Pharmacokinetics Insulin C 254 H 377 N 65 O 76 S 6

1. Discuss the four main processes that make up pharmacokinetics (absorption, distribution, metabolism, and excretion), and appropriately apply these processes to clinical usefulness. 2. Discuss the advantages and disadvantages of the various techniques of drug administration as they relate to pharmacokinetics, noting especially any barriers to absorption associated with intravenous, intramuscular, and oral administration. Students should also compare oral administration with parenteral administration. 3. Describe blood flow to tissues, the ability of a drug to exit the vascular system, and the ability of a drug to enter cells, and then discuss characteristics of drug molecules that can alter these processes.

4. Compare drugs with short half-lives to those with long half-lives. Discuss the negative effects of repeated drug doses. 5. Discuss the consequences of drug blood levels that fluctuate considerably or erratically between doses, and describe how nurses identify such fluctuations. Discuss measures that traditionally are used to minimize fluctuation. 6. Describe the ultimate “goal” of drug metabolism, also known as biotransformation. Discuss the general processes involved in drug metabolism, and describe in what major/vital organs most drug metabolism occurs. Discuss special considerations in drug metabolism. 7. Discuss the importance of excretion of a drug from the body and some of the routes from which the drug may be excreted.

8. Discuss the importance of understanding the time course of drug responses (plasma drug levels, single-dose time course, drug half- life, and drug levels produced with repeated doses). Explain why clinicians often monitor plasma drug levels, and describe how these levels are regulated to prevent drug toxicity. Identify the two factors that largely determine the duration of a single-dose time course, and compare drugs with short half-lives to those with long half-lives. Discuss the negative effects of repeated drug doses. 9. Discuss the consequences of drug blood levels that fluctuate considerably or erratically between doses, and describe how nurses identify such fluctuations. 10. Discuss measures that traditionally are used to minimize fluctuation.

Pharmakon (drug or poison) Kinesis (motion) Pharmacokinetics (the study of drug movement throughout the body)

* By applying knowledge of pharmacokinetics to drug therapy, we can help maximize beneficial effects and minimize harm.

* If you can nail this chapter, the rest is a breeze. * Understanding this chapter is key.

All phases of pharmokinetics involve movement across the cell Three ways to cross a cell membrane Channels and pores Transport systems P-glycoprotein Direct penetration of the membrane

* Very few drugs cross the membrane using this means. * Channels are very small & highly specific * Only smallest molecules can pass & only if it is the right channel

* Carrier systems that can move drugs from one side of the membrane to another * Some require energy, some do not * All are selective – depends on the drug structure ** Superstar → P-glycoprotein * Transmembrane protein that transports a wide variety of drugs * Present in the liver, kidneys, placenta, intestines and the capillaries of the brain

Most common – why? * Most drugs too big to fit through channels or pores * Most drugs lack transport systems How is this possible? * Drugs must be lipophilic (lipid soluble) * Some molecules are not lipophilic and can not cross the membrane → Polar molecules

* Molecules with uneven distribution of electrical charge * No net charge * Equal number of protons & electrons * Like dissolves like water molecule

* Molecules that have a net charge * Only very small ions are able to cross membranes

* Molecules that have at least one atom of Nitrogen * Carry a +ve charge at all times * Unable to cross most membranes Eg. Turbocurarine (Curare)

* Certain drugs can exist in charged or uncharged forms * Many drugs exist as weak organic acids or weak organic bases. * Who’s your neighbour? Acids tend to ionize in basic media Bases tend to ionize in acidic media e.g. Aspirin (acetylsalicylic acid) (stomach & gut) Acetaminophen

* pH across the membrane * Drug molecules tend to gather on the side of the membrane where the pH most favours ionization Acids like to hang out on the basic (alkaline) side Bases hang out on the acidic side = Ion trapping (pH partitioning) Where’s the party?

The movement of a drug from its site of administration into the blood * Rate of absorption determines how soon effects will begin * Amount of absorption helps determine how intense the effects will be.

* Factors affecting drug absorption * Characteristics of commonly used routes of administration * Pharmaceutical preparations for oral administration * Additional routes of administration

* Rate of dissolution * Surface area * Blood flow * Lipid solubility * pH partitioning See Table 4-1 Properties of Major Routes of Drug Administration (Lehne, p.32)

* Intravenous Barriers to absorption Absorption pattern Advantages Disadvantages * Intramuscular Barriers to absorption Absorption pattern Advantages Disadvantages

* Subcutaneous No significant barriers to absorption * Oral Barriers to absorption Absorption pattern Drug movement following absorption Advantages Disadvantages

* Tablets * Enteric-coated preparations * Sustained-release preparations

* Topical * Transdermal * Inhaled * Rectal * Vaginal

Topical - Peripheral tissue activity - Systemic side effects less likely - If analgesic, applied directly over painful site - Insignificant serum levels Transdermal - Systemic activity - Potential for adverse effects - If analgesic, may be applied away from painful site - Serum levels necessary for effect

* The movement of drugs throughout the body Blood flow to tissues Exiting the vascular system Entering cells Drug distribution is determined by these three factors

* Drugs are carried by the blood to tissues and organs of the body * Abscesses and tumors Low regional blood flow impacts therapy Pus-filled pockets, not internal blood vessels Solid tumors have limited blood supply

* Typical capillary beds Drugs pass between capillary cells rather than through them

* Tight junctions between the cells that compose the walls of most capillaries in the CNS * Drugs must be able to pass through cells of the capillary wall * Only drugs that are lipid soluble or have a transport system can cross the BBB to a significant degree

* Membranes of the placenta do NOT constitute an absolute barrier to the passage of drugs Movement determined in the same way as other membranes * Risks with drug transfer Birth defects: mental retardation, gross malformations, low birth weight Mother’s use of habitual opioids: birth of drug- dependent baby

* Drugs can form reversible bonds with various proteins. * Plasma albumin is the most abundant and important. Large molecule that always remains in the bloodstream Impacts drug distribution

* Some drugs must enter cells to reach site of action. * Most drugs must enter cells to undergo metabolism and excretion. * Many drugs produce their effects by binding with receptors on external surface of the cell membrane. Do not need to cross the cell membrane to act

* Also known as biotransformation * Defined as the enzymatic alteration of drug structure * Most often takes place in the liver

* Hepatic drug-metabolizing enzymes * Therapeutic consequences of drug metabolism * Special considerations in drug metabolism

* Most drug metabolism that takes place in the liver is performed by the hepatic microsomal enzyme system, also known as the P450 system. * Metabolism doesn’t always result in a smaller molecule.

* Accelerated renal drug excretion * Drug inactivation * Increased therapeutic action * Activation of prodrugs * Increased or decreased toxicity

* Age * Induction of drug-metabolizing enzymes * First-pass effect * Nutritional status * Competition between drugs

* Defined as the removal of drugs from the body * Drugs and their metabolites can exit the body through: Urine, feces, air, sweat, saliva, breast milk, or expired air

* Steps in renal drug excretion Glomerular filtration Passive tubular reabsorption Active tubular secretion * Factors that modify renal drug excretion pH-dependent ionization Competition for active tubular transport Age

* Breast milk * Other non-renal routes of excretion Bile Enterohepatic recirculation Lungs (especially anesthesia) Sweat/saliva (small amounts)

* Plasma drug levels * Single-dose time course * Drug half-life * Drug levels produced with repeated doses

* Clinical significance of plasma drug levels * Two plasma drug levels defined Minimum effective concentration Toxic concentration * Therapeutic range

* The objective of drug dosing is to maintain plasma drug levels within the therapeutic range.

* The duration of effects is determined largely by the combination of metabolism and excretion. * Drug levels above MEC – therapeutic response will be maintained.

* Defined as the time required for the amount of drug in the body to decrease by 50% * Percentage vs. amount * Determines the dosing interval

* The process by which plateau drug levels are achieved * Time to plateau * Techniques for reducing fluctuations in drug levels * Loading doses vs. maintenance doses * Decline from plateau