Chapter 2: Drug action & Handling Lisa Mayo, RDH, BSDH Pharmacology DH206

Thank you laura!!

Learning Objectives Pharmacodynamics Pharmacokinetics Routes of drug administration Factors that alter the effect of a drug

Objective #1 Pharmacodynamics Definitions Dose-Response Relationships (potency, efficacy, ceiling effect, toxicity) Drug-Receptor Interactions

Pharmacodynamics 1.) Definitions Pharmacodynamics: describes the actions of a drug on the body Involves drug-receptor interaction, mechanism of action, drug response, dose-response relationship Therapeutic effect: intended effect of the drug in the body Drug Indication: therapeutic uses of the drug in the body Contraindication: situation or circumstance when a drug should NOT be given Undesirable effects: (CH3) Side Effects Adverse Effects Toxic Effects

Pharmacodynamics 1.) Definitions Site of Action Location within the body where the drug exerts its therapeutic effect Ex: aspirin’s site of action is on the hypothalamus to reduce fever Mechanism of Action Explains how a drug produces its effects Drugs do NOT impact a new function in an organism Drugs either intensify same actions or block actions in the body Drugs speed up or slow down reactions in the body

Pharmacodynamics 2.) Dose-Response curve Determine correct DOSE of drugs to give to patients Determines POTENCY & EFFICACY of a drug’s action Response of any drug depends on the amount given: this is called dose-response relationship Dose: amt of drug given to produce a desired effect Response: the effect of that dosage A curve results when DOSE of a drug is plotted against the INTENSITY of it’s effect ↑ dose = ↑ magnitude of response Threshold dose: minimum dose of a drug needed to produce a therapeutic/measurable response

Pharmacodynamics 2.) Log-dose curve Log dose-effect curve Therapeutic range of the drug is plotted where the dose is increasing sharply Max response of a drug may exhibit is plotted where the curve plateaus: also called ceiling effect Max Response Therapeutic Range

Pharmacodynamics 2.) Log-Dose Curve Log dose-effect curve Once ceiling effect attained: if give more drug, no further effect will be observed Doses above ceiling effect usually result in toxicity & adverse effects Max Response Therapeutic Range

Pharmacodynamics 2.) POTENCY (p.13) Potency: measure of strength or concentration of a drug Potency is shown by the location of that drug’s curve along the x-axis Less-potent drugs: need more to produce a desired effect equivalent to that of a more potent drug Determined by the affinity of a drug for its receptors Potency usually expressed in terms of median effective dose (ED50) – next slide BEER VS JACK DANIELS

Pharmacodynamics 2.) POTENCY The dose that will produce an effect that is HALF of the maximal response is referred to as the EFFECTIVE DOSE 50 (ED50)

Pharmacodynamics 2.) EFFICACY (p.13) Maximum intensity or effect of a drug that can be reached Ability to produce a therapeutic effect regardless of the dose Efficacy & potency often describe the success of drug therapy Drugs may be equally efficacious, but differ in potency (see next slide)

Board Review Question The strength of a drug with regard to it’s ability to achieve a desired effect is termed A. efficacy B. potency C. therapeutic effect D. tolerance

BOARD Review Answer Potency of a drug is a function of the amount of the drug required to produce an effect

Board Review Question In comparing two drugs, the dose-response curve for the drug that is more efficacious would A. Be closer to the Y axis B. Be farther from the Y axis C. Have a greater curve height D. Have a higher median effective dose

BOARD Review Answer C: The efficacy of a drug increases as the height of the curve increases Efficacy is an expression of maximal activity of a drug The other choices all refer to indicators of drug potency, not efficacy

Pharmacodynamics 2.) Toxicity (CH3) Therapeutic index (TI): ratio of a drug’s toxic dose to its therapeutic dose Safe drugs = High TI Toxic drugs = Lower/Smaller TI Small changes in dose can kill you faster LD50 term used to describe when 50% test subject die The ratio LD50/ED50 is the therapeutic index (TI) of a drug TI = LD50 ED50

TI=LD50 ED50 Median Effective Dose ED50 Dosage of Drug “Sleep” curve never hits 400 on x-axis but if Dr prescribes a dose too high, will hit LD Lethal Dose = Death TI=LD50 ED50 Median Effective Dose ED50 Dosage of Drug

Review What does ED50 stand for? What does LD50 stand for? If a drug has a narrow TI, is the drug safer?

pharmacodynamics 3.) drug-receptor interactions Drugs have an effect in the body by binding to a receptor Drug receptor: protein located on all cell membranes Drugs attach to specific receptors & produce an effect Drug attachment done in 2 ways (next slide) Direct/Specific drug receptor Indirect/Nonspecific drug reaction

pharmacodynamics 3.) drug-receptor interactions Drug attachment done in 2 ways: Direct/Specific drug receptor (most common) Drugs directly binding to cell receptors Cells have 100s of receptors: only certain ones specific for a drug Drugs bind & form Van der Waal bonds (weak, reversible bonds) Indirect/Nonspecific drug reaction Drugs do NOT bind to receptors but instead saturate the water or lipid parts of a cell – drug actions occur based on degree of saturation

pharmacodynamics 3.) drug-receptor interactions LOCK-AND-KEY FASHION OF DRUGS TO THEIR RECEPTORS Drug+Receptor → Drug-Receptor → Effect Complex eventually efficacy can be measured (max drug action)

pharmacodynamics 3.) drug-receptor interactions Different drugs often compete for the same receptor sites (morphine & acetaminophen) The drug with stronger affinity for the receptor will bind to more receptors than the drug with weaker affinity Drugs with stronger affinity for receptor sites are more potent drugs Morphine Acetaminophen Receptor

pharmacodynamics 3.) drug-receptor interactions 3 classifications of drug-receptor complexes Agonist Partial Agonist Antagonist/Blocking Drugs All 3 have an affinity for a receptor, they differ in what they cause the receptor to do!

pharmacodynamics 3.) drug-receptor interactions Agonist Drug that rapidly combines with a receptor to initiate a response Rapidly dissociates/releases from receptor High efficacy Partial Agonist Binds to receptor, produces a mild therapeutic response May inhibit action of agonist when given at the same time (acts like antagonist sometimes)

pharmacodynamics 3.) drug-receptor interactions Antagonist/Blocking Drugs Binds to receptor but does NOT dissociate Has NO positive response or efficacy Blocks reaction of the agonist Ex: naloxone – morphine antagonist – given if have morphine OD 3 different types (next slide) Competitive Noncompetitive Physiologic

pharmacodynamics 3.) drug-receptor interactions Antagonist/Blocking Drugs Competitive: drug that occupies a significant proportion of the receptors and thereby prevents them from reacting maximally with an agonist Noncompetitive: can exert action 2 ways React with receptor to prevent an agonist-receptor response Act to inhibit some event that leads to a response Physiologic: Has affinity for a different receptor site than the agonist but decreases the effect of the agonist by producing an opposite effect via different receptors

NBQ Which of the following terms is related to the amount of drug administered? Dose Response Agonist Toxicity

NBQ Which of the following terms is related to the amount of drug administered? Dose Response Agonist Toxicity

NBQ An individual has an overdose on oxycodone, a narcotic, and is administered a narcotic antagonist. Which of the following features describes antagonist drugs? Binds to the same receptor sites as agonist drugs Binds to the receptor to reduce the actions of the agonist Have a greater affinity to the receptor than agonists Have a lesser affinity to the receptor than agonists

NBQ An individual has an overdose on oxycodone, a narcotic, and is administered a narcotic antagonist. Which of the following features describes antagonist drugs? Binds to the same receptor sites as agonist drugs Binds to the receptor to reduce the actions of the agonist Have a greater affinity tot eh receptor than agonists Have a lesser affinity to the receptor than agonists

Objective #2 Pharmacokinetics Definition Absorption Distribution Metabolism Excretion Clinical Applications

Pharmacokinetics definition Describes what a drug does once inside human body (ADME) Absorption Distribution Metabolism Excretion Drugs usually enter body at a site distant from its intended target – must travel through bloodstream in the body

Pharmacokinetics Absorption ADME

Pharmacokinetics absorption Entrance of a drug into the blood stream Drug must first be dissolved in body fluids Requires the drug to pass through biologic membranes The rate of absorption of a drug influenced by: Physicochemical factors (physical & chemical conditions such as temperature, redux potential…) Site of absorption (determined by route of administration: IV, oral, rectal….) The drug’s solubility

Pharmacokinetics absorption Topics for Absorption Passage across cell membranes Effects of ionization: review of basic chemistry, acid-base effects on drugs

Pharmacokinetics absorption Passage Across Membranes Before a drug is absorbed = must pass through cell membrane to get to the organ that has the receptor for the drug Drugs are best absorbed in small intestine & stomach Site of drug action: final destination of the drug

Pharmacokinetics absorption Passage Across Membranes Cell membranes: composed of lipids, proteins, & carbohydrates “Like dissolves like” Lipids: make up biphospholipid layer of cells Drugs that are water soluble do NOT pass through this layer with ease Lipid soluble drugs pass with ease (passive diffusion) LIPID SOLUBILITY OF A DRUG IS ONE OF THE MOST IMPORTANT DETERMINANTS OF THE PHARMACOKINETIC PROPERTY OF THAT DRUG!! Proteins: contain small water channels/pores Water soluble drugs can pass through this structure easily (passive diffusion) Lipid soluble drugs do NOT pass through this structure with ease

Pharmacokinetics absorption Passage Across Membranes IV drugs pass directly into bloodstream Orally administered drug ↓ Pass down esophagus Small intestine Blood for distribution to its target organ

Pharmacokinetics absorption Passage Across Membranes Mechanism of drug transfer across membranes occurs by one of the following: Passive diffusion Facilitate diffusion Active transport Pinocytosis

Pharmacokinetics absorption Passage Across Membranes Passive diffusion Most drugs absorbed this way (water or lipid soluble) Movement from high to low concentration, along a concentration gradient Lipid soluble a drugs pass directly through cell membrane Water soluble drugs pass through water channels or pores No energy is required for his form of diffusion Ex: General anesthetics pass blood-brain barrier quickly due to being a lipid soluble drug – fast onset of action

Pharmacokinetics absorption Passage Across Membranes Facilitated diffusion/Passive-mediated transport Carrier PRO transports drug that is too large to passively diffuse No energy is needed for transport Ex: penicillin, aspirin Active transport Carrier PRO transports a drug against a concentration gradient Requires use of ATP Not common in pharmacology Ex: vitamin B12, amino acids

Pharmacokinetics absorption Passage Across Membranes Pinocytosis Involves engulfment of fluids or particles by a cell Minor role in drug movement Cell membrane traps the substance ↓ Forms a vesicle Detaches and moves to inside the cell Requires LARGE amount ATP

ATP ATP

Pharmacokinetics absorption Effects of ionization READ PAGE 17: EFFECTS OF IONIZATION

Pharmacokinetics absorption Effects of ionization Most all drugs are weak acids or bases Weak electrolytes dissociate in solution: Non-ionized + Ionized form Un-ionized/non-ionized/uncharged Lipid soluble Cross lipid cell membranes easily Ionized/charged Low lipid solubility Cannot easily cross lipid membranes

Pharmacokinetics absorption Effects of ionization The pH of tissues at the site of administration and dissociation characteristics (acid dissociation constant, or pKa) of the drug will determine the amount of drug in the ionized vs non-ionized state (ex: aspirin absorption in stomach vs mouth) Portion in each state will determine the ease with which the drug penetrates tissue Ex: acidic drugs (aspirin) are mostly un-ionized when they are in an acidic fluid (gastric juices) so drug absorption is favored (same hold true for basic drugs) Ex: acidic drugs (aspirin) is mostly ionized when in alkaline fluids so absorption occurs at a slower rate & to a lesser extent (same holds true for basic drugs)

Pharmacokinetics absorption Effects of ionization Memorization Tricks Unionized = mimic lipid = ↑ absorption, ↓ excretion Ionized = mimic water = ↓ absorption, ↑ excretion Acidic drugs in basic solution = ↑ excretion Basic drugs in acidic solution = ↑ excretion Acidic drugs in acidic solution = ↓excretion Basic drugs in basic solution = ↓ excretion ↓ Absorption ↑ Absorption

Pharmacokinetics absorption: chem review Effects of ionization pH of body fluids vary greatly Low pH (high acid) = gastric juices (1.5pH which will dissolve metal) High pH (high base) = blood & plasma (facilitates the transport of O2)

Pharmacokinetics absorption: chem review Effects of ionization The acid-base nature of drugs is useful in treating drug toxicity (OD) Drugs are excreted by kidneys in an ionized form To ↑ drug excretion = alter pH of urine Ex: increase renal excretion of an acid drug (aspirin), the urine is alkalized (pH>7) Alkaline urine - acidic drugs are mostly ionized & more rapidly excreted

Pharmacokinetics absorption: Chem Review Effects of ionization (not need to know for test) Example: stomach made of parietal cells Interior of parietal cells protected from the acidic juices of stomach by their membrane Membrane allows H2O & neutral molecules to pass in&out but blocks movement of ions like H+ H+ can cross membrane through ACTIVE TRANSPORT (using ATP) (cont’d next slide)

Pharmacokinetics absorption: chem review Effects of ionization (not need to know for test) Stomach: eating stimulates H+ SECRETION If acid content excessively high = influx H+ through membrane by active transport & back to plasma Causes muscle contraction, pain, swelling, bleeding, inflammation Antacids will neutralize HCl and ↓ H+ concentration In rxn = all those chemical breakdown into different molecules w/ CO2 and H2O (CO2 makes patient belch)

Pharmacokinetics absorption: chem review Effects of ionization Strong acid/bases = rxns will go to completion Weak acids/bases = rxns ionize only to a limited extent in water (less than 100%) Degree to which a weak acid ionizes depends on the concentration of the acid and the equilibrium constant for the ionization All weak acid/bases vary in their strength of ionization Some weak acids are weaker than other weak acids

Pharmacokinetics absorption: chem review Effects of ionization A symbol of Ka is used when discussing acids and bases and their strength K=symbol used when a molecule breaks apart A=acid Ka is the acid dissociation (molecules breaking apart) constant In Pharmacology, not use Ka, use pKa which is a log-rhythm of Ka Ka= 2.0x103 so the pKa=2.0 Larger pKa = weaker the acid (see next slide) pKa = acid dissociation constant (when 50% of the drug is ionized and 50% is unionized)

Smaller pKa Stronger acid Larger pKa Weaker acid Smaller pKa Weaker base Larger pKa Stronger base

Pharmacokinetics absorption: chem review Effects of ionization Getting drugs into the body can be done 2 ways: Hydrophilically: soluble in aqueous solutions Dissolves well in water molecules Polar molecules Lipophically: fats, alkanes, oil Cell membranes made of lipids Non-polar molecules General Rule for molecule solubility: LIKE-DISSOLVES-LIKE Hydrophilic like hydrophilic (polar dissolves polar) Lipophilic likes lipophilic (non-polar dissolves non-polar)

Pharmacokinetics absorption: chem review Effects of ionization (not on test) Generic Acid RXN HA + H2O A- + H3O+ H will be donated eventually Anion Hydronium ion A=any acid Conjugate base *Acids will dissociate to form a conjugate base*

Pharmacokinetics absorption: chem review Effects of ionization (not on test) Strength of conjugate base in solution HCl → H+ + Cl- Strong acid Weak conjugate base (Will not readily react w/H+ free ion) HF → H+ + F- Weak acid ← Strong conjugate base (will readily react w/H+ free ion)

Pharmacokinetics absorption: chem review In pharmacology, we need to relate to pH of tissues to the pKa of drugs RULES Acidic drugs become more non-ionized in acidic pH Basic drugs become more non-ionized in basic pH Acidic Drug Basic Drug Acid pH (stomach) Non-Ionized Ionized Basic pH (Plasma) Ionized Non-Ionized

Pharmacokinetics absorption: chem review Hydrophilic = Ionized molecules (charged) Lipophilic = Non-Ionized molecules (non-charged) Lipophilic molecules penetrate cell membranes because they are made of lipids (LIKE-DISSOLVES-LIKE) Ionized Molecule Water soluble Cell Membrane Non-Ionized Molecule Fat soluble

Pharmacokinetics absorption: chem review Summary: 3 things need to know to find out if a drug is Hydrophilic or Lipophilic Whether drug is acid or base (will be told) pKa of the drug (pH at which number of ionized molecules = number of non-ionized molecules, next slide) pH of tissue into which the drug is going to be placed

Pharmacokinetics absorption: chem review Acid drugs become more non-ionized in acidic pH WHAT IS THE PkA? When 50% ionized & 50% non- ionized which is 6 (↑ absorption) pH 2 pH 6 pH 8 More absorption Less absorption Acid drug Acid tissue 75% drug NI 25% drug I Acid drug Neutral tissue 50% drug NI 50% drug I Acid drug Basic tissue 25% drug NI 75% drug I Non-Ionized Ionized

Pharmacokinetics absorption: chem review Basic drugs become more non-ionized in basic pH WHAT IS THE PkA? When 50% ionized & 50% non- ionized which is 8 pH 2 pH 9 pH 8 Less absorption More absorption Basic drug Acid tissue 2% drug NI 98% drug I Basic drug Basic tissue 75% drug NI 25% drug I Basic drug Neutral tissue 50% drug NI 50% drug I Non-Ionized Ionized

Pharmacokinetics absorption: chem review If know the pKa and pH of the tissues Can figure out if drug mostly ionized or mostly non-ionized Can then figure out if hydrophilic or lipophilic Can then know if drug will cross the cell membrane or dissolve in water Ex: drugs given by mouth have to dissolve across a membrane (lipophilic drugs) Ex: drugs given by IM (intramuscular injection) have to be able to dissolve in water (hydrophilic drugs)

Read p.17 “weak acids”

Pharmacokinetics absorption: (Book) Effects of ionization: Weak Acids If pH of the site absorption increases (becomes more basic), H+ concentration falls (pH ↑ = H+↓) This results in an increase in the ionized form (A–) (hydrophilic), which cannot easily penetrate tissues If the pH of the site absorption falls (more acidic), H+ concentration will rise (pH↓ = H+↑) This results in an increase in the un-ionized form(HA) (lipophilic), which can more easily penetrate tissues HA + H2O → A- + H3O+

Read p.17 “weak acids”

Pharmacokinetics absorption (Book) Effects of ionization: Weak Bases If the pH of the site rises (more basic), the H+ concentration will fall This results in an increase in the un-ionized form (lipophilic), which can more easily penetrate tissues If the pH of the site falls (more acidic), the H+ concentration will rise This results in an increase in the ionized form (hydrophilic), which cannot easily penetrate tissues

Pharmacokinetics absorption Effects of ionization Summary In the presence of infection, the acidity of the tissue ↑ (pH ↓) Effectiveness of local anesthetics decrease In the presence of infection, the H+ increases because of accumulating waste products in the infected area Low pH = acidic tissue = lots extra H+ loose & convert anesthetic into SALT form (RNH+) so it will not penetrate fatty tissues because is hydrophillic & will not mix with fatty tissue Tissues also swollen, lots of fluid = dilutes anes Big open dilated blood vessels carry anes away faster = wears off faster

Pharmacokinetics absorption Effects of ionization Summary Regardless of pH & ionization, absorption usually occur in small intestine where there is more surface area due to presence of microvilli on the surface Enteric-coated tablets (aspirin, erythromycin) have a layer (wax/cellulose polymer) on the outside to protect the stomach lining from exposure to these acidic drugs Blood flow to the organ can affect absorption (Ex: nitroglycerin administered sublingual because will have faster absorption due to high vascularity of the organ)

NBQ A patient is taking clindamycin for prophylaxis against bacterial endocarditis. In order for the clindamycin to be absorbed into the blood, it must pass through 3 barriers: epithelial cells + blood vessels + brain 2 barriers: epithelial cells + blood vessel 1 barrier: blood No barrier: drug goes directly into blood

NBQ A patient is taking clindamycin for prophylaxis against bacterial endocarditis. In order for the clindamycin to be absorbed into the blood, it must pass through 3 barriers: epithelial cells + blood vessels + brain 2 barriers: epithelial cells + blood vessel 1 barrier: blood No barrier: drug goes directly into blood

NBQ All of the following statements are TRUE about lipid soluble drugs EXCEPT which one? Readily absorbed through blood vessel wall Slowly absorbed through cell membrane Goes through the blood-brain barrier Can be given by inhalation

NBQ All of the following statements are TRUE about lipid soluble drugs EXCEPT which one? Readily absorbed through blood vessel wall Slowly absorbed through cell membrane Goes through the blood-brain barrier Can be given by inhalation

NBQ Which of the following statements is TRUE regarding absorption of local anesthetics? Lidocaine (pKa 4) is not absorbed easily through lipid membranes Lidocaine (pKa 7.9) has a fast onset because the tissue pH is close to the pKa Lidocaine (pKa 8.3) has a faster onset than lidocaine Lidocaine (pKa 7.7) has a slow onset of action because it is highly ionized

NBQ Which of the following statements is TRUE regarding absorption of local anesthetics? Lidocaine (pKa 4) is not absorbed easily through lipid membranes Lidocaine (pKa 7.9) has a fast onset because the tissue pH is close to the pKa Lidocaine (pKa 8.3) has a faster onset than lidocaine Lidocaine (pKa 7.7) has a slow onset of action because it is highly ionized

Review What does pKa stand for? Acid drugs will be in greatest unionized state when placed into ______ tissue. If a drug has a fast rate of excretion, what does this mean for absorption? If pKa is small – is the acid strong or weak? If pKa is small – is the base strong or weak? Is H+ concentration high or low in acidic state?

Pharmacokinetics distribution ADME

Pharmacokinetics distribution Once a drug in the bloodstream through absorption – then distribution will occur Distribution phase: time is takes drug to get through lymph, blood, plasma to target organ The manner in which a drug is distributed in the body will determine: How rapidly it produces the desired response Duration of that response Whether a response will occur at all

Pharmacokinetics distribution Factors Affecting Drug Distribution Presence of specific tissue barriers Blood-brain barrier & placenta are lipid barriers Blood flow Greater blood flow = greater rate of distribution of the drug to that organ Drugs distributed faster to the heart, kidney, brain than to skeletal muscle, adipose tissue, skin which have lower blood flow Solubility of the drug Hydrophilic drugs like insulin – do not penetrate lipid cell membranes, entirely distributed in the extracellular fluid Lipophilic drugs (general anesthetics, alcohol) do cross lipid layer & are more evenly distributed in all fluids Plasma-PRO binding or free drug (next slide)

Pharmacokinetics distribution Plasma PRO binding or un-bound/free drug Many drugs are bound to plasma-PRO (esp albumin) Degree of PRO-binding depends on concentration of drug in the blood & affinity of that drug for the PRO PRO-binding ↓ distribution of the drug from the plasma to intended receptor Some drugs are highly bound to plasma PRO (99%), while other drugs are not bound to any significant degree Binding is reversible Some drugs compete for PRO-binding sites: remember drug with higher affinity for the receptor wins – can cause problems if 2nd drugs knocks 1st drug from the PRO - ↑ levels of 1st drug in system Only the un-bound/free drug can exert the pharmacologic effect (NBQ) Only the free drug can pass across cell membranes

Pharmacokinetics Distribution Blood-Brain Barrier This barrier is an additional lipid barrier that protects the brain by restricting the passage of electrolytes & other water-soluble substances Since brain composed of large amts of lipids, lipid-soluble drugs pass readily to the brain To penetrate the central nervous system, a drug must cross the blood-brain barrier

Pharmacokinetics metabolism ADME

Pharmacokinetics metabolism Whenever a drug is taken into the body – the body immediately starts trying to eliminate it Why you can smell alcohol on someone's breath – part of ethyl alcohol excreted via respiratory system Metabolism is the chemical alteration of drugs & foreign compounds in the body

Pharmacokinetics metabolism LIVER is the main organ involved in metabolism Grp of enzymes found in liver are called DMMS (drug microsomal metabolizing system) DMMS uses cytochrome P-450 enzymes that are important in oxidation & reduction rxns that convert drugs into their metabolites (next slide) Function of DMMS: convert lipid-soluble drugs into water-soluble so they can be excreted by kidneys & not reabsorbed into circulation Remember: lipid drugs more readily absorbed Water-soluble form of drugs can be excreted

Pharmacokinetics metabolism/biotransformation Metabolites will be formed during metabolism Metabolic product Is more ionized/polar/hydrophilic then the original drug Increase excretion of the drug

Pharmacokinetics metabolism/biotransformation DRUG Ingested Metabolic product formed (MP) MP+ Less lipid soluble/More water soluble Kidney absorption of MP+ increased, ↓ plasma-binding & fat storage More easily excreted from the body Metabolism begins (Liver)

Pharmacokinetics metabolism/biotransformation Drug metabolism is an enzyme-dependent process Drugs can be metabolized 3 ways Active to inactive An inactive metabolite is formed from an active drug Most common process Inactive to active An inactive drug (also called prodrug) will be transformed to an active compound once ingested Ex: vyvance used to tx ADHA is inactive – once ingested – changes composition in the GI tract – then active metabolite produced Helps reduce abuse of ADHD drugs

Pharmacokinetics metabolism/biotransformation Drugs can be metabolized 3 ways Active to active An active parent drug may be converted to a second active compound, which is then converted to an inactive product Ex: Valium is active anti-anxiety drug – metabolized into active metabolite desmethyldiazepam = Valium’s action prolonged because of its active component combining with metabolite active component This is why Valium’s half-life can be 20 hours

Pharmacokinetics metabolism/biotransformation 2 phases of drug biotransformation Phase I: occurs in liver Place drugs into the correct chemical state to be acted upon by Phase II conjugative mechanisms Prepares chemicals for phase II metabolism and subsequent excretion Drugs that are lipid soluble go through, if water form – can skip this phase Phase II True “detoxification” step in the metabolism process Turns drugs into highly water-soluble compounds

Faster Excretion Slower Excretion

Pharmacokinetics metabolism/biotransformation Phase I Liver uses enzymes to make lipid-soluble drugs more water-soluble by adding or unmasking functional groups (-OH, -SH, -NH2, -COOH, etc.) Cytochrome P450 enzymes located in liver Concentration affected by drugs like ethanol, narcotics, barbiturates, smoking, etc… When take these drugs repeatedly, P-450 enzyme concentrations will ↑ in the body = called enzyme induction ↑ P450 = ↑ rate of metabolism = thus a↓ in effects of meds taken Ex: smoker/alcoholics have higher levels of P-450 = LA will not work as effectively and they will need higher levels of to achieve full anesthesia TOLERANCE patients develop to drugs/meds explained in part by P-450 actions

Pharmacokinetics metabolism/biotransformation Table 2-1 lists drugs that increase (induce) P-450 enzymes List to know for boards: Alcohol, tobacco, antidepressants, anticonvulsants, NSAIDs, antidepressants, antipsychotics, antiarrhythmics, erythromycin, antidepressants, benzos, calcium-channel blockers, opioids

Pharmacokinetics metabolism/biotransformation Different P-450 enzymes CYP3A4 Most common enzyme that metabolizes drugs used in dentistry Ex: lidocaine, erythromycin, clarithromycin CYP2D6 Codeine, Prozac, Propranolol CYP2C9 Ibuprofen Certain drugs can decrease or increase action of these enzymes Ex: grapefruit juice inhibits CYP3A4 metabolism of Xanax – results in elevation of drug in system

Pharmacokinetics metabolism/biotransformation Phase I Lipid molecules are metabolized by the 3 processes Oxidation: Causes the loss of part of the drug molecule by incorporating O2 into the drug. MOST COMMON Reduction: occurring in liver with hepatic enzymes Hydrolysis: Adding water to molecules Ex: ester compounds metabolized this way. Enzymes found in plasma = break up ester & add H2O. Ester anes inactivated by plasma cholinesterases

Oxidation-redux rxns: chem review

Pharmacokinetics metabolism/biotransformation Phase II Involve conjugation with endogeneous substrates to further increase water solubility of the drug Glucuronic acid, acetic acid, amino acid, sulfuric acid The most common conjugation occurs with glucuronic acid

Pharmacokinetics metabolism/biotransformation Phase I and II - Summary: Products are generally more water soluble These reactions products are ready for renal excretion There are many complementary, sequential and competing pathways Phase I and Phase II metabolism are a coupled interactive system interfacing with endogenous metabolic pathways

NBQ Displacement of a drug from plasma albumin binding sites would usually be expected to: Decrease the amount of distribution Increase blood levels of the drug Decrease the metabolism of the drug Increase the metabolism of the drug

NBQ Displacement of a drug from plasma albumin binding sites would usually be expected to: Decrease the amount of distribution Increase blood levels of the drug Decrease the metabolism of the drug Increase the metabolism of the drug

review What is a prodrug? Do hydrophilic drugs have faster excretion? Name something that can induce enzyme induction.

Pharmacokinetics excretion ADME

Pharmacokinetics excretion Drugs may be excreted by any of several routes, but renal excretion is most important Lungs, bile, feces, skin, sweat, saliva, breast milk Drugs may be excreted unchanged or as metabolites Need conversion into hydrophilic compounds first & preferably in ionized form Acidic drugs mostly ionized by alkaline urine Aspirin/barbiturate OD – will want patient to ingest sodium bicarb to alkaline the urine to allow for more rapid excretion of acidic drug

Pharmacokinetics excretion Drugs may be excreted by any of several routes, but renal excretion is most important Renal Route Extrarenal routes Biliary routes Drugs may be excreted unchanged or as metabolites

Pharmacokinetics excretion: Renal Renal: Elimination of substances in the kidney can occur through 3 routes: Glomerular filtration (most common) Active tubular secretion Passive resorption

Pharmacokinetics excretion: Renal Glomerular filtration (most common) The unchanged drug or its metabolites are filtered through the glomeruli and concentrated in renal tubular fluid

Pharmacokinetics excretion: Renal Active tubular secretion When drug too large for glomerular filtration Requires energy Drug transported from bloodstream, across renal cells, & into renal tubular fluid

Pharmacokinetics excretion: Renal Passive tubular diffusion Keeps drugs useful to the body such as water, glucose, salts Resorbs those drugs and puts them back into blood stream

Pharmacokinetics excretion: extrarenal routes Gases used in general anesthesia are excreted across lung tissue by simple diffusion Alcohol is partially excreted by the lungs (Breathalyzer)

Pharmacokinetics excretion: biliary The major route by which systemically absorbed drugs enter the GI tract and are eliminated in feces Drugs excreted in bile may be reabsorbed from the intestines (enterohepatic circulation) This enterohepatic circulation prolongs a drug’s action Ex: tetracycline

Pharmacokinetics clinical applications Half-Life Kinetics Drug Dose

Pharmacokinetics 1.) half-life READ P.18 “HALF-LIFE”

Pharmacokinetics 1.) half-life The amount of time that passes for the concentration of a drug to fall to 1/2 of its original level Indicator of how long a drug will produce its effect in the body Helps define time intervals between doses When the half-life is short = duration of action is short When the half-life is long = duration of action is long

Pharmacokinetics 1.) half-life Uusally need 4-5 half-lives for drug to be completely eliminated Pen VK given 4x/day but Amox only given 3x/day Due to difference in half-lives of 2 drugs Half-life of 2% Lidocaine w 1:100,000 is 90-120 minutes Why many patients need more anesthetic during long procedures?

Pharmacokinetics 2.) kinetics The mathematical representation of the way in which drugs are removed from the body First & Zero Oder Kinetics/Elimination http://www.youtube.com/watch?v=iwVqXeSIOEc

Pharmacokinetics 2.) kinetics Kinetics: First-order kinetics Most drug elimination follows 1st-order Rate of drug metabolism is proportional to drug concentration Constant % of drug eliminated from body per unit of time In = Out Effect: half life of drug is constant and predictable Half life is the amount of time it takes to eliminate 50% of the drug Clinician knows exactly what will happen and when Decrease chances of toxicity ↑ drug concentration = ↑ rate of metabolism

Pharmacokinetics 2.) kinetics Kinetics: Zero-Oder Kinetics Clinicians do not want to be at zero order kinetics/elimination because the drug plasma is increasing but the body is not eliminating it In = Out Effect: drug will build-up and can lead to toxicity Clinician cannot predict when body will eliminate the drug Drug elimination is at a constant rate in spite of the amt of drug present Ex: aspirin, alcohol, phenytoin(anti-seizure) Too many beers = can lead to high blood plasma concentrations as enter into zero-order kinetics = toxicity = death

Pharmacokinetics 3.) drug dosing Drug dose: quantity of a drug administered Drug w/high rate of absorption = smaller doses needed Drug w/high rate of elimination = larger doses needed Loading dose: large initial dose to rapidly establish a therapeutic plasma drug concentration May need to establish a rapid response in life-threatening situations Maintenance dose: subsequent doses that are smaller than loading dose Maintained for a desired stead-state plasma drug concentration Ex: Pen VK for dental infections 1,000mg immediately (loading dose) 500mg 4x/day doses (maintenance dose)

Review What is half-life? What is a loading dose? What is a maintenance dose?

Objective #3 route of drug administration

Objective #3 route of drug administration Routes of Administration Enteral: Drugs absorbed from GI system Oral, sublingual, buccal, rectal Slower onset of action than parenterally administered agents Parental: Bypass GI system IV, IM, Subcutaneous, Intradermal, Intrathecal Topical

route of drug administration Enteral Oral PO: written Rx directions, means oral route Most common, convenient route Sublingual & Buccal (between cheek & tongue) Absorption through mucosa Rectal Suppository used when a drug is too irritating to stomach, patient nauseous, cannot swallow, pt unconscious Common route for infants, children, older adults

route of drug administration parental Deliver drugs under skin, subcutaneous tissue. Muscle, cerebral spinal fluid, veins Needle at different degree depth and angles Fast absorption, rapid onset Useful for emergencies, unconsciousness, lack of cooperation, or nausea Some drugs must be administered by injection to remain active (insulin) Need good asepsis

route of drug administration Parental IV Administered via vein Used for emergency Produces the most rapid drug response The absorption phase is bypassed More predictable drug response because easy to control drug dose

route of drug administration parental INTRAMUSCULAR Absorption of drugs injected into the muscle occurs as a result of high blood flow through skeletal muscle Useful for irritating drugs Rapid absorption: many blood vessels in muscles Site: deltoid, gluteus muscle Hep B vaccine

route of drug administration parental SUBCUTANEOUS (SC OR SQ) Injection of liquid into connective tissue under skin Dental anesthetics, insulin

route of drug administration PARENTAL INTRADERMAL Injection into dermis TB. Allergy testing INTRATHECAL Less common Spinal anesthesia

route of drug administration topical Application to body surfaces Major barrier is stratum corneum (outermost layer of skin) Some absorption systemically Can be done through Sublingual administration: Oraquix, dental antibiotics (Arestin, Atridox, PerioChip) admin through GCF Nasal passages or trachea: rapid absorption due to presence many capillaries in resp tract, dosing difficult Transdermal: nitroglycerine, smoking cessation

NBQ Which of the following routes will a drug follow after intravenous administration? Vein, general circulation, liver, kidney Esophagus, stomach, small intestine, liver, kidney Liver, small intestine, kidney Vein, liver, general circulation, kidney

NBQ Which of the following routes will a drug follow after intravenous administration? Vein, general circulation, liver, kidney Esophagus, stomach, small intestine, liver, kidney Liver, small intestine, kidney Vein, liver, general circulation, kidney

NBQ Which of the following reasons explains why an IV drug achieves very high initial blood concentration levels? Drugs made of small molecules Drugs have a higher pH No barrier to absorption Expensive to give

NBQ Which of the following reasons explains why an IV drug achieves very high initial blood concentration levels? Drugs made of small molecules Drugs have a higher pH No barrier to absorption Expensive to give

nbq Which of the following routes of drug administration bypasses the GI tract? Intravenous Oral Buccal Sublingual

nbq Which of the following routes of drug administration bypasses the GI tract? Intravenous Oral Buccal Sublingual

nbq A patient had an injection of lidocaine with epi. Which of the following types of injections was given? Subcutaneous Intravenous Intramuscular Sublingual

nbq A patient had an injection of lidocaine with epi. Which of the following types of injections was given? Subcutaneous Intravenous Intramuscular Sublingual