PHA4107 Pharmacokinetics 2024.pdf

Principles of pharmacokinetics/ pharmacodynamics 1: January 15, 2024 Dylan Burger, PhD [email protected] RGN2513 Outline Pharmacokinetics- basic principles Drug absorption Movement of drug across membranes Drug ionization Routes of absorption Bioavailability Distribution Compartments and drug seque...

Principles of pharmacokinetics/ pharmacodynamics 1: January 15, 2024 Dylan Burger, PhD [email protected] RGN2513 Outline Pharmacokinetics- basic principles Drug absorption Movement of drug across membranes Drug ionization Routes of absorption Bioavailability Distribution Compartments and drug sequestration Volume of distribution Blood brain barrier Placental drug transfer and teratogenicity Protein binding Format In person lectures Additional (optional practice problems) Key terms crossword A few notes 1. There will be math! On the exam only basic math skills will be assumed (i.e. 500/10=50; 200-100=100 etc…). 2. Where possible I prefer to test applied knowledge. 3. I was born in the 80s…sorry FACTORS INFLUENCING DRUG RESPONSES Administered dose of drug Pharmacokinetics Concentration of drug at site of action, duration of effect Pharmacodynamics Drug Response Pharmacology Pharmacokinetics vs. Pharmacodynamics Pharmacokinetics Pharmacodynamics  Study of the factors determining the amount of drug at the receptor site Study of the mechanisms by which drugs produce their biological effects  What the body does to the drug What the drug does to the body  absorption, distribution, metabolism and excretion (ADME)  Dose – Concentration Drug receptor interactions Dose – Response relationship relationship (January 19) PHARMACOKINETICS Pharmakon (greek for drug/poison) + kinesis (motion)- a drugs movement throughout the body. Determines ability of drug to act and duration of action Knowledge of pharmacokinetics helps choose most effective route, dosage & schedule and permits prediction of changes in concentration of a drug with time. PHARMACOKINETICS- Absorption Absorption – Movement of drug from site of administration into blood - Generally this involves crossing a biological membrane - CRITICAL determinant of how rapidly effects of a drug will be seen o Dependent upon o Chemical and physical (i.e. size) properties of the drug o Larger drugs [i.e. tissue plasminogen activators, Alteplase] have difficulty crossing membranes o Surface area for penetration o Greater surface area means a greater chance for absorption o Route of Administration o pH at site of absorption Movement across cell membranes Membranes function as a barrier to the free movement of drug into (and out of) the bloodstream Ability to cross membrane determines where and how long a drug will be present in the body Membrane Structure Passage of Drugs Across Membranes 3 ways to cross a membrane Channels and pores Transport Systems Penetration of the membrane Passage of Drugs Across MembranesChannels and Pores Typically used to facilitate ion flow (i.e. potassium and sodium) May be exploited for absorption of certain drugs (i.e. lithium) Rare mechanism of drug absorption Only very small compounds (molecular weight below 200 Da) can pass through channels/pores 13 Passage of Drugs Across MembranesTransport Systems Large protein-mediated movement of drugs across a membrane. Structure-specific/selective Most drugs absorbed via transport share similarity with endogenous compounds (i.e. vitamins) In some cases no expenditure of energy is necessary and a drug moves with a concentration gradient (passive transport) In other cases direct expenditure of energy is needed to move a drug against a concentration gradient (active transport) ATP-dependent- primary active transport Coupled transport down a concentration gradient is used to fuel movement- secondary active transport Passage of Drugs Across MembranesPenetration of the Membrane Most common mechanism of absorption Most drugs are too large for channels and lack transport systems Cell membranes are primarily lipids. “Like dissolves like”. Thus to directly penetrate membranes, a drug must be lipid soluble (lipophilic). Many drugs are weak acids/bases They exist as both ionized and unionized (charged/uncharged) forms in a ratio that varies according the pH of the surrounding environment Uncharged (unionized) is sufficiently soluble in membrane lipids to cross cell membranes Ionized form is incapable of crossing membranes. How to cross a membranes Movement Across Membranes Unionized form, capable of crossing membranes HowDrug to cross a membranes Ionization The Henderson Hasselbach Equation can be used to assess a drug’s ionization state HA+H2O⇋ H++A− pH = pKa + log ( [A-] / [HA] ) Ionized form (does not cross) Unionized form (crosses membrane) Note if pH= pKa then A- = HA 50% of drug will be ionized Variation in pH in digestive system The pH at the site of absorption can vary greatly in the intestine. Major impact on orally administered drugs Do NOT Memorize Me! Cook et al. (2012) J Contr Rel morphine pKa 8 aspirin pKa 3.5 HA H+ + A- BH+ H+ + B pH 3 7 10 if pHenv < pKa, then relatively more HA or BH+ [i.e. stomach, pH =1-3], then aspirin (A) would be absorbed more readily but base (morphine) would be absorbed less if pHenv > pKa, then relatively more A- or B [i.e. intestine, pH=7], then morphine (B) is absorbed more readily but acid (aspirin) would be absorbed less pH and Absorption- Clinical Considerations The high acidity of the stomach can lead to inactivation of many drugs. Conversely many drugs can be particularly damaging to stomach lining. Enteric coating- a polymer barrier applied to oral drugs to prevent exposure in the stomach. Surface is stable at low pH but breaks down in more neutral/alkaline environments (i.e. small intestine) Drug ionization The Henderson Hasselbach Equation can be further re-arranged for quick calculation of percent ionization. where x = -1 if acid drug or 1 if basic drug If pH=pKa then drug ionization is 50% 100 100 1+10x(0) 1+100 100 1+1 50% Drug Ionization: Sample Question 1 X16823 is an acidic drug that is used for the management of “wolf fever”. Scott Howard needs to take X16823 before attending the dance at Beacontown high school. If the pKa of X16823 is 6.9 and the pH of the stomach is 2.5 what percentage of drug will be ionized when administered? Can Scott take this drug orally or will he need to utilize another method of administration? Drug Ionization: Sample Question 1 X16823 is an acidic drug that is used for the management of “wolf fever”. Scott Howard needs to take X16823 before attending the dance at Beacontown high school. If the pKa of X16823 is 6.9 and the pH of the stomach is 2.5 what percentage of drug will be ionized when administered? where x = -1 if acid drug or 1 if basic drug 100 100 1+10-1(2.5-6.9) 1+104.4 100 1+25118.9 100 25119.9 0.003% Can Scott take this drug orally or will he need to utilize another method of administration? The overwhelming majority of drug will be unionized and able to be absorbed in the stomach. Scott can likely take this drug orally Digestive system (other considerations) Proteolytic enzymes in the digestive system can inactivate drugs Example: Insulin, liraglutide, “peptide drugs” Emerging approaches such as nanoparticles, permeation enhancement and conjugation may enable use of oral peptide drugs https://doi.org/10.1016/j.drudis.2021.01.020 Routes of absorption Topical Enteral Parenteral Classes of Absorption Intravasal Extravasal 25 Via GI tract Avoids digestive system Direct entry to vasculature Administered outside of blood vessels Routes of absorption- Topical (local effect) Drug administered externally directly at site of action Examples: ear/eye drops, antibiotic creams (polysporin), sunscreens Barriers to absorption Advantages No barriers, drug immediately reaches site of action Easiest route of administration Drug administered=drug at site of action. Absorption pattern N/A Disadvantages Irritation can occur at site of action. Limited applicability, site of action must be external. Skin absorption Routes of absorption- Topical (systemic effect) Drug administered externally, is absorbed through skin and enters bloodstream through dermal vessels. Examples: Nicotine, nitroglycerine, estrogen patches Barriers to absorption Advantages Skin and adventitia around dermal blood vessels Convenience, sustained release reduces need for repeated dosing Absorption pattern Disadvantages Generally slow and incomplete Best with low dose, low MW, lipid soluble drugs Limited uses (few drugs will cross the skin at sufficient concentrations) Types of skin absorption Transcellular absorption: Generally for small, non-polar compounds Intercellular: Less selective since drug does not cross cell membrane (minor contributor to drug absorption) Follicular absorption: Generally for small, non-polar compounds. *For the vast majority of compounds follicular absorption is minimal (but not zero). Sample question #2 The drug #Wadsworthdidit is a medium molecular weight, polar sunblock applied topically. Mrs. White applied this sunblock prior to visiting the Clue Mansion. Interestingly, it was found later that a small amount of #Wadsworthdidit had entered her bloodstream causing Flames on the side of her face. Q. Given what you know about #Wadsworthdidit, what is the most likely route of skin absorption for the drug? A. N.B. Entering the bloodstream does NOT mean that a chemical will be active once it does! A drug must be at a certain threshold to achieve its effects. More on this later Routes of absorption- Oral (PO) Drug is swallowed and absorbed through the digestive system Examples: Acetominophen, ACE inhibitors, Statins Barriers to absorption - Epithelial lining of GI tract - Capillary wall of blood vessels in GI system Absorption pattern - Slow and variable Advantages Painless Easy Economical Can be done at home Potential reversibility Disadvantages Requires conscious and cooperative patient Potential for inactivation in stomach Variability in absorption (first-pass effect) Routes of absorption- Sublingual (SL) Drug is placed beneath the tongue Examples: Buprenorphine (suboxone), nitroglycerin, nifedipine Barriers to absorption Dermal layer in the tongue (highly vascularized) Absorption pattern Rapid entry to bloodstream Advantages Rapid absorption Reversible (spit out drug) First pass effect avoided (largely) May be used in unconscious patients. Disadvantages Drug may have unpleasant taste Irritation of mucous membrane can occur Drug may inadvertently be swallowed (altered PK) Note sublingual may be considered either enteral (since it involves the mouth) or parenteral (since it avoids the first-pass effect). Routes of absorption- Intravenous (IV) Drug administered by injection directly to vein Examples: morphine, anesthetics Barriers to absorption- None Absorption pattern- N/A Advantages Immediate action No first pass effect takes place. Preferred in emergency situations Compatible with unconscious patient Real-time titration of dose is possible. Large volume of drug might be injected by this route Diluted irritant might be injected Blood plasma or fluids might be injected in conjunction with drug. Disadvantages Irreversible, greater risk associated with dosing calculations Potential for infection Phlebitis(Inflammation of the blood vessel) might occur Infiltration of surrounding tissues might result. Highly lipid soluble drugs not compatible Routes of absorption- Rectal (PR) Drug administered rectally Solid form- suppository Liquid or gas - enema Examples: indomethacin (anti-inflammatory) Barriers to absorption Advantages Drug is absorbed through rectal lining and enters enteric circulation Compatible with unconscious patients Avoids nausea and vomiting Cannot be destroyed by stomach enzymes Absorption pattern Slow, although more rapid than oral. Partial “first pass effect” Disadvantages Its rectal Partial first pass effect Routes of absorption- Subcutaneous (SC) Drug is administered under the skin Examples: Insulin Barriers to absorption Advantages Capillary wall of dermal vessels Absorption is slow and constant Compatible with highly lipid soluble drugs Absorption pattern Generally slow Disadvantages Limited volume may be injected Potential for local inflammation/ abscess formation Absorption dependent upon blood flow to the region Routes of absorption- Intramuscular (IM) Drug injected directly into muscle Examples: Barriers to absorption Advantages Capillary wall of muscle vessels Absorption is slow and constant Compatible with highly lipid soluble drugs Absorption pattern Generally slow Disadvantages Limited volume may be injected Potential for local inflammation/ abscess formation Absorption dependent upon blood flow to the region Routes of absorption- Inhalation Drug is taken in during breathing through lung Examples: inhaled corticosteroids, nitrous oxide Barriers to absorption Advantages Alveolar lining, lung capillary wall Rapid onset of action Certain drugs can be targeted to lung with lower systemic levels (bronchodilators) Absorption pattern Disadvantages Better for gaseous drugs than solids Technique can impact degree of drug delivery/absorption Rapid Routes of absorption- Time to action Route of Drug Administration Delay time for Action (rough approximation) Intravenous 30-60 seconds Inhalation 2-3 minutes Sublingual 3-5 minutes Intramuscular /Subcutaneous 10-20 minutes Rectal 5-30 minutes Ingestion 30-90 minutes Absorption- First Pass Effect (Pre-systemic metabolism) - A rapid inactivation of drug prior to entry into the systemic circulation. - Drugs absorbed in GI tract enter the portal circulation. Therefore they are exposed to the liver (and its rich drug metabolizing enzymes) prior to distribution to the rest of the body. Major consideration for drugs taken orally. Certain drugs (i.e. morphine, nitroglycerin, buprenorphine) are subject to such an extensive first pass effect that they must be given via alternative routes. Absorption - Bioavailability (F) Bioavailability: Fraction of unchanged drug that reaches the systemic circulation. This fraction will be reduced by incomplete absorption and by hepatic metabolism (first-pass effect) A (i.v) Concentration F = AUC po  dose absorbed AUC iv  dose administered AUC = area under curve AUC = body’s total exposure to the drug. It a function of the dose that enters the systemic circulation via the administration route and drug clearance B (oral) Time Absorption - Bioavailability F = AUC dose absorbed AUC dose administered IV administration F=1 (100% of drug reaches the systemic circulation) Other routes of administration, F is usually