He later proposed the use of benzoic acid for the treatment of gout

Answer 38

``` Liver Lungs Kidney Brain Intestine ```

Answer 39

``` Inactive Polar Water soluble Excreted more easily Some may be more active than original drug ```

Answer 40

Most are, but some are not

Answer 41

Drugs absorbed from GIT must pass through liver to reach the general circulation. As a result of metabolism in GIT, a fraction is lost.

Answer 42

Most drugs and xenbiotics are lipid soluble | The aim of metabolism is to produce compounds with increased water solubility

Answer 43

Higher water solubility facilitates excretion primarily in the urine or in some cases into the bile Metabolism into water soluble compounds stops reabsorption of drug molecules from urine through renal tubular membranes back into plasma

Answer 44

By changing the route of administration E.g. IV, IM, SC, or topical application However not all drugs can be administered by an alternate route so we would need to alter the drug structure to minimise FPM

Answer 45

Some enzymes are stereospecific and altered stereochemistry can produce different substrates. enantiomers may be metabolised by different routes, producing different metabolites e.g. S warfarin metabolite has the OH , R warfarin metabolite does not.

Answer 46

``` R ibuprofen (inactive) is metabolised into s ibuprofen (active) If a racemic mixture is adminstered, 70:30 mixture of S:R is excreted ```

Answer 47

Metabolites may be pharmacologically inactive Or they can be active and Exhibit a similar activity to the drug e.g. Diazepam Exhibit a different activity to the drug E.g. Iproniazid (antidepressant) is metabolised to isoniazid (anti TB) Be the sole cause of activity e.g. Prodrugs