Absorption/Distribution Drug effects are affected by Absorption and Distribution –Absorption refers to the entrance of drug into the blood stream –Distribution refers to distribution to the various tissues once in the blood

Drug Forms Aqueous –Water and sugar and added drug Alcoholic –Drug dissolved in EtOH (5- 20%) Solid Capsules –Gelatin dissolves in stomach releasing drug Delayed –release –2-3 single doses released over time Enteric coated –Acid resistant covering prevents digestion in stomach Suppositories –Self explanatory Ointments –Petrolatum or lanolin for topical absorption Transdermal –Bandage or patch and absorbed through skin for up to 24 h

Routes of Administration Oral (PO) –Safest and most convenient –Typically takes min for appearance in blood –Can be removed by gastric lavage or induced vomiting Parenteral –Any route that does not involve GI tract

Parenteral Administration IM –Intramuscular injections- short action (min) Gluteals or deltoids –Gluteals and sciatic nerve IV –Intravenous injection – immediate action Directly into bloodstream Drug cannot be withdrawn once administered Inhalation – short action –Nose, mouth into lungs during inspiration

The Five Rs Right patient Right drug Right dose Right route Right time

Absorption Drug must be dissolved in body fluids Drugs must pass through membranes (except IV administration) –GI –Blood vessels –Many drugs rely on passive diffusion to be absorbed (concentration gradient)

Absorption affected by –Lipid solubility More fat soluble compounds diffuse easily across membranes –Drug ionization Like Na+ and Cl- ions do not diffuse readily across membranes Basic drugs (aspirin) are un-ionized in the stomach and more readily absorbed Acidic drugs (morphine, streptomycin) un-ionized in lower GI and more readily absorbed

Liquid formulations are typically absorbed more quickly Solid tablets or capsules must dissolve in body fluids before they can be absorbed –Slows down the absorption process

Drug Distribution Distribution of drug to tissues affected by factors such as –plasma protein binding –Blood flow –Blood brain barrier

Plasma Protein Binding Primarily albumin and globulins –Proteins help regulate osmotic balance Many drugs attracted to proteins –Some are bound to proteins –Some are unbound (free to circulate) –Only unbound drugs exert effect

Blood Flow Various organs receive different blood flow Liver, kidneys and brain have largest supply –These organs exposed to largest amounts of drugs Adipose has poor supply –Does not receive large amounts of drugs –Lipid soluble drugs can accumulate

Blood Brain Barrier An extra layer of lipid membrane that protects the brain –Water soluble compounds do not cross blood brain barrier effectively –Drugs that are intended to act on the brain must have a lipid soluble chemistry E.g benzodiazepines treat anxiety and convulsions Some antibiotics are not lipid soluble and cannot treat infections of the brain

Drug Metabolism Conversion of foreign substances to chemical forms that can be eliminated (biotransformation) –Renal, intestinal, respiratory Main organ of transformation is liver Drug microsomal metabolizing system or cytochrome P450 system Converts lipid soluble compounds to water soluble –Easily eliminated in the urine

Metabolic conversions can inactivate drugs by converting to more easily excretable form –Also typically less active at receptor Conversions can also activate “pro-drugs” –E.g. codeine is metabolized to morphine a more potent form of opiates

Phase I and Phase II reactions Phase I –Drug is oxidized or reduced to more polar form More readily excreted Phase II –Drug is conjugated to glutathione Increases the polarity of the drug even more Phase II is not dependent on phase I although often happens after I

Induction Liver P450 system responsible for Phase I reactions P450 can be induced by consistent drug administration –E.g. chronic alcohol use Increases metabolism and excretion of drug resulting in tolerance

Inhibition Co-incidental administration of two drugs metabolized by same P450 system will result in inhibition of conversion of each of the drugs –Can result in increased potency, duration of action of drug –May often result in adverse effects

First Pass Metabolism Drugs that are orally administered are absorbed and pass into portal circulation These drugs pass through liver prior to distribution Many of these drugs are metabolized (activated or inactived) extensively Protective mechanism

Excretion Three primary routes of excretion –Renal – urine –GI – feces –Respiratory – exhaled gases Kidney is primary organ of excretion

Renal Excretion Blood is filtered through the glomerulus of the kidneys –Most filtered substances are eventually reabsorbed –exceptions- urinary waste products Waste products are water soluble and usually ionized So,.. Excreted drugs must be water soluble and ionizable

The Kidney

The Nephron

Urine Formation 1) Filtration Movement of materials across the filtration membrane into Bowman’s capsule 2) Reabsorption Solutes are reabsorbed across the wall of the nephron into the interstiial fluid Water is reabsorbed across the wall of the nephron by osmosis 3) Secretion Solutes are secreted across the wall of the nephron into the filtrate

GI Excretion After oral administration, unabsorbed drug passes through GI tract and is excreted in feces Some drugs can be reabsorbed in the intestinal tract

Respiratory Excretion Typically, general anesthetic gases are not totally absorbed –Remnants exhaled Some drugs are metabolized to products that can leave exchange with blood and air in lungs –Exhaled also

Half Life Time required for the concentration of a drug in the blood to fall to half of its original level Dependent on ADME Affected by liver or kidney disease Necessary to determine dosing regimen

Bioavailability Amount of drug that is actually absorbed into the blood stream Dependent on route of administration –E.g. drugs with high First Pass metabolism will not have good oral bioavailability –Necessary to administer parenterally

Patient Profile Age Pregnancy Smoking and drinking Liver or kidney desease Pharmacogenetics Drug interactions Psychological factors

Age Drug metabolism (P450) enzymes –Underdeveloped in young –Compromised in elderly –Adult dosages may not be extrapolated to children or elderly

Pregnancy Drug effects in pregnant women can have drastic effects on unborn, or no effects at all – FDA pregnancy categories –Teratogenic drugs –Drugs affecting breast feeding

Smoking and Drinking Both induce P450 enzymes Can effectively lower effective drug concentration in blood Can more activate pro-drugs more effectively

Liver or Kidney Disease A damaged liver will metabolize drugs to a lesser extent –Can result in greater or lesser active drug Damaged kidneys excrete less drug metabolites