Drug Absorption Flashcards
Epithelium layers
Simple epithelium = a single layer
Stratified = multiple cell layers
Trascellular pathway
Soluble drug passes through the apical membrane through epithelium, into the basement membrane and blood supply
Trans = across
Paracellular pathway
Soluble drug passes through apical membrane through a cell-cell junction, passes between two epithelial cells to reach the basement membrane and blood supply
Para = alongside
Common route of absorption
Most common route of absorption is via tight junctions that act as pathways for hydrophilic molecules
Paracellular pathways are minor
Paracellular pathway: tight junctions
Neighbouring cell membranes fused by intimate connections between cell surface proteins, forming a band around the entire cell (rate limiting)
Allows passage of small, hydrophilic molecules
Paracellular pathway: adherents junctions
Connect actin filaments in the cytoskeletons of neighbouring cells
Paracellular pathway: desmosomes
Most common
Fibrous proteins cross the gap between cells and anchor keratin filaments in cytoskeletons together
Paracellular pathway: gap junctions
Intracellular, hydrophilic pores
Membranes close together but not fused
Allows small molecules like acids, sugars, nucleotides and vitamins to pass directly between neighbouring cells
Enables direct cell to cell electrical conductivity
Transcellular pathway: passive diffusion
Diluted diffuse into cells down a concentration gradient - must partition into the lipid bilayer and out again into cytoplasm
An aqueous pore is a continuous, hydrophilic channel created by transmembrane aquaporin protein, some allow transport of small, neutral solutes like urea and glycerol
Facilitated diffusion
Selective
Carrier mediated
Down a concentration gradient
Active transport
Selective
Carrier mediated
Against a concentration gradient and requires energy
Minor pathway: endocytosis
Internalisation of plasma membrane which engulfs extracellular fluid
Pinocytosis = fluid engulfed
Phagocytosis = monocytes/macrophages engulfed particles
Resulting endosome may fuse with lysosomes and the contents are degraded by lysosomal enzymes
The drug may escape lysosomal degradation and be released through basolateral membrane
Harmful pathogens are taken up by the lung due to endocytosis
Passive diffusion pathway
When a system is not in equilibrium so flux occurs
Flux = conc x velocity x area
To improve diffusion
Only viscosity and particle radius can be manipulated to improve diffusion
Fick’s law
Flux = area x diffusivity x partition coefficient x change in conc gradient
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Membrane thickness
Partition coefficient
Usually expressed as log P
P= C oil
———
C water
Oil/water partition coefficient
Lipid soluble drugs= P>1 (logP>0)
Water soluble drugs = P<1 (logP<0)
Equally distributed drugs P=1 (logP=0)
Most drugs have log P between 0 and 5
Log P values and absorption
LogP<0 very soluble, poor partitioning
Log P>5 poorly soluble, partitioning too good, sensitive to metabolism
Optimum range for oral delivery is between 0 and 3
Acidic/basic drugs
Most drugs are weak acids or bases so exist in solution in equilibrium of un-ionised and ionised forms, depending on the pH of the environment and the pka of the drug
AH + H2O A- + H30+
B + H20 BH+ + OH-
AH and B is unionised drug (lipophilic) and is optimal for transport
A- and BH+ is the ionised form of the drug (hydrophilic) and has reduced transport
The drug accumulated on the side of the membrane where pH favours ionisation (called pH partition hypothesis)
Henderson Hasselbalch equation
Acids : pH = pka + log10 [A-]
——
[AH]
Bases : pH = pka + log10 [B]
———
[BH+]
Unionised is absorbable
Ionised is unabsorbable
pH partition hypothesis
Does not consider:
Type of epithelium
Surface area of absorption
Ionised drugs absorbed to a small extent
Active transport of drugs
Time of drug at delivery site
Mass transfer of fluids
Charged drugs forming ion pairs with oppositely charged species
Pairing ions increased lipophilicity of drugs - preferably pairing with ions that have fatty acid chains
Any hydrogen bonds have to be broken before the drug can enter the lipophilic plasma membrane
% oral absorption decreases as the number of hydrogen acceptors in a molecule increases
Components of the GI tract
Oesophagus
Stomach
Small intestine
Colon
Role of HCl
Ingestion of food stimulates secretion of HCl and pepsinogen from mucosal lining
HCl is antiseptic and promotes conversion of pepsinogen to pepsin
Pepsin degrades polypeptides and short peptides pass through the stomach unaffected
Role of duodenum
The acid contents of the stomach are neutralised by bicarbonate secretions which enable optimum enzymatic digestion of food
Bile duct delivers secretions from the pancreas here
Majority of absorption occurs in the jejunum while ileum absorbs remaining nutrients (particularly fats)
Villi have lymph and blood system connections
Role of the colon
Reduced surface area and no villi
Contains aerobic and anaerobic bacteria that may metabolise drugs
Some drugs can be absorbed here if they survive bacteria
Absorption slower due to viscous contents
Absorption of acids and bases
Strongly acidic/basic drugs are poorly absorbed
Basic drugs dissolve easily in the stomach
pH of GI tract
Stomach: 1.3-3.5 Duodenum: 5.0-7.0 Jejunum: 6.0-7.0 Ileum: 6.0-7.5 Colon: 5.5-7.0 Rectum: 7.0
Peristalsis
Muscular movements of GI tract propel food and drink through the intestines
Mix contents of intestines with digestive juices
Preparing unabsorbed material for excretion
Optimal drug absorption
Sufficient residence time at absorption site
Drug not absorbed if movement too fast
If too slow, no pharmacological effect and drug may be degraded and epithelium becomes irritated
Patterns of GI motility: interdigested
Also digested state (fed)
Interdigestive (fasted) state
Has alternating cycles of activity called migrating motors complex
Each cycle lasting 90-120 mins and has 3 phases
1. Quiescence (30-60mins and no bike production)
2. Irregular contractions (20-40mins and some bile production)
3. Housekeeper waves (10-20mins with mucus production)
Digestive contractions per min
4-5
Mix contents and pass them down the tract
Length depends on type of meal
Gastric emptying
Stomach gradually releases contents into small intestine (zero order)
Larger meals mean quicker emptying rate initially
Fatty acids in food reduce emptying rate (proportional to conc and fatty acid chain length)
Triglycerides, carbohydrates and amino acids reduce emptying rate (conc dependent due to osmotic pressure)
Emptying rate
Acids reduce emptying rate
Alkalis increase rate at low conc and decrease rate at high conc
Narcotics, AChs and ethanol reduce emptying rate
Laying on left side reduced emptying rate as pyloric sphincter is on the left side so body works against gravity to pump the drug through
Emptying rate reduced by ulcers
Enzymes in duodenum
Trypsin
Chymotrypsin
Elastase
Charboxypeptidases
Enzymes in small intestine
CYP expression
Esterases and glucuronosyl transferases
Role of bike
Facilitated excretion of endogenous compounds
AIDS digestion’s of fat-soluble vitamins
Food can potentially alter drugs due to
Delayed gastric emptying Stimulation of bile secretion (increased solubilisation and absorption of lipophilic drugs) Increased viscosity of luminal contents Stimulation of hepatic blood flow pH changes in GI tract Physical or chemical interaction Competition for uptake transporters
Largest effect with e/c tabs and reduced effect with well dispersed dosage forms
Efflux pumps
Important P-glycoprotein found in apical membrane of small and large intestine (also liver, kidney, pancreas, BBB, cancer cells)
Multi drug resistance protein is also an efflux pump, substrates are mostly lipophilic or cationic
P-gp localised with CYP3A on apical membrane, enhancing metabolism
Mucus in GI tract
Covers the length of the GI tract
Secreted by submucosal glands and goblet cells
Protective barrier to some drugs
Advantages of oral drugs
Convenient Accessible Good compliance Large surface area Rich blood supply Prolonged retention Zero order release Cheap
Oral drug disadvantages
Variable
Adverse reactions
High metabolic activity and hepatic first pass effect
pH extremes
Efflux pumps
Intestinal motility
Impermeability of epithelium (esp to large, hydrophilic peptides)
Improve oral deliver by
Increasing drug lipophilicity (prodrugs)
P-gp inhibitors
Cytoadhesion
Mucoadhesive patches
P-gp inhibitor in chemo
Prevent chemotherapeutic drugs entering cancerous cells and can prevent oral delivery
Co-administration of chemo and p-gp inhibitors prevents drug efflux from endothelial cells and increased oral bioavailability
P-gp inhibitors
Also inhibit CYP3A4 which causes reduced drug clearance
Third gen p-gp are specific for the transporter and are clinically effective
Yeah
what is the buccal lining
inside cheeks
what is sub-lingual
mucosa under the tongue
what is the gingeval
mucosa around the gums
what is labial
lips
what is platal
roof of mouth
what epithelium is the oral mucosa
stratified squamous epithelium
layers of oral mucosa
epithelium, basement membrane, lamina propria (rich in collagen), sub mucosa
what are membrane-coating granules
lipid deposits between cells
non-keratinised oral structures
buccal and sublingual
good permeability, so often targeted for drug delivery
keratinised oral structures
gingeval
palatal
keratin layer protects from mechanical activity in the mouth
enzymes in saliva
aminopeptidases, carboxypeptidases, esterases, carbohydrases, lysosomes
what is residence time
the time a dosage form spends at the target site of delivery
sustained residence time gives prolonged drug effect
