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Biological membranes as a barriers to drugs(pH trapping)

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Biological membranes as a barriers to drugs(pH trapping)

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Transport of drugs across the membrane, Passive Diffusion, carrier mediated, Facilitated, Endocytosis, Ion transport and pH trapping.
Blood brain barrier and(BBB) stratergies to overcome BBB

Transport of drugs across the membrane, Passive Diffusion, carrier mediated, Facilitated, Endocytosis, Ion transport and pH trapping.
Blood brain barrier and(BBB) stratergies to overcome BBB

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Biological membranes as a barriers to drugs(pH trapping)

  1. 1. BIOLOGICAL MEMBRANES AS A BARRIERS TO DRUGS PRESENTED BY: FREYA CARDOZO UID: 198612
  2. 2. BIOLOGICAL MEMBRANES  All human cells are limited by a lipid bilayer membrane  The membrane consist of a. Hydrophobic lipid core – The hydrocarbon tails of the amphiphilic lipids viz phospholipids, glycolipids and cholesterol b. Hydrophilic surface – The phosphate heads and hydroxy group of cholesterol c. Proteins – Intracellular or Extracellular and Transmembrane proteins  This unique design of the membrane presents challenges in the entry of drugs.
  3. 3. TRAVERSING THE MEMBRANE  Small non polar molecules easily diffuse through the membrane due to their lipophilic nature  Inorganic ions and small water soluble molecules pass the membrane via aqueous filled pores or perforation of 4 -10 A0  But, most therapeutic drug molecules are large and ionic thus bypassing these membranes involves is a challenge and involves various transport mechanisms Urea Progesterone Aspirin Warfarin
  4. 4. MECHANISMS OF DRUG TRANSPORT  The passage of drugs across the membrane is called drug transport  Mechanisms of transport 1. Passive Diffusion 2. Carrier mediated transport – a. Facilitated diffusion b. Active Transport 3. Pore transport 4. Ion pair transport 5. Endocytosis
  5. 5. PASSIVE DIFUSSION  90% drugs enter the cell by passive diffusion  Occurs along the concentration gradient, no energy consumed  Not-saturable and Nonselective  No carrier needed  Depends on lipid solubility  Depends upon the pKa of the drug and pH of the medium  Rate of diffusion can be given by Frick’s law.
  6. 6. FRICK’S LAW  The law states that, the drug molecules diffuse from a region of higher concentration to one of lower concentration until equilibrium is attained and the rate of diffusion depends on the concentration gradient of the drug across the membrane, the thickness, area and permeability of the membrane.  Mathematically it can be expressed by the following equation,  Where, C1 and C2 are the intracellular and extracellular concentration of the drug respectively.  Limitations – It does not consider factors like ionic charge, pH and charge gradients across the membrane
  7. 7. DO YOU RECALL?  In which form will the drug pass the membrane passively? a) Charged or Ionized b) Uncharged or Neutral? Relation between pKa and pH ? What is pKa? How is the strength of an acid or base related to dissociation?
  8. 8. ASPIRIN  Acetyl salicylic acid  Weak acid  pKa = 3.5  Absorbed from the stomach Protonated form Deprotonated form
  9. 9. pH TRAPPING  Net diffusion of acidic and basic drugs across lipid bilayer membranes is affected by a charge based phenomenon called pH trapping.  The extent of drug trapping on one side of the membrane depends on drug's acid dissociation constant pKa and by the pH gradient across the membrane.  The Henderson-Hasselbalch(H-H) equation describes this relation  For a weak acid, HA A- + H+ the H-H equation is, Mouth pH= 6.8 Stomach pH= 1-3 Blood pH=7.4 Small intestine pH=5-7.5
  10. 10. IN THE MOUTH  Substituting in Henderson-Hasselbalch(H-H),  pH= 6.8~ 7 and pKa(Aspirin)=3.5~4 pKa= pH+ log[NI]/[I] 4=7+log[NI]/[I] -3=log[NI]/[I] Taking antilog on both sides, [NI]/[I]=0.001=1/1000  i.e only 1 molecule will be unionized or protonated & 1000 molecules will be ionized or deprotonated  Thus, Aspirin in the mouth will be present in the ionized form & thus is NOT ABSORBED Mouth pH= 6.8
  11. 11. IN THE STOMACH  pH= 1 and pKa(Aspirin)=3.5~4  Substituting in Henderson-Hasselbalch(H-H), pKa= pH+ log[NI]/[I] 4=1+log[NI]/[I] 3=log[NI]/[I] Taking antilog on both sides, [NI]/[I]=1000=1000/1  Aspirin in the stomach - unionized or uncharged form & thus is ABSORBED from the stomach into the blood.  The pH of blood is 7.4, at this pH drug will be ionized and thus cannot re-enter the stomach. Trapped! Stomach pH= 1-3 Blood pH=7.4
  12. 12. FACTORS AFFECTING DRUG TRANSPORT For weak electrolytes (partially ionised) drugs diffusion would depend on- 1. Degree of ionisation 2. pH of the surrounding environment 3. Lipid: water partition coefficient of their undissolved form
  13. 13. CARRIER MEDIATED TRANSPORT Facilitated diffusion Active transport
  14. 14. FACILITATED DIFFUSION  Occurs along a concentration gradient, no energy consumed  Requires carriers  Saturable  Structure specific  Mixed order kinetics also called as Michaelis-Menten kinetics  Examples - Antineoplastic agents, B1, B2 and B12
  15. 15. ACTIVE TRANSPORT  Requires energy & carried out by transporters viz ABC transporters and SLC(Solute Linked Carriers) ABC transporters SLC transporters 49 genes- classified into 7 families 52 families with 386 transporters Primary active transporters Secondary active transporters P-gp & Cystic fibrosis Transmembrane Regulator (CFTR) OATs, OCTs,Serotonin (SERT) & Dopamine (DAT) transporters
  16. 16. ENDOCYTOSIS  Involves engulfing extracellular materials within a segment of the cell membrane to form a saccule or a vesicle (hence also called as corpuscular or vesicular transport) which is then pinched-off intracellularly  Fats, starch, oil soluble vitamins and drugs viz Insulin  Absorbed into the lymphatic circulation thus bypass the first pass metabolism  Types : a. Phagocytosis(cell eating) : adsorptive uptake of solid particulates b. Pinocytosis(cell drinking): uptake of fluid solute. Eg. Sabin vaccine https://www.immunopaedia.org.za/immunology/archive/neonatal-immunity-2/intestinal- mucosa/b-cell-humoral-immunity/vaccine-associated-paralytic-polio/
  17. 17. ION PAIR TRANSPORT  Drugs that ionize at all pH  Low o/w partition coefficient values  Penetrate  forming reversible neutral complexes with endogenous ions. e.g. mucin of GIT.  Complex  lipophilicity & aqueous solubility to pass the membrane  Quaternary ammonium compounds  Inderal (Propranolol) is a basic drug that forms a complex with oleic acid to form neutral complex. Transport of cationic drug across the lumen of GI
  18. 18. SR. NO. TRANSPORT MECHANISM CHARACTERISTICS GI LUMEN MEMBRANE BLOOD 1. Passive Diffusion Drugs with high lipophilicity & Mol.wt : 100-400 Da 2. Pore transport Water soluble drugs Mol.wt > 100 Da 3. Carrier mediated transport Structure specific Carriers- OATs, OCTs Vit B, Antineoplastic drugs 4. Ion pair transport Drugs that ionize at all pH Propranolol+oleic acid 5. Endocytosis Larger molecules Sabin vaccine, Insulin
  19. 19. BARRIERS  Capillary endothelial barrier  Blood Placental barrier  Blood testis barrier  Blood cerebrospinal barrier  Blood brain barrier
  20. 20. BLOOD BRAIN BARRIER  The BBB is a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from non-selectively crossing into the extracellular fluid of the central nervous system  What makes the BBB so difficult to cross? 1) Endothelial cells - Tight junctions : limit the paracellular flux of solutes - Transporters : Efflux transporters – Pgp transporters - Release of inactivating enzymes 2) Basement membrane - Pericytes 3) Astrocytes https://www.youtube.com/watch?v=enM__fmRYeo&t=21s
  21. 21. HOW ARE DRUGS ADMINISTERED? Approaches for drug delivery to the brain  Intrathecal delivery  Disruption of BBB – Chemical methods/ Focused ultrasound  'Trojan horse' strategy  Inhibition of Pgp efflux pumps  Delivery system  Enzymatically resistant analogs- Phosphorothioate OligoNucleotides (PONs) http://www.radtechonduty.com/2017/03/intrathecal-and-intraarticular-contrast.html
  22. 22. CASE STUDY A 28 year old male presented in the accident and emergency department with a left-sided facial swelling and difficulty swallowing. He has a 3 day history of increasing left sided facial swelling. He had been assessed in an emergency doctor 24 hours before admission, who had prescribed erythromycin 250 mg QDS, which had failed to reduce either the size of the swelling or the associated symptoms. On examination, the patient was in an early septic shock (BP 98/65, pulse 142, respiratory rate 24, temperature 39.5); he was pale and sweaty. He had extensive swelling of the left buccal and submandibular tissue spaces and his lower left and right first and second molar teeth were grossly decayed. His airway was patent but mouth opening was restricted. Following fluid resuscitation the patient was taken to have the grossly carious molar teeth removed under general anaesthetic. Pre-operatively, the haemoglobin level was 11.4 g/dL. When the full blood count was repeated 24 hours after the surgery the haemoglobin had dramatically reduced to 6.9g/dL. There was initial concern that the contaminated venous blood specimen had been processed, but second sample confirmed that the automated count was correct. On detailed questioning, the patient described episode of melaena following admission which he had failed to inform the medical or nursing staff about. In addition, he revealed that he had been taking NSAID preparation (Ibuprofen and Nurofen). He also gave a history of epigastric pain two days prior the episode of melaena but had no other GI symptoms. The facial swelling had restricted his eating, so he had been ingesting NSAIDs on an empty stomach. An upper gastro-oesophageal endoscopy(OGD) was organized and revealed an extensive erosive gastritis and duodenitis, but without evidence of mucosal ulceration. Routine duodenal biopsies found no histological evidence of coeliac disease and CLO testing was negative for Helicobacter pylori. As precaution, all the NSAIDs were discontinued and the patient transfused with 3 units of packed cells. A proton pump inhibitor (lansoprazole 30 mg once daily) was initiated. The patient was discharged 5 days after the admission and was maintained on the proton pump inhibitor for a month. A follow-up endoscopy was arranged 6 weeks post-discharged.
  23. 23. REFERENCES  Biopharmaceutics and Pharmacokinetics–A Treatise by Brahmankar D.M ; Jaiswal Sunil.B; second edition 2009.  Principles of pharmacology: the pathophysiologic basis of drug therapy by Golan D.E., 2nd Edition, 2007, Lippincott Williams and Wilkins.  Roth, M., Obaidat, A., & Hagenbuch, B. (2012). OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. British journal of pharmacology, 165(5), 1260–1287. https://doi.org/10.1111/j.1476-5381.2011.01724.x  Daneman, R., & Prat, A. (2015). The blood-brain barrier. Cold Spring Harbor perspectives in biology, 7(1), a020412. https://doi.org/10.1101/cshperspect.a020412  Banks, W.A. Characteristics of compounds that cross the blood-brain barrier. BMC Neurol 9, S3 (2009). https://doi.org/10.1186/1471-2377-9-S1-S3  Milner, N., Dickenson, A., & Thomas, A. (2006). The use of NSAIDs in dentistry: A case study of gastrointestinal complications. Dental update, 33(8), 487-490.
  24. 24. THANKYOU!

Notas do Editor

  • Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker class. It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance anxiety, and essential tremors. with oleic acid
  • CNS ECs also express an extremely low level of leukocyte adhesion molecules (LAMs), as compared with ECs in other tissues greatly limiting the amount of immune cells that enter the CNS 
  • production of dark sticky faeces containing partly digested blood, as a result of internal bleeding or the swallowing of blood.

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