CHAPTER 3 ( (Other Factors ( Disease States
i. Altered albumin or drug -…
- Disease States
i. Altered albumin or drug - binding protein concentration
ii. Altered or reduced perfusion to organs/tissues
iii. Altered tissue pH
During Pregnancy, the growth of the uterus, placenta and fetus increase the volume available for distribution of drugs.
High in fats will increase the free fatty acid levels in circulation thereby affecting binding of acidic drugs such as NSAIDS to Albumin
- Molecular Size
- 250 and 450 Da MW
- Tiny drugs (150-200 Da) with low Po/w values like caffeine can passively diffuse through cell membranes.
- Larger drugs cannot passively cross membranes. Require specialized protein-based transmembrane transport systems. Slower distribution
- Drugs < Thousand Da simply diffuse between the lipid molecules that make up membranes, while anything larger requires specialized transport
- Binding to serum albumin proteins
- If drugs strongly biund to the plasma proteins, drug distribution to other compartment is reduced and slowed (e.g, Barbiturates)
- A drug that binds plasma protein diffuses less efficiently than a drug that doesn't.
- Plasma proteins that bind drugs:
i. Albumin important to acidic drugs; Most abundant plasma protein; Synthesized in liver; Concentration changes with disease
ii. a-acid glycoprotein important to basic drugs; Lower concentration than albumin; Varies in individual if disease states
- Ionization pKa
- Ionized forms are more polar, thus retarded by cell membranes, but more soluble in water
- Lipid soluble drugs pass through membranes and low water tissues more rapidly
- Lipophilic may be distributed/stored in fat
- Lipophilic may be poorly taken up in the blod/need a carrier
- Hydrophilic may be rapidly secreted due to polarity
Concentration of the drug
- Higher the concentration of the drug at the administration site, higher the absorption rate of that drug.
- Solubility of some low-soluble drug molecules can be increased by formation a complex with another drug molecule.
- Decreasing the particle size of the drug fastens its dissolution so, increases the absorption rate.
- Salt formation, salt forms of weak acids and weak base drugs are more easily absorbed compare to their original forms.
- Crystal forms, amorphous structure of drug has higher dissolution rate compared to its crystalline structure
- Solvate form, the hydrates are more soluble in water compared to other solvates
Degree of ionization
- Determined by Handersen-Hasselbach equation:
i. For weak acid drugs, if acidity of medium increase (decrease pH), unionized form of drug molecule increase, so the absorption rate increases
- Molecular size increase, absorption rate decrease
- Product age and storage condition
i. Product aging and storage conditions can adversely affect the bio-availability by change in especially the physiochemical properties of the dosage forms
ii. Example: Precipitation of drug in solution; Hardening of table; Change in particle size of suspensions
Solutions>Emulsions>Suspensions>Capsules>Tablets>Coated Tablets> Enteric Coated Tablets> Sustained Release Product
- Dosage forms
i. Apart from the proper selection of the drug,
clinical success often depends to a great extent
on the proper selection of the dosage form of that drug.
ii. As a general rule, the bio-availability of a drug:
Pharmaceutical ingredients. More number of excipients in the dosage form, more complex it is, causing difficulties for absorption and bioavailability
- Disintegration time (tablets/capsules)
i. Rapid disintegration important to have a rapid absorption.
So, lower disintegration time is required.
ii. Coated tablets: Have long disintegration time, Fast dispersible tablets have short disintegration time
- GI diseases, blood flow, gut contents
- CVS diseases, blood flow
- Hepatic disease, enzymes for metabolism
- In infants patients; incomplete development
of biological system, the gastric pH is high.
Intestinal SA and blood flow to GIT is less.
Results in altered absorption pattern
- Elderly patients; impaired biological system,
altered gastric emptying. Intestinal SA and
blood flow to GIT decreased. Higher incidence
of bacterial growth in small intestine.
- Food-drug interactions
i. Digested food contain amino acids, fatty acids, etc
that may affect intestinal pH and solubility of drugs
ii. Affected bioavailability of a drug; Delay in gastric
emptying; Stimulation of bile flow; A change in the pH of GIT
- Fluid volume
i. Large vol results in better dissolution, rapid
gastric emptying and enhanced absorption.
Area of absorption
- If the surface area that allows the absorption of the drug molecules is wide, then absorption rate from that surface becomes high
Blood flow (at site application)
- If blood flow is high at site of application,
it causes an increase in absorption rate.
- Placental Barrier
i. Placental membranes are lipid and allow free passage of lipophilic drug, while restricting hydrophilic drugs
ii. The placental P-gp also serves to limit fetal exposures to maternally administered drugs
iii. However, restricted amounts of nonlipid soluble drugs, when present in high concentration or for long periods in maternal circulation, gain access to the fetus. Thus, it is an incomplete barrier and many drugs, taken by the mother; can affect the fetus or the newborn
iv. Penicillins, azithromycin, and erythromycin do not affect the fetus and can be used during the pregnancy
- Blood Brain Barrier (BBB)
i. Has tight junction,lack large intra cellular in endothelial membrane
ii. Transporter in endothelial cells extrude drugs
iii. Glial cells surround endothelial cells
iv. Less protein concentration in interstitial fluid
- Various approaches to promote crossing BBB:
i. Use of permeation enhancers such as Dimethyl Sulfoxide
ii. Osmotic disruption of the BBB by infusing internal carotid artery with Mannitol
iii. Use of Dihydropyridine Redox system as drug carriers to the brain
- Capillaries in the brain are not leaky, have tight junctions, and are not leaky, have tight junctions, and are covered with astrocyte feet. These properties prevent materials from moving in and out easily, and are the basis of the blood-brain barrier
- Capillaries in the body are leaky and have few tight junctions. Materials can move in and out relatively easy.
Different mechanism for drug to be transported across biological membranes
- Passive diffusion
- Carrier Mediated transport
i. Facilitated diffusion
ii. Active transport
- The uptake of substances into or across membrane/tissues, reaching the systemic circulation.
- Drugs given in solid form must dissolve in the aqueous biophase before they are absorbed. For poorly water soluble drugs (aspirin), The rate of dissolution governs the rate of absorption.
- If a drug is given as water solution, it is absorbed faster that the same given in solid form or as a oily solution.
- Absorption involves transportation of the drug across the biological membranes
- The distribution of drugs can occur in 4 patterns:
- Distribution only in plasma:
- Distribution to all body fluids homogenously:
- Concentration in specific tissues:
Iodine in thyroid, tetracyclines in teeth and bones
- Non-homogenous distribution pattern:
Most of drugs distributed in this pattern according to their abilities to pass through the cell membranes to different tissues
- Drug is absorbed into the systemic circulation after uptake
- Then the drugs are distributed throughout the body and go to the site of action
- Distribution of drug means how the drug travels in the bloodstream and how it goes into and comes out of other areas of the body
- During this, drugs cross different membranes to reach other compartments of the body & cells of the tissues
- What drug does to the body
- What body does to the drug