Pharmacokinetics

What is Pharmacokinetics?

Pharmacokinetics is the movement of drugs throughout the body. The phases of pharmacokinetics are absorption, distribution, metabolism, and excretion.

Absorption

Drug absorption is the movement of the drug into the bloodstream after administration

- 80% of drugs are enteral

- Drugs that are not PO do not pass through the GI tract

- Sublingual, buccal, IM, IV, SQ, nasal sprays, eye/ear drops, inhalants, transdermal, parenteral

- Drug dissolution is the action of disintegrating into useable chemicals for the body to absorb

- Drugs in liquid form have a faster rate of dissolution than solids for GI absorption

- Generally, both solid and liquids, get absorbed and dissolute faster in acidic pHs (1 or 2) than alkaline fluids

- Very young and older adults have less gastric acidity, which causes slower absorption for drugs primarily absorbed in the stomach

- Enteric-coated (EC) drugs can resist the acidity of the stomach and are absorbed in the alkaline portion of the small intestine

- EC medications should not be crushed or altered because it can affect the drug absorption

- Most PO drugs are absorbed across the mucosal lining of the small intestine

- Blood flow, pain, stress, hunger, fasting, food, and pH all affect drug absorption

- Poor circulation caused by [[Shock!]], vasoconstrictor drugs, or diseases can cause decreased absorption by decreasing the concentration gradient across intestinal mucosa (reducing passive diffusion), altered transit time, and reduced removal from the intestinal tract

- Drugs given rectally are absorbed slower than the GI tract because the small intestine has villi which increases the surface area for absorption

- The makeup of the suppository (e.g. fatty bases or water-based) may also affect the absorption speed

Distribution

Distribution is the movement of drugs from the circulation to body tissues

Perfusion

- Drugs are easily distributed in highly perfused organs like the liver, heart, and kidneys

- Tissues with low perfusion like muscle, fat, and peripheral organs result in decreased drug distribution

Brain

- The blood-brain barrier (BBB) protects the brain from ~98% of drugs on the market

- Drugs that are highly lipid soluble with a low molecular weight are able to cross by diffusion or transport proteins

- E.g. [[Pharmacology/MISC/Benzodiazepines]]

- Water-soluble and free drugs are unable to cross the BBB

Pregnancy

- During pregnancy, drugs can cross the placenta as much as they do other membranes, which affects the fetus and mother

- Drugs taken during pregnancy can have varying effects on a fetus

- First trimester can lead to spontaneous abortion

- Second semester can lead to spontaneous abortion, teratogenesis, or other subtler defects

- Third trimester may alter fetal growth and development

Bioavailability

- Bioavailability is the percentage of administered drug available for activity

- Factors that affect bioavailability include the following:

- Drug form (e.g. inhalation, transdermal, capsule, EC, liquid)

- Route

- Gastric mucosa and motility

- Administration with food and other drugs

- Changes in liver function

- Decrease in liver function or hepatic blood flow can increase the bioavailability of a drug only if it is metabolized by the liver

- Less is destroyed by hepatic metabolism in the presence of liver disorder

Protein Binding

- Drugs that are more than 90% bound to protein are known as highly-bound drugs

- These drugs have very little bioavailability because the free-floating drugs are the ones that are used by the body

- When multiple H-B drugs are administered together, they compete for sites, which leads to increased free drug levels and result in drug accumulation and toxicity

- Drugs that are less than 10% bound to protein are known as weakly protein-bound drugs

- These drugs have very high bioavailability because the free-floating drugs are the ones that are used by the body

- Protein binding can be altered by low plasma blood levels

- Poor protein binding levels can be very dangerous with drugs that have high binding rates because it can lead to toxicity and drug accumulation

- Patients with liver or kidney disease or malnourished may have significantly lower albumin levels

- Older adults are at higher risk for hypoalbuminemia

- Especially if they suffer from multiple chronic illnesses

Metabolism

Metabolism (biotransformation) is the process by which the body chemically changes drugs into a form that can be excreted

Liver

- The liver is the primary site of metabolism

- Drugs that pass through the liver are partially metabolized into inactive forms and excreted, which reduces the total bioavailability of the drug prior to distribution, known as the first pass effect

- Drugs from routes that do not enter the portal circulation (IM, SQ, IV, nasal, sublingual, buccal, transdermal, inhalation) do not experience the first pass effect, only those that pass through the GI tract

- A large percentage of drugs are lipid-soluble, which the liver converts to water for renal excretion

- Hepatitis and cirrhosis can lead to altered metabolism and excess drug accumulation and toxicity can result

Drug Metabolism

Prodrugs

- Prodrugs are inactive drugs that become active after they are metabolized

- Designed to increase bioavailability

- A prodrug may be used to improve any part of pharmacokinetics, decrease toxicity, or target specific site of action

Half-Life

- Drug half-life is the time it takes for the body to get rid of half of the amount of the drug

- Previous doses, metabolism, and elimination effect the half-life of a drug

- Understanding how long a drug's half-life is is necessary to reach the steady state

- A steady state occurs when the amount of drug administered equals the amount of drug being eliminated

- Usually takes ~4 half-lives to reach a steady state

- For drugs with long half-lives, a loading dose may be required

- A loading dose is a singular large dose (higher than the maintenance dose) used to give the patient the level they need to reach a therapeutic effect

Excretion

Excretion occurs when the body is eliminating the metabolized waste products from the body

- The kidneys are the primary excretion site

- Prerenal, intrarenal, and postrenal conditions affect drug excretion

- In normally functioning kidneys, they would excrete free drugs, water-soluble drugs, and drugs that are unchanged

- Drugs can also be excreted through bile, sweat, the lungs, saliva, and breast milk

- Urine pH influences drug excretion

- Acidic urine promotes the elimination of weak base drugs and alkaline urine promotes the elimination of weak acid drugs

- The respective drugs are more readily ionized and less likely to be reabsorbed by the kidneys