Drug Absorption And Routes Of Administration Flashcards

Question

the absorption is dependent on?

Answer 1

– The site of absorption – The nature of the drug

Answer 2

are tissues composed of one or more layers of cells. The layers are supported by a basement membrane which lies on top of the supporting connective tissue. • They can be classified by their: 1. Shape: – Squamous - Columnar - cuboidal 2. Stratification (number of cell layers) – Simple - stratified 3. Specialization (some epithelia will have a specialized function) – Keratinized - ciliated

Answer 3

Blood vessels: single layer squamous cells Oral : single layer of columnar, with villi and microvilli to increase their surface area Buccal: keratinized stratified squamous cells

Answer 4

• Mucus is synthesized and secreted by goblet cells • Mucus is viscous in nature and is composed of highly glycosylated peptides known as mucins and inorganic salts in water. • Its main rule is to protect and lubricate the epithelial lining. • In drug delivery: mucus serves a physical barrier to absorption. Viscosity and thickness of the mucus layer and any interaction that the drug or the delivery system may have with the mucus must be considered.

Answer 5

1. Passive diffusion: • Involves diffusion of drug across the lipid bilayer of the cell • Driven by concentration gradient • The rate is governed by Fick’s law • Factors controlling the rate of diffusion include:  Drug concentration  Partition coefficient of the drug  Area of absorptive tissue • The lipophilicity of the drug is of a particular importance as the drug must diffuse across the cell membrane  An optimum logP is usually observed for passive diffusion. 2. Carrier-mediated transport: – Involves specific carrier proteins in the cell membrane – Can be classified into  Facilitated diffusion: with the concentration gradient  Active absorption: against the concentration gradient 3. Endocytosis: – Involves internalization of substances by engulfment of the cell membrane  forms a membrane-based vesicle with the cell called endosomes. – It allows for large molecules or particulates to enter the cell.

Answer 6

– Through the gaps between the cells – Governed by passive diffusion – Only for small molecules – Can be enhanced by penetration enhancers which damages the tight junctions  possible toxicity.

Answer 7

– Substances can be pushed back out of the cells by an energy-dependent efflux system. – There are various apical transmembrane proteins which can transport drug out of the cell.

Answer 8

The main function of biological membranes is to contain the aqueous contents of cells and separate them from an aqueous exterior phase. – To achieve this, membranes are lipoidal in nature.

Answer 9

nutrients to pass into the cell and waste products to move out  biological membranes are selectively permeable.

Answer 10

Membranes have specialized transport systems to assist the passage of water-soluble materials and ions through their lipid interior. • Lipid-soluble agents can pass by passive diffusion through the membrane from a region of high concentration to one of low concentration.

Answer 11

Biological membranes differ from polymer membranes in that they are composed not of polymers but of small amphipathic molecules: – Phospholipids with two hydrophobic chains – Cholesterol – Sphingolipids • All these components associate into lipoidal bilayers in aqueous media. • Embodied in the matrix of lipid molecules are proteins which are generally hydrophobic in nature  they are embedded in the matrix of lipid molecules. • Thus, the membrane has a hydrophilic exterior and a hydrophobic interior.

Answer 12

Cholesterol is a major component of most mammalian biological membranes – Its removal causes the membrane to lose its structural integrity and to become highly permeable. • Cholesterol complexes with phospholipids and its presence reduces the permeability of phospholipid membranes to water, cations, glycerol and glucose. • The shape of the cholesterol molecule allows it to fit closely in bilayers with the hydrocarbon chains of unsaturated fatty acids. • The present consensus of opinion is that cholesterol condenses and rigidifies membranes without solidifying them

Answer 13

giving them their ability to re-form and to adapt to changed environments. • Biological membranes behaves as a continuous hydrophobic phase through which nonelectrolytes permeate. • However, a fraction of the membrane may be composed of aqueous channels which are continuous across the membrane. – That is, there are pores which offer a pathway parallel to the diffusion pathway through the lipid.

Answer 14

pores play a minor part in the transfer of drugs • Nevertheless, in the case of ions and charged drugs such as the quaternary ammonium compounds the pore pathway must be important. • These pores may be provided by the conjunction of hydrophilic faces of proteins or the polar heads of fatty acids and phospholipids orientated in the appropriate direction. • The fluid mosaic model, in particular, allows the protein–lipid complexes to form either hydrophilic or hydrophobic ‘gates’ to allow transport of materials with different characteristics

Answer 15

– The nature of the membrane. – Its degree of internal bonding and rigidity – Its surface charge – The nature of the solute being transported: Drugs with little affinity for the membrane are unlikely to permeate

Answer 16

egative charge this might influence permeation. • Studies has shown that membranes with unionized surfaces (such as cellophane) or positively charged surfaces such as collagen have different permeability characteristics for ionic drugs. – For example, the order of permeation in collagen membranes is: unionised > anionic > cationic form. .. – Collagen is rich with basic amino acids lysine, arginine and histidine. – The pKa of lysine and of arginine is about 10. – At pH 7.4 (physiological pH) the basic groups in these amino acids are positively charged. – Therefore, cationic drugs will be repelled from the surface

Answer 17

• Tissues derived from the ectoderm (the epidermis, the epithelium of nose and mouth, and the tissues of the nervous system) have protective and sensory functions. • Tissues evolved from the endoderm, such as the epithelium of the gastrointestinal tract, have evolved mainly to allow absorption

Answer 18

a plot of percentage absorption versus log P would be parabolic with the optimum value designated as log Po. • By noting the values of optimal partition coefficient for different absorbing membranes and surfaces, one can deduce something about their nature (how lipophilic it is)

Answer 19

– Initially, increasing the lipophilicity tends to improve the absorption via biological membranes. – However, when log P value becomes too high  protein binding, low solubility and binding to extraneous sites cause a lower measured activity.

Answer 20

The larger drug molecules are  the poorer will be their ability to traverse biological membranes.

Answer 21

• As most drugs are weak electrolytes  it is to be expected that the unionised form (U) of either acids or bases is the more lipid-soluble species and thus, it will diffuse across the membrane • On the other hand, the ionised forms (I) will be rejected. • And since ionization is pH-dependent  drug absorption and solute transport across membranes is considered as well pH-dependent

Answer 22

– Absorption and ionizations are both dynamic processes and that the small amount of unionized drug absorbed is replenished – The bulk pH is not the actual pH at the membrane

Answer 23

– The local pH at the membrane is lower due to the attraction of hydrogen ions by the negative groups of membrane components so that in the intestine: • The bulk pH is around 7 • The surface pH is near 6

Answer 24

– Variability in pH conditions – pH at membrane surfaces – Convective water flow – Unstirred water layers – Effect of the drug – Ion pairing – Other complicating factors

Answer 25

The variation in the stomach pH in human subjects is remarkable. – Keep in mind that each pH unit represents a ten-fold difference in hydrogen ion concentration. – While the normally quoted range of stomach pH is 1– 3  studies using pH-sensitive radiotelemetric capsules have shown a greater spread of values, ranging up to pH 7. – This means that the dissolution rate of many drugs will vary markedly in individuals  this is indeed one of the reasons for individual-to-individual variation in drug availability. – The scope for variation in the small intestine is less  although in some pathological states the pH of the duodenum may be quite low owing to hypersecretion of acid in the stomach

Answer 26

– This is expected because the hydrogen ion concentration at the surface would be greater (and hence pH lower) at the membrane surface as hydrogen ions would accumulate near anionic groups. – The secretion of acidic and basic substances in many parts of the gut wall is also a complicating factor  the local pH in the region of the microvilli of the small intestine will undoubtedly influence the absorption of weak electrolytes. • A drug molecule in the bulk will diffuse towards the membrane surface and so meet different pH conditions from those in the bulk phase. • Whether or not this influences the extent of absorption will depend on the pH changes and the pKa of the drug in question. • The negative charge on the membrane will attract small cations towards the surface and small anions will be repelled  one might thus expect some selectivity in the absorption process. • The use of microelectrodes revealed the existence of a layer on the (rat) jejunum with a pH of 5.5 when the pH of the bathing buffer was 7.2. • The existence of this more acid layer has also been demonstrated on the surface of the human intestine

Answer 27

– The movement of water molecules into and out of the alimentary canal (GIT) will affect the rate of passage of small molecules across the membrane. – The reasons for water flow are the differences in osmotic pressure between blood and the contents of the lumen – It can be appreciated that the absorption of water soluble drugs will be increased if water flows from the lumen to the blood side across the mucosa (provided that drug and water are using the same route). – Water movement is greatest within the jejunum. • Absorption of benzoic acid, salicylic acid, benzyl alcohol and digitoxin has been shown to be increased by efflux of water from the lumen and decreased by flow into the lumen. • One likely explanation is that when water flows from the lumen the drug becomes concentrated and drug absorption is increased because of the more advantageous concentration gradient. • Suggestions that water flow affects the ‘unstirred’ layers close to the membrane may also be valid in interpreting these data.

Answer 28

– A layer of relatively unstirred water lies adjacent to all biological membranes. – The boundary between the bulk water and this unstirred layer is indistinct but, nevertheless, it has a real thickness. – During absorption, drug molecules must diffuse across this layer and then on through the lipid layer. • Compounds with a large permeability coefficient (lipophilic compounds) may be able to penetrate across cell membranes much faster than they can be transported through the unstirred layer. • Under these circumstances diffusion through the water layer becomes the ratelimiting step in the absorption process.

Answer 29

– Drugs must be in their molecular form (dissolved) before diffusional absorption processes take place. – Bases are expected to be more soluble than acids in the stomach, but it is impossible to generalize in this way. – Although the basic form of a drug as its hydrochloride salt should be soluble to some extent in this medium  this is not always so. – Indeed, the free bases of (for example chlortetracycline, dimethylchlortetracycline and Methacycline) are more soluble than their corresponding hydrochlorides in the pH range of the stomach • It has been shown that mean plasma levels following administration of the free base and the hydrochloride of these tetracyclines reflect the differences in solubility  the bases giving higher levels. • The reason is most likely the influence of high ionic strength on the solubility of the drug substance (the common ion effect). • As absorption of the tetracyclines takes place mainly from the duodenum  it is vital that they reach the intestine in a dissolved or readily soluble form, as their solubility is low at the pH conditions prevailing in the duodenum. • The presence of buffer components in the formulation also creates a pH microenvironment around dissolving particles which may aid drug dissolution. • If dissolution is the rate-limiting step in the absorption process  this will be significant in determining absorption. • Bulk pH will then give little help in calculating the solution rate on the basis of a knowledge of saturation solubilities in bulk conditions.

Answer 30

– Phenomenon: quaternary ammonium compounds that are ionized under all pH conditions, still show some absorption. – Explanation: The interaction of such drugs in the charged form with other ions to form absorbable species with a sufficient lipid solubility – These ions which pair with drug are organic and their origin is not clear. – The significance of the phenomenon is that ion pairs have the property of being almost neutral species  so that the ion pair can partition into an oily phase when its parent ionic species cannot. • This property is important in drug absorption and drug extraction procedures

Answer 31

– The very high surface-area of the small intestine also upsets the calculation of absorption based on considerations of theoretical absorption across identical areas of absorbing surface. – Changes in bulk pH: for example, on ingestion of antacids or drugs such as cimetidine which reduce gastric acid secretion. • Cimetidine administration would show a rise in resting pH from below 2 to near neutrality. – In the following cases, drugs might not be absorbed in the way they are expected: • Drugs that are unstable in the gastrointestinal tract (for example, erythromycin). • Drugs that are metabolized on their passage through the gut wall • Drugs that are hydrolysed in the stomach to active forms (prodrugs) • Drugs that bind to mucin or form complexes with bile salts • Drugs that are substrates for efflux system • Drugs that are absorbed in micellar form

Answer 32

• This hypothesis is not valid because it focus on the ionization state of the molecule (dissociated versus undissociated). • However, the ionization state of the molecule is not everything. It is only one aspect of the big picture, which is the polarity of the molecule and the drug partitioning from GIT fluid to intestinal mucosa and then from intestinal mucosa to plasma. • A balance in the polarity and thus, the partition coefficient is required for faster penetration and transport through the intestinal wall