Pcol 1 and 2

• Clinical Pharmaceutics

  • Quantitative study of drug movement in, throughout the body
  • Study of the time course of a drug's movement through the body
  • Understanding of what the body does to (or with) the drug
  • Application of Therapeutic Drug Monitoring (TDM) and individualization of drug therapy

  
• Pharmacokinetics

  What the body does to the drug? (Absorption, Distribution, Metabolism, Excretion (ADME))

  
• Pharmacodynamics


  What the drug does to the body? (Drug concentration at the site of action or in the plasma is related to a magnitude of effect)

  
• STUDY OF DRUG OVERTIME
• Biological Membrane

  • Bilayer of phospholipid and cholesterol molecule – 100 Å thick
  • Extrinsic and intrinsic protein are embedded in the membrane
  • Glycoprotein – on the surface
  • Protein varies from cell to cell
  • Paracellular spaces and channels are also present

  
• Drugs are transported through the following

  • Passive diffusion
  • Filtration
  • Specialized transport
• Passive Diffusion

  • Drug diffuses from higher concentration to lower concentration across the membrane
  • Lipid soluble drugs – dissolving lipoidal matrix of membrane
  • Diffusion will depend on lipid solubility of drug, difference in concentration, pH of tissue
• Filtration

  • Passage of drug across the aqueous pores in the membrane or through the paracellular spaces
  • Lipid insoluble drugs crosses membrane, depends on size of pores and drug molecule

  
• Specialized Transport

  • Carrier Transport
  • Facilitated Diffusion
  • Active Transport
• Carrier Transport

  • Transmembrane protein – carriers and transporters for physiologically important ions, nutrients, metabolites, transmitters
  • They also translocate xenobiotics including drugs metabolites
  • Specific for the substrate
  • Depends on the requirements of energy
• Carrier Transport

  1. Transmembrane protein binds with their substrate transiently

  2. Conformational changes – carrying the substrate to the other side of membrane

  3. Dissociates

  4. Return back to its original position
• Facilitated Diffusion

  • Belongs to super family of solute carrier (SLC) transporter
  • Operates without need of energy – transport in the direction electrochemical gradient
  • Higher to lower concentration
  • Example: glucose in muscle and fat cells by GLUT 4
• Active Transport

  • Requires energy and acts against the electrochemical gradient
  • Selective accumulation of solutes on 1 side
  • Inhibited by metabolic poison
  • Example: levodopa and methyl dopa absorbed from the gut- aromatic amino acid transport

  
• Primary Active Transport

  • Directly by the hydrolysis of ATP
  • Transporter belongs to superfamily of ATP binding cassette (ABC)
  • Only efflux of solute from cytoplasm i.e. to extracellular fluid or intracellular organelle
  • Also known as uniport

  
• Secondary Active Transport

  • Another type of SLC
  • Energy to pump one solute is derived from downhill movement of another solute (mostly Na+)
  • SYMPORT/CONTRANSPORT -concentration gradient is such that both solute move in same direction
  • ANTIPORT/EXCHANGE transport- move in opposite direction
  • Mediates uptake and efflux of drug and metabolite
• Specialized Transport: Endocytosis


  • Very little importance to the drug translocation
  • Large protein molecules and other metabolic waste
• Absorption

  • Movement of drug from its site of administration into circulation
  • Not only amount of absorption but also rate of absorption is important
  • Except when given I.V the drug has to cross biological membrane which is governed by solubility, concentration, area of absorbing surface, vascularity of absorbing surface, route of administration

  
• Bioavailability

  • A concept for oral administration
  • Useful to compare two different drugs or different dosage forms of same drug
  • Rate and extent of absorption of a drug
  • Fraction of administered drug that reaches systemic circulation in unchanged form
  • Bioavailablity by I.V is 100 % but by other routes it decreases to some extent due to incomplete absorption, first pass metabolism, local binding
  • Bioavailability is not a characteristic solely of the drug preparation: variations in enzyme activity of gut wall or liver, in gastric pH or intestinal motility all affect it

  
• Distribution

  • Once the drug has gained access to blood it gets distributed to other tissues
  • The extent of distribution of a drug depends on lipid solubility, ionization at physiological pH, extent of binding to plasma, tissue protein : Fat, difference in regional blood flow, disease like CHF, Uremia, cirrhosis
• Apparent Volume of Distribution

  • Volume that accommodate all the drugs in body, if the concentration throughout was same as in plasma
  • V = dose administered/plasma drug concentration

  
• Types of Volume of Distribution

  • Intravascular
  • Extracellular Uniform
  • Intracellular
• Redistribution

  • Highly lipid soluble drugs gets distributed to high perfusion low capacity tissues like heart, brain, kidney and low perfusion high capacity tissues like muscle fat
  • When plasma concentration of drug falls, drug is withdrawn from this site prolonging the action of drug
  • Greater the lipid solubility faster is its redistribution
  • Short acting drugs can be prolonged by administering slowly and continuously – low perfusion high capacity tissues
• Blood Brain Barrier

  • Capillary endothelial cells in brain have tight junction and lack large intercellular pores and above that there is layer of neural tissue
  • In Choroid plexus, capillaries are lined by choroidal epithelium with tight junction – blood-CSF barrier
  • Both this membrane allows lipoidal drug and limit the entry of non-lipoidal drug
  • BBB is deficient in Chemoreceptor Trigger Zone (CTZ) in medulla oblongota and Peri-ventricular site – anterior hypothalamus
  • Exit of drug from brain is not dependent on lipid solubility but on bulk flow of CSF and non specific organic anion and cation transport
• Placental Barrier


  • Placental membrane is lipoidal and allows free passage of lipophillic drugs, while restricting lypophobic drugs
  • But higher concentration of lypophobic drugs in maternal circulation – gain access to fetus
• Plasma Protein Binding

  • Physiochemical affinity for plasma proteins
  • Acidic drugs – albumin, Basic drugs – α1 acid glycoprotein
  • Extent of binding depends on individual compound – no generalization for pharmacological class can be made
• Clinical Significance of Protein Plasma Binding (PPB)


  • Highly PPB drugs – intravascular compartment except large paracellular spaces (capillaries) smaller volume of distribution
  • Temporary storage of drug – bound protein is not available for action
  • High degree of PPB – long acting – bound fraction is not available for metabolism, unless it is exclusively extracted by liver or kidney
  • One drug can bind to many sites of the protein or two or more drug can bind at same site
  • Displacement interaction
  • Hypoalbuminemia – binding is reduced, thus high concentration of free drug may be attained
• Metabolism

  • Also known as biotransformation
  • Chemical alteration in the body
  • Causes loss of biological activity and thereby excretion via renal route – increases hydrophilicity
  • Primary site of drug metabolism: Liver, Kidney, intestine, lungs, plasma
• Biotransformation

  • Activation - few drugs are administered in inactive form (PRODRUG) and needs to be activated to form active metabolite
  • Inactivated - active metabolite and most drugs are inactivated

  
• Phases of Metabolism

  • Phase I (Non-synthetic, Functionalization, Catabolic)
  • Phase II (Synthetic, Conjugation, Anabolic)

  
• Phase I

  • Non-synthetic, Functionalization, Catabolic
  • Functional group is generated - more chemically reactive
  • Oxidation, reduction or hydrolysis
  • Cylcization - Formation of ring from straight carbon chain
  • Decylization - Opening of the ring of the cyclic molecule

  
• Phase II

  • Synthetic, Conjugation, Anabolic
  • Results in inactive products (Exception: active sulfate metabolite of minoxidil)
  • Both phases decrease lipid solubility, thus increasing renal elimination
• Phase I Reactions

  • Hydroxylation
  • Oxygenation at C, N or S atoms
  • N/O dealkylation
  • Oxidative deamination
  • Reduction
  • Hydrolysis
• Phase I: Oxidation

  • Addition of oxygen/negatively charged radical or removal of hydrogen/positively charged radical
  • Insertion of O - short lived highly reactive quinone/epoxide/superoxide
  • Most important metabolizing drug reaction
• Phase II: Glucouronide Conjugation


  Drug containing hydroxyl or carboxylic acid group gets conjugated

  
• S atoms

  Atoms of the element sulfur
• N/O dealkylation

  • Type of thing
• Oxidative deamination


  • Type of thing
• Phase I

  First phase of drug metabolism
• Cyclization

  1. Formation of ring from straight carbon chain

  2. Ex: Proguanil

  
• Decyclization


  1. Opening of the ring of the cyclic molecule

  2. Ex: Barbiturates & Phenytoin