Pharmacokinetics: How Drugs are Handled by the Body

Four Basic Processes in Pharmacokinetics Pharmacokinetics: the study of the movement of drugs through the body Processes: –Absorption –Distribution –Metabolism –Elimination

Six ways drugs can be administered Orally (swallowed when taken by mouth) Rectally (drug embedded in a suppository, which is placed in the rectum) Parenterally (given in liquid form by injection with a needle and syringe) Inhaled through the lungs as gases, vapors, or as particles carried in smoke or in an aerosol Absorbed through the skin (usually as a drugh-containing skin patch) Absorbed through mucous membranes (from snorting or sniffing drug)

Oral Must be soluble and not destroyed by gastric juices Must be able to cross into blood Liquids absorbed faster than tablets Can cause upset stomach and vomiting Hard to predict how much will be absorbed

Injection Three types –intravenous –intramuscular –subcutaneous Disadvantages –rapid absorbtion leaves little time to respond to unexpected drug reaction or accidental overdose –requires use of sterile techniques –once administered cannot be recalled

Drug Distribution At any given time, only a very small portion of the total amount of a drug that is in the body is actually in contact with its receptors. Most of the administered drug is found in areas of the body that are remote from the drug’s site of action. Wide distribution often accounts for many of the side effects of a drug

Membranes that Affect Drug Distribution cell membranes walls of the capillary vessels blood-brain barrier placental barrier

Blood Brain Barrier Required to protect brain from –bacteria –viruses –toxins Required because neurons cannot regenerate Blocks the movement of most drugs into the brain Fat soluble drugs move best

Placental Barrier Drugs cross placental barrier primarily by passive diffusion Fat soluble substances cross rapidly and without limitation Placenta is not a barrier to drugs Psychoactive drugs will be present in the fetus at a concentration quite similar to that in the mother

Termination of Drug Action Four main routes through which drugs leave body –kidneys –lungs –bile –skin The major route is renal excretion Drug must be metabolized by enzymes in liver to a form that can be excreted rapidly and reliably

Time Course Distribution Half Life: time for drug to reach 50% of its peak concentration Elimination Half Life: time for drug concentration to fall 50% Steady State Concentration: the level of drug achieved in blood with repeated, regular-interval dosing

Therapeutic Drug Monitoring Process of correlating the plasma level of drugs with therapeutic response. Large scale clinical trials are performed and blood samples are drawn at multiple time periods (short term and long term) Statistical models used to monitor and adjust patients dosage

Drug Tolerance A state of progressively decreasing responsiveness to a drug. Person requires larger dose to achieve effect Three mechanisms: –metabolic tolerance: liver produces extra enzymes and metabolizes it faster –cellular-adaptive tolerance: receptors adapt sensitivity or increase or decrease number of receptors –behavioral conditioning processes: environmental cues associated with drug become conditioned stimuli that elicit conditioned response opposite to the drug effect

Physical Dependence Needs drug to avoid withdrawal symptoms –called abstinence syndrome

Pharmacodynamics: How Drugs Act

Pharmacodynamics Study of the interactions of a drug and the receptors responsible for the action of the drug in the body. To produce an effect, a drug must bind to and interact with specialized receptors, usually located on cell membranes. –Called -- drug-receptor binding

Six Points about Drug-Receptor Interactions A receptor is usually a membrane-spanning protein that has binding sites for an endogenous neurotransmitter and appropriate drug molecules This membrane-spanning protein is not a simple globule but a continuous series of either 7 or 12 alpha-helical coils embedded in the membrane

Six Points The endogenous neurotransmitter (and presumably drugs also) attaches inside the space between these coils and is held in pace by ionic attractions This reversible ionic binding of the neurotransmitter specific for that receptor may activate the receptor, usually by changing the structure of the protein. This change allows a “signal,” or “information,” to be transmitted through the receptor to the inside of the cell.

Six Points The intensity of the resulting transmembrane signal is thought to be determined by the percentage of receptors that are occupied by molecules of neurotransmitter. A drug can affect the transmembrane signal by binding either to the receptor for the endogenous neurotransmitter or to a nearby site.

Binding of a Drug Results in One of Three Possible Actions Binding to a receptor site normally occupied by the endogenous neurotransmitter can initiate a cellular response similar or identical to that exerted by the transmitter. The drug thus mimics the action of the transmitter. This is termed an agonistic action and the drug is termed an agonist for that transmitter.

Three Actions Binding to a site near the binding site for the endogenous transmitter can facilitate transmitter binding. This is also an agonist action.

Three Actions Binding to a receptor site normally occupied by a neurotransmitter but not initiating a transmitter- like action blocks access of the transmitter to its binding site, which inhibits the normal physiological action of the transmitter. This is called an antagonistic action and the drug is termed and antagonist for that neurotransmitter or receptor site.

Dose Response Curve Plot of the relation between drug doses and the response elicited at each dose level.

Drug Safety and Effectiveness The dose of a drug that produces a specific response varies considerably between individuals. ED 50 : The dose of a drug that produces the desired effect in 50% of the subjects LD 50 : The dose that is lethal for 50% of the subjects therapeutic index: The ratio of LD 50 to ED 50

Drug Interactions Main Effects -- Therapeutic Effects Side Effects With most drugs you have to have some side effects to get the therapeutic effect. Serious side effects are possible –serious allergies –blood disorders –liver or kidney toxicity –abnormalities in fetal development

Placebo Effects Placebo: a pharmacologically inert substance that elicits a significant therapeutic response. Produced by –conditioning –expectancy –self liberation of endogenous neurotransmitters

Placebo Effects Placebos can therapeutically empower patients to stimulate their psychophysiological self-regulation abilities Patient biases and distortions have consequences on therapeutic effectiveness of a drug Must be aware of mental expectations, social setting, predispositions