Pharmacology, Jan 10, 2007

 Epithelial Barriers o Principles of Medical Pharmacology, Kalant, et al. 2007, pg. 17 o Don’t need to know details like ‘zona occludens’  3 types of capillaries that allow drug to move in o Capillaries with macula  Small opening within the capillary wall  Capillaries themselves are not connected  Pinocytosis  Fenestrae • Transient • Channels that open up and then close off and open up somewhere else o Fenestrated capillaries  Permanent holes  Secretory organs (Pituitiary, thyroid…) or organs of excretion (KI)  Free drug – can only pass through here. Others are too big. Therefore when talking about metabolic issues, refers to free drugs o Major membrane that drugs can penetrate is BBB  Almost all cells are in contact with each other, except: • Pituitary, pineal gland, area postrema (vomit c), choriod plexus, median eminence.  Protects blood from xenobiotics, therefore pros and cons  Mechanisms of Absorption o Familiar terms o No matter how drug given, it will always have to cross membranes  Hydrophobic or lipophilic o Passive diffusion  Needs to be more lipophilic  Certain situations where membranes have water layer outside the membrane, therefore need some hydrophobic properties needed.  What else helps to pass passively? • Charge o If charged, will not pass by membrane easier • Size o The larger the M.Wt, the greater the prevention o Pores that allow passive diffusion are only so big • Polarity o Related to charge  Passive Diffusion o Lipid solubility depend partition coefficient  How lipid soluble something is  The higher the partition coefficient the more lipid soluble  The more lipid soluble the easier it passes through the membrane

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o Drugs also get taken into the body and cells through active transport  Energy powered mechanism o Facilitated diffusion  Not energy dependent Kalant, et al Principles of Medical Pharm. Pg. 21 o Tree branches sticking out – glycocalyx  Attracts water o Needs quality of both, but need correct ratio Gap junctions o Communicating from cell to cell Passive diffusion o Factors influence passive diffusion  Partition coeffienct • If high will pass  S.A • Bigger the S.A, easier to pass through memb • Where is there the biggest S.A? o Microvilli, found in S.I o Most drugs absorbed here, second in ST  pH and Drug protonation • will get a question on the test in this area The pH Factor o Weak acid on its own is charged o When proton attaches to a weak acid, get a protonated form that is nonionized or not charged or uncharged o Protonated weak acid, means that the H is connected to the A o Weak bases on their own are not charged, but when stick a H, they are charged o Protonated base is charged o Only the nonionized/uncharged form is lipid soluble o pH is key to understand Only the non-ionized form is lipid soluble o No plus or minus to the form will move into the area Hendersen-Hasselbalch equation o pKa higher, more protonated forms than unprotonated forms o lower pKa, more unprotonated form o hint for test question!!! Example: ST vs. intestines o ST is acidic, therefore a lot of protons hanging around o If drug X is a weak acid and is in the ST, what’s going to happen?  The H + will attach  Will get absorbed

Most likely drug X will be absorbed in the ST, where there are more H+ than intestines where there are less H+ o If drug X is a weak base?  Want the substance to be nonprotonated to be absorbed  Don’t want it in an environment with a lot of H+ hanging around, therefore better absorbed in the intestines than in the ST Factors influencing Drug Action o How quickly passing through GI tract o Mesentaeric blood flow  More blood in the area more possibility of getting absorbed o Site of administration  Plays a role in how well absorbed into the system Drug Distribution o Make environment acidic or more basic o Intracellular environment is always more acidic than what we see extracellularly, so some drugs get into cells and then can’t get out b/c of charge Pathway of drug distribution (chart) o Many different areas that can have drug distribution Vol. of Distribution o Not as concrete o Gives a number for all pharmacologist for a number needed for distribution o Mathematical calculation summarizes the definition o Low Vd  Drug is staying inside blood and highly protein bound  A lot is plasma protein bond o High Vc  Little of drug is conc in plasma, most of it has moved out (opp of low Vd)  Intracellular protein bound Vd is 3L = plasma vol (Plasma vol is approx 3L) Low Vd concentrated in plasma Vd is 15L = extracellular fluid (20% of body weight) Vd is 45 L = total body water Factors affecting distribution o A drug will bound to plasma protein with varying affinity o Which system in the body would have the least blood profusion?  Adipose tissue  Skin o Systems that are most plasma profuse  Brain  Blood 

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o Lipid solubility  Major distribution and absorption factors  Especially seen in BBB o Drug ionization  pH factor is important Factors Influencing Drug o Plasma protein binding o Lipid solubility of drug will play a role when person’s body type in consideration o Solubility and partition coeffiecient o Existence of BBB, stopping distribution Biotransformation o Xenometabolism/drug metabolism o Transformation and elimination are responsible for the gradual decline of drug concentration over time o Largest concentration is in the LIV, where we will be spending more time learning about Role of biotransformation o Xenobiotics – other foreign compounds o Metabolite – drug that is broken down  Broken down to more water soluble compounds  If more water soluble, less likes to move out of the plasma, then plasma can take to KI and KI can get rid of it through urine o Many different forms of metabolites o Prodrug – inactive form of the drug  Has a very large first pass effect (first place it goes in the body is the LIV)  Goes to LIV and then is active Phases of Biotransormation o Phase I  A lot of times will deactivate a drug  Breaks it up and creates reactive component  Chops it up to make it more reactive in the body  Passing through and getting a phase I response can be very deadly  Get reactive metabolites coming out of body o Phase II  Major mechanism  Conjugation reaction • Major mechanisms to detoxify, deaden the drug • Makes it very water soluble and very likely to leave the body  Metabolites will come out as being deactivated Summary of possible sequential relationships…

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o Upper box – Phase I reaction, lower is Phase II reaction o Final product is exreted product o Most ideal pathway is the fat line  Phase I reaction, weakens then goes to Phase II, becomes more water soluble, more polar and then excreted o Sometimes parent drug can go to phase II ‘Phase I’ Mechanism o Oxygen molecule is usually added, water is excreted, compound changed to something more hydrophilic o Oxidative reaction  Very important!!!!  Cytochrome P450 • Not just one enzyme, name of a family of enzymes • When do research, come across CYP3A12 • This family is so important b/c enzymes can be induced an inhibited • Family of different isozymes • So one drug won’t be just metabolized, maybe 80% by that one, 10% by another one, and 5% by another one CYT P450 Enzyme Family o P450 is a family of isozymes o Each isoform catalyzes a different (but overlapping) spectrum…. o Hydrolytic reactions o Reductive Reactions CYT P450 Enzyme Family o Many drugs, herbs, nutrients alter drug biotransformation by INHIBITING or INDUCING P450 enzymes o Interactions may occur if these inducers/inhibitors are given together with drugs that need P450 for metabolism o (i.e. Alcohol consumption, P450, and drug use)  Need to know what effects it’s going to have in the LIV to know if it’s going to react or not ‘Phase 2’ Mechanisms o Add a clump to the different metabolites, and makes them more water soluble o Can possibly ask a multiple choice questions re: Phase I and Phase II  know what lies in each category Factors affecting biotransformation o Vitamins  A, B1, B2, C, E, K o Minerals  Calcium magnesium, iron, copper, zinc, and iodine o Hydrocarbons

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 Burned foods induce biotransformation o Disease states  Liver cirrhosis Genetic variations of biotransformation o 20mg of acetylation has 2 hours to have an effect o Every 4 hours has to take another dose o Slow acetylator, therefore take it later than 4 hours, not sooner o The only biotransformation that drug undergoes is biotransformation o if a slow acetylator  so normally 2 hours is when normally get a drug effect and between 2 to 4 hours is when the drug is gone  start to get effect of the drug in about 2 hours and stop after 4 hours  get more out of the drug, need less of it Drug/Elimination/Clearance o Clearance  How many ml/min the body can get rid of the drug Drug Elimination: KIDNEY o Drug reabsorbed into the body Excretion via the KI o Passive tubular resorption  Want it charged so that it’s absorbed by the KI and excreted  How many overdoses occur Renal Clearance o Note:  Renal excretion rate/plasma [drug] Clearance by the LIV o First Pass effect o Intrinsic clearance  See higher concentration of LIV enzymes of a higher affinity between drug and enzyme First Pass Effect o By the time it gets to the LIV get a lot more to the organs Enterohepatic cycling o Conjugated drugs may be hydrolyzed into free drug by intestinal bacteria which facilitates the drug’s re-absorption o Example:  Antibiotics may kill gut bacteria therefore decrease enterohepatic cycling of estrogen (therefore a lower therapeutic effect; i.e. birth control) Elinimation half-life o Definition:  >the time required to eliminate half of the rug amount from the body

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 > the time it takes to reduce the plasma [drug] by 50%  The half-life will change if either the drug’s …. Factors Influencing Drug Action: Early Ages o Usually around 2 years old, the LIV metabolizes quicker than that of an adult Factors Influencing Drug Action: Aging Adults o More likely to be on a variety of drugs o Albumin  Major protein carrier of drugs  If decreases with age, then have to be worried about adverse effects  Need to take less and more often o Lean body mass  Change is body distribution, so drug concentrates in different areas  Need to adjust dose to compensate o LIV weight decreases with age o Drugs that are highly protein bound need to be given in lower dosages in the elderly Factors influencing Drug Action: Drug Interactions o Action of the drug on the target site, and therefore pharmacological effect in the body o Calcium channel blockers and grapefruit  70% of this drug will be eliminated the minute given to a person  Know that it takes 3mg to get a therapeutic effect, thus need to give person 10mg and bypass eliminate the first effect  If drinking grapefruit juice, deactivates cytochrome P450  If cytochrome P450 not working, they are getting beyond therapeutic levels of the drug Factors Influencing Drug Action: Disease o Renal disease  Affects how well the drug gets out of the body  People who have renal disease depend of prostaglandins to help maintain residual renal function o Viral infection  Someone with the flu can be susceptible to various drug interactions o Alzheimer-type dementia  Seen particularly with anticholenergic Homework: o How do NSAIDs and Anticoagulants work?