Membrane transport
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Mechanisms of Bio transport and biotransportation. Absorption of drugs and factors effecting it
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Membrane transport
- 1. Membrane Transport Dr Naser Ashraf Tadvi Associate Professor Pharmacology Ayaan Institute of Medical Sciences
- 2. Objectives • Enlist various bio-transport mechanisms • Describe : – Simple diffusion – Facilitated diffusion – Active transport – Filtration – Endocytosis • Describe membrane transporters • Describe factors affecting absorption
- 4. Transport mechanisms across biological membranes • Passive diffusion (Non ionic / simple diffusion) • Filtration • Specialized transport – Active transport – Facilitated diffusion • Pinocytosis or Phagocytosis
- 5. Passive diffusion • Bidirectional process • Drug molecules move from a region of higher concentration to lower concentration until equilibrium is attained • The rate of diffusion is directly proportional to conc. Gradient across cell membrane • Lipid soluble drugs are transported across membrane by passive diffusion • It does not require energy
- 6. AQUEOUS DIFFUSION • Most biological membranes are water permeable. • In gut, cells are joined tight epithelial junction, water passes through the cells. • Water carries water soluble substances of LMW. • Urea, alcohol LIPID DIFFUSION • Hydrophobic lipid substances are dissolved in this manner. • O2,CO2,N2, unionized substances.
- 7. • Passive diffusion occurs through.. – Concentration gradient – Lipid solubility. • Ionized water soluble less absorbed. • Unionized lipid soluble better absorbed.
- 8. Factors affecting drug absorption • Aqueous solubility(transport across membrane) • Effect of pH • Area of absorbing surface – More the area more is absorption hence maximum absorption occurs in the intestine even for acidic drugs. • Vascularity of the absorbing surface – More vascularity more is absorption • Route of administration – Sublingual absorption is more than oral for lipid soluble drugs
- 9. Effect of pH • Henderson-Hasselbalch equation • For acids • For bases
- 10. What can we understand from Henderson-Hasselbalch equation • pKa value is more for strong base and weak acid and vice a versa • Weakly acidic drugs like aspirin, phenytoin remain predominantly unionized in acidic medium and weak basic drugs remain unionized in alkaline medium • Weakly basic drugs better absorbed from the intestine where pH is alkaline
- 11. What can we understand from Henderson-Hasselbalch equation • pKa = pH at which unionized and ionized form of the drug is at equilibrium • 1 unit increase or decrease in pH, leads to 10 times increase or decrease in ionization depending on whether it is acidic or basic drug • Strongly acidic drugs are ionized at all pH
- 12. FILTRATION • Involves transport of drugs through intercellular/ paracellular spaces or aqueos channels • Occurs along conc. gradient • Doesn’t require energy • MW<100 can pass through it. • Capillaries have large pores, except BBB.
- 14. Specialized transport • Facilitated diffusion – Carrier mediated transport but does not require energy – The drug attaches to carrier in the membrane which facilitates its diffusion across the membrane – transport of molecules from region of higher concentration to lower concentration – E.g: • Glucose transport in muscles by GLUT-4 • Absorption of Vit B12 from gut • Transport of Amino acids in brain
- 16. Active transport • The drug molecules move from region of low concentration to high concentration against the conc. gradient • It requires energy • Active transport can be – Primary active transport – Secondary active transport
- 17. Primary active transport • Energy obtained directly by hydrolysis of ATP • They mediate only efflux of solutes from cytoplasm either to extracellular fluids or into intracellular organelli • E.g P-glycoprotein transporter
- 19. Secondary active transport • Symport – Carrier moves the substrate A against its conc. gradient by utilizing energy from down hill movement of another substrate B in same direction • Antiport – Carrier moves substrate A against its conc. gradient and is energized by downhill movement of another substrate B in opposite direction A B A B
- 20. Symport
- 21. Antiport
- 22. Examples of active transport • Transport of glucose and amino acids and neurotransmitters • L dopa & methyl dopa actively absorbed from gut by aromatic amino acid transporter
- 23. Pinocytosis • Process of transport across cell in particulate form by formation of vesicles • Proteins and big molecules can rarely be transported by this mechanism • Insulin transport in Brain
- 24. Membrane transporters • ABC super family: (ATP Binding cassette superfamily) – Example P glycoprotein (ABCB1 or MDR1 ) – Active transport • Solute Linked carrier group (SLC) – Facilitated as well as Active transport – Examples • Neurotransmitter transporters: SERT, DAT, NET • Others: glucose, cholesterol transporter
- 25. P Glycoprotein • Inducers – Rifampicin – Diazepam • Inhibitors – Verapamil – Amiodarone – Cyclosporine – Itraconazole – Erythromycin
- 26. References • Principles of Pharmacology By HL Sharma, KK Sharma 3rd edition. • Essentials of Medical Pharmacology by KD Tripathi 8th Edition • Basic and Clinical Pharmacology by Betram G Katzung, 14th edition
Editor's Notes
- This is bilayer of 100 Angstrom thick of phospholipid and cholesterol molecules. Polar groups are oriented at the two surfaces, and non polar hydrocarbon chains are embedded in matrix to form a continous sheet. Extrinsic and intinsic protein molecules are adsorbed on protein bilayer. Glycoproteins or glycolipids are formed on surface by attachment to polymeric sugars amino sugars or sialic acid. Some intrinsic protein extend through full thickness of membrane, surround fine aqueos pore. Paracellular spaces, channels may also be present in some epithelial cells/ endothelial cells. Other adsorbed proteins have enzymatic activity, carrier, receptor, or signal transduction properties,
- Non ionized drugs can diffuse passively across biological membranes at a rate proportional to their lipid : water partition coefficient . This means drugs which are highly lipid soluble can diffuse rapidly whereas drugs which are less lipid solubkle diffuse slowly Polar drugs , heparin and ions aminoglycosides are lipid insoluble and cannot cross cell membrane by diffusion and are not absorbed from GIT and remain more or loss confined in ECF
- Size of intercellular spaces is variable from region to region in intestinal epithelium it is only 4 Angstrom . And allows passage of only very small water soluble molecules <100 MW can pass through it e.g urea. Capillary endothelial cells in muscle and fat have large pores 40 A, and helps in transport of relatively large water souluble molecules Filtration is very important mechanism of of transport of drugs after parenteral administration by subcutaneous route and intramuscular route. In CNS the gap between vascular endothelial cells is almost zero (Tight junction and no water souluble molecule can pass through it
- This may be carrier mediated or by pinocytosis
- The drug molecules move from region of low concentration to high concentration against the conc. gradient Resulting in selective accumulation of drug on one side of the membrane Drugs related to normal metabolites can utilize the transport processes meant for these. Eg L dopa and methyl dopa are actively absorbed from gut by aromatic amino acid transporter . In additon body has developed some non selective transporters like P-Glycoprotoein to deal with xenobiotics Primary active transport or secondary active transport depending upon source of driving force
- Transporters belong to superfamily of ATP binding cassete whose intracellular loops have ATPase activity
- Intraneuronal and granular uptake of NE in symapthetic neurons