Clinical Pharmacology for Medical Students_USMLE Step 1 & 2 Review by Marc Imhotep Cray, M.D.

Clinical Pharmacology for

Medical Students A USMLE Step 1 & 2 Review (Practice Q&A included) Marc Imhotep Cray, M.D.

Topical Outline Acronyms General Principles Drug Nomenclature Phases of Clinical Drug Testing Drug Administration Pharmacokinetics Absorption Distribution Metabolism (Biotransformation) Elimination Pharmacokinetic Calculation

Marc Imhotep Cray, M.D.

Pharmacodynamics Dose-Response Relationship Effects of Drugs on Receptors Effectiveness and Safety Therapeutic Indices Therapeutic Drug Monitoring Adverse Drug Reactions Approach to Suspected ADRs Variability in Drug Response Drug Interactions Autonomic Pharmacology Common Drug Endings

Acronyms ACE angiotensin converting enzyme ACh acetylcholine ADR adverse drug reaction ARB angiotensin receptor blocker BBB blood brain barrier Cl clearance Cr creatinine CSF cerebrospinal fluid CSFa certain safety factor CYP cytochrome P450 protein DIN drug identification number F bioavailability GFR glomerular filtration rate HH Henderson Hasselbalch Marc Imhotep Cray, M.D.

NDC National Drug Code NE norepinephrine Po/w partition coefficient of a drug PD pharmacodynamics PDE phosphodiesterase Pgp p-glycoprotein PK pharmacokinetics RCT randomized controlled trial TBW total body water TDM therapeutic drug monitoring TI therapeutic index Vd volume of distribution

General Principles Drug Nomenclature Phases of Clinical Drug Testing Drug Administration

Marc Imhotep Cray, M.D.

Drug Nomenclature chemical name: describes chemical structure; consistent in all countries (e.g. N-(4-hydroxyphenyl) acetamide is acetaminophen) NDC: assigned by FDA (US) non-proprietary name: approved name (post-phase III trial), official name (listed in pharmacopoeia), or generic name (offpatent) such as acetaminophen proprietary (trade) name: brand name or registered trademark (e.g. Tylenol®) Marc Imhotep Cray, M.D.

Phases of Clinical Drug Testing  pre-clinical: testing a drug in a controlled environment (lab) on animal or human cells before human testing to discern PK and toxicological profile  phase I: first administration to healthy human volunteers, following animal studies; to determine PK and PD  phase II: first administration to patients, small sample sizes; to determine initial safety and efficacy, dose range, PK, and PD  phase III: large sample sizes, often double-blinded RCT; comparative (new drug vs. placebo or standard of care) to establish safety and efficacy  phase IV: post-marketing surveillance, wide distribution; to determine effects of long-term use, rare ADRs, ideal dosing, and effects in real-world practice Marc Imhotep Cray, M.D.

Drug Administration  choice of route of administration (RoA) depends on:    

drug properties local and systemic effects desired onset and/or duration of action patient characteristics

Marc Imhotep Cray, M.D.

Routes of Drug Administration Route

Advantage

Disadvantage

Oral (PO)

Convenient, easy to administer Large surface area for absorption Inexpensive relative to parenteral administration

Incomplete absorption Hepatic first-pass effect Potential GI irritation

Buccal/Sublingual (SL) Rapid onset of action No hepatic first-pass effect

Must be lipid-soluble, non-irritating Short duration of action

Rectal (PR)

Almost no hepatic first-pass effect Use when NPO, vomiting, or unconscious

Inconvenient, irritation at site of application Erratic absorption

Intravenous (IV)

No hepatic first-pass effect Hard to remove once administered Slow infusion or rapid onset of action Risk of infection, bleeding, vascular Easy to titrate dose injury extravasation Expensive

Intrathecal

Direct into CSF Bypass BBB and blood-CSF barrier

Marc Imhotep Cray, M.D.

Risk of infection 8

Routes of Drug Administration contâ&#x20AC;&#x2122;d. Route

Advantage

Disadvantage

Intramuscular (IM)

Depot storage if oil-based = slow release of drug Aqueous solution = rapid onset of action

Pain/hematoma at site of injection

Subcutaneous (SC)

Non-irritating drugs, small volumes Constant, even absorption Alternative to IV

Pain at site of injection Smaller volumes than IM May have tissue damage from multiple injections

Inhalation

Immediate action in lungs Rapid delivery to blood No hepatic first-pass effect

Must be gas, vapor, or aerosol

Topical

Easy to administer Localized (limited systemic absorption)

Effects are mainly limited to site of application

Transdermal

Drug absorption through intact skin No hepatic first-pass effect

Irritation at site of application Delayed onset of action Hydrophilic drugs not easily absorbed

Marc Imhotep Cray, M.D.

Pharmacokinetics Absorption Distribution Metabolism (Biotransformation) Elimination Pharmacokinetic Calculation Marc Imhotep Cray, M.D.

Important PK Equations Single-Dose Equations (1) Volume of distribution (Vd)

Abbreviations:

(2) Half-life (t1/2) Multiple Doses or Infusion Rate Equations (3) Infusion rate (k0) (4) Loading dose (LD) (5) Maintenance dose (MD) Marc Imhotep Cray, M.D.

Pharmacokinetics  study of “what the body does to a drug”  definition: relationship betw. drug administration, time-course/rate of absorption and distribution, concentration changes in body compartments, and drug’s removal from body (=ADME)

Marc Imhotep Cray, M.D.

Absorption  definition: movement of drug from site of admin. into plasma  Mechanisms of Drug Absorption  most drugs are absorbed into systemic circulation via passive diffusion  other mechanisms include active transport, facilitated diffusion, and pinocytosis/phagocytosis

Marc Imhotep Cray, M.D.

Factors Affecting Rate and Extent of Drug Absorption Po/w (oil/water) partition coefficient of a drug local blood flow at site of admin. (e.g. sublingual vessels facilitate rapid absorption of SL medications) molecular size (e.g. drugs w smaller molecular weight absorb faster)  pH and drug ionization  drugs are usually weak acids (e.g. ASA) or weak bases (e.g. ketoconazole) and thus exist in ionized and non-ionized forms  non-ionized forms cross cell membranes much faster than ionized (charged) forms  ratio of ionized to non-ionized forms is determined by body compartment pH and drug pKa (HH equation)

total surface area for absorption  small intestinal villi are primary site of absorption for most oral drugs

Marc Imhotep Cray, M.D.

Bioavailability (F)  definition: proportion of dose that reaches systemic circulation in an unchanged state

 decreased by limited drug absorption or first-pass effect  IV dose has 100% bioavailability (F = 1)

Marc Imhotep Cray, M.D.

First-Pass Effect  definition: drug metabolism by liver and/or gut before it reaches systemic circulation resulting in reduced F  occurs w PO admin. of a drug: GI tract (absorption) → portal vein to liver (first-pass metabolism) → systemic circulation  occurs less w PR admin. b/c drug absorbed in colon bypasses portal system Examples of Drugs with High First-Pass Effect • Levodopa • Morphine • Propranolol • Lidocaine • Organic nitrates Marc Imhotep Cray, M.D.

Examples of Drugs with Low First-Pass Effect • Diazepam • Digoxin • Phenytoin • Warfarin 16

Efflux Pump  Pgp (P-glycoprotein 1) is a protein found in various parts of body that acts as a multidrug efflux pump involved in transport of drugs out of cells 

 

for example, opposes intestinal absorption (e.g. dabigatran etexilate) and also enhances renal elimination of certain drugs (e.g. digoxin, etoposide, paclitaxel, tacrolimus, cyclosporine) some drugs (e.g. macrolide antibiotics) inhibit Pgp function leading to ↑serum levels of drugs transported by Pgp o Pgp inducers (e.g. St. John’s wort) do opposite some tumors overexpress Pgp leading to multidrug resistance to chemotherapeutic agents

Note: Pgp also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette subfamily B member 1 (ABCB1) or cluster of differentiation 243 (CD243) Marc Imhotep Cray, M.D.

Distribution definition: movement of drugs betw. different body compartments and to site of action

Distribution of TBW Total Body Water 60% of body weight

major body fluid compartments include  Plasma Extracellular Fluid  interstitial fluid 16-20%  intracellular fluid  transcellular fluid (e.g. CSF, peritoneal, pleural)

Intravascular Plasma 4%

Intracellular Fluid 40-44%

Interstitial Fluid 12-15%

tissue compartments include fat, brain

Marc Imhotep Cray, M.D.

In Netter's Atlas of Human Physiology, body water is broken down into following compartments:  Intracellular fluid (2/3 of body water) is fluid contained within cells  In a body containing 40 liters of fluid (ie. about 72 kg total weight), about 25 liters is intracellular→ amounts to 62.5% (5/8), close enough to 2/3 rule of thumb  Extracellular fluid (1/3 of body water) is fluid contained in areas outside of cells  For a 40 liter body, about 15 liters is extracellular → amounts to 37.5%  Again, this is close to 1/3 rule of thumb cited here o Plasma (1/5 of ECF) Of 15 liters of extracellular fluid, plasma volume averages 3 liters→ This amounts to 20% o Interstitial fluid (4/5 of ECF) Transcellular fluid (a.k.a. "third space," normally ignored in calculations) contained inside organs, such as gastrointestinal, cerebrospinal, peritoneal, and ocular fluids Marc Imhotep Cray, M.D.

Factors Affecting Rate and Extent of Drug Distribution     

physiochemical properties of drug (e.g. Po/w and pKa) pH of fluid plasma protein binding binding within compartments (i.e. depots) regional blood flow

Marc Imhotep Cray, M.D.

Volume of Distribution (Vd) Vd: apparent volume of fluid into which a drug distributes maximum actual Vd (anatomic fluid volume accessible to drug) = TBW (TBW~40 L for average adult)  a calculated value (Vd) = amount of drug in body ÷ plasma drug conc.  a theoretical value that does not correspond to an anatomical space (i.e. can exceed TBW)  small Vd corresponds to a drug that concentrates in plasma and/or binds plasma proteins to a high degree o Vd of plasma protein bound drugs can be altered by liver and kidney disease

 large Vd corresponds to a drug that distributes into tissues (fat, muscle, etc.)= most is not in blood (measured) space→ therefore “appears” to distribute in a large volume Marc Imhotep Cray, M.D.

Volume of Distribution cont'd.  example: amiodarone distributes into TBW (actual Vd = 40 L)→ but it also concentrates in fat tissues giving instead an apparent Vd of 400 L, therefore to achieve a given plasma conc. of amiodarone, we dose as though drug distributes into 400 L of body fluid

Marc Imhotep Cray, M.D.

Plasma Protein Binding (PPB)  drug molecules in blood exist in an equilibrium of two forms: 1. bound to plasma protein: acidic drugs bind to albumin, basic drugs bind to α1-acid glycoprotein 2. free or unbound: can leave circulation to distribute into tissues and exert an effect, subject to metabolism and elimination

bound fraction is determined by drug conc., binding affinity, and plasma protein conc. (number of binding sites)  reduced number of binding sites (e.g. hypoalbuminemia) or  saturation of binding sites (e.g. competition/displacement) may result in ↑ conc. of free drug→ which is often metabolized w no harmful effects, although→ toxicity is possible Marc Imhotep Cray, M.D.

Plasma Protein Binding cont’d. Multiple drugs and endogenous substances can compete for same protein binding sites For example  ASA displaces highly protein-bound acidic drugs such as phenytoin thus increasing risk of toxicity  Sulfonamide displaces bilirubin which could potentially lead to jaundice and kernicterus in neonates

NB: Special consideration must be given in dosing patients in hypoalbuminemic states (e.g. liver failure or nephrotic syndrome) to prevent drug toxicity  Highly protein-bound drugs (e.g. warfarin, digoxin, diazepam, furosemide, amitriptyline) will exert a greater effect in these pts than in healthy individuals b/c of higher levels of free drug Marc Imhotep Cray, M.D.

Question A 23-year-old G1P0 woman who is 39 weeksâ&#x20AC;&#x2122; pregnant has dysuria with increased urinary frequency, and becomes febrile. She takes some medication prescribed for a previous urinary tract infection (UTI), and continues to use it through delivery. At term she gives birth to a mildly jaundiced boy who is otherwise healthy. Five days later, however, she brings the infant to the emergency department stating that the baby has become fussy, refuses feeding, and wails at a high pitch. He soon becomes extremely lethargic and stops producing urine. Which of the following medications did the mother most likely take to treat her UTI? A. Amoxicillin B. Ampicillin C. Nitrofurantoin D. Ofloxacin E. Trimethoprim-sulfamethoxazole Marc Imhotep Cray, M.D.

Answer The correct answer is E. Trimethoprim-sulfamethoxazole (TMP/SMX) is one of most common treatments for simple UTIs, most of which in general population are caused by Escherichia coli  Sulfamethoxazole binds to, and will displace, unconjugated bilirubin from albumin  In a newborn, this can lead to kernicterus (bilirubin encephalopathy), a disorder of newborns caused by deposition of bilirubin in brain  The basal ganglia are particularly affected  Common early symptoms include lethargy, poor feeding, and absent Moro reflex  If infants survive, they can develop seizures, mental retardation, deafness, choreoathetoid movements, and decreased upward eye movements Answer A is incorrect. Amoxicillin is not associated with kernicterus Answer B is incorrect. Ampicillin is not associated with kernicterus Answer C is incorrect. Nitrofurantoin, commonly used to Tx UTIs, is not assoc. w kernicterus. Answer D is incorrect. Ofloxacin is not associated with kernicterus Marc Imhotep Cray, M.D.

Depots a body compartment in which drug molecules tend to be stored and released slowly over a long period of time fat is a depot for very lipid soluble drugs (e.g. diazepam)

some oil-based medications are injected IM for slow release (e.g. depot medroxyprogesterone acetate q3mo; depot risperidone q2wk)

Marc Imhotep Cray, M.D.

Barriers (relative) body structures that limit or prevent diffusion of drug molecules, such as placenta or BBB (a barrier composed of tight junctions betw. capillary endothelial cells and astrocytes) many of these barriers result, in part, from activity of multidrug efflux pumps (e.g. Pgp), which serve as a natural defense mechanism against drugs and xenobiotics need to consider dosing route if drugs are meant to cross these barriers

Note: Main Factors Governing Penetration of BBB • Small molecular size (<500 Da) • High lipid solubility • Active transport mechanisms (e.g. Pgp efflux pump) Marc Imhotep Cray, M.D.

Metabolism (Biotransformation) definition: chemical transformation of a drug in vivo to enhance elimination sites of biotransformation include liver (main), GI tract, lung, plasma, kidney as a result of process of biotransformation:  an inactive prodrug may be activated (e.g. tamoxifen to endoxifen; codeine to morphine)  a drug may be changed to another active metabolite (e.g. diazepam to oxazepam)  a drug may be changed to a toxic metabolite (e.g. meperidine to normeperidine)  a drug may be inactivated (most drugs) Marc Imhotep Cray, M.D.

Drug Metabolizing Pathways phase I (P450) reactions  minor molecular changes introduce or unmask polar groups on a parent compound to increase water solubility (e.g. oxidation-reduction, hydrolysis, hydroxylation) o change in Po/w is typically minimal compared to phase II, and o often phase I places a polar “handle” on a lipophilic drug to allow for phase II

 mediated by CYPs found in endoplasmic reticulum  product of reaction can be excreted or undergo further phase II reactions Marc Imhotep Cray, M.D.

Drug Metabolizing Pathways cont’d. phase II (conjugation) reactions  conjugation w large polar endogenous substrates (e.g. glucuronidation, glutathione conjugation, sulfation)  dramatically increases water solubility and renal elimination  can result in biologically active metabolites (e.g. glucuronides of morphine)  can occur independently of phase I reactions

Marc Imhotep Cray, M.D.

Cytochrome P450 System  CYPs are a superfamily of heme proteins that are grouped into families and subfamilies according to their amino acid sequence 

are responsible for metabolism of drugs, chemicals, and other substances

Nomenclature: CYP3A4  “CYP” = cytochrome P450 protein o 1st number = family o letter = subfamily o 2nd number = isoform

 CYP1, CYP2, and CYP3 families metabolize most drugs in humans  Most important isoforms are CYP3A4 and CYP2D6, therefore anticipate drug interactions if prescribing drugs using these enzymes Marc Imhotep Cray, M.D.

Factors Affecting Drug Biotransformation genetic polymorphisms of metabolizing enzymes  individual genotypes may determine rate of drug metabolism (e.g. poor, intermediate, extensive, or ultrarapid metabolizers)  may lead to toxicity or ineffectiveness of a drug at nml dose o tamoxifen and codeine are prodrugs activated by CYP2D6  nonfunctional alleles reduce effectiveness, whereas overactive/duplicated alleles impart “ultrarapid metabolizer” phenotype o warfarin is metabolized by CYP2C9  nonfunctional alleles lead to greater effect and lower dose requirements o clopidogrel is a prodrug activated by CYP2C19, thus patients who are poor CYP2C19 metabolizers have a higher incidence of cardiovascular events (for example, CVA or MI) when taking clopidogrel Marc Imhotep Cray, M.D.

Factors Affecting Biotransformation cont’d. enzyme inhibition may sometimes be due to other drugs  CYP inhibition leads to an ↑conc. and bioavailability of substrate drug (e.g. erythromycin [CYP3A4 inhibitor] can predispose pts to simvastatin toxicity [metabolized by CYP3A4])

enzyme induction  certain medications enhance gene transcription leading to an ↑ in activity of a metabolizing enzyme  a drug may induce its own metabolism (e.g. carbamazepine) or that of other drugs (e.g. phenobarbital can induce metabolism of OCPs) by inducing CYP system For examples of CYP Substrates, Inhibitors and Inducers see: http://www.medicine.iupui.edu/CLINPHARM/ddis/main-table Marc Imhotep Cray, M.D.

Factors Affecting Biotransformation cont’d. liver dysfunction (e.g. hepatitis, alcoholic liver, biliary cirrhosis, or hepatocellular carcinoma) may ↓ drug metabolism, but may not be clinically significant due to liver’s reserve capacity renal disease often results in ↓ drug clearance extremes of age (neonates or elderly) have reduced biotransformation capacity doses should be adjusted accordingly

Marc Imhotep Cray, M.D.

Factors Affecting Biotransformation cont’d. nutrition: insufficient protein and fatty acid intake ↓ CYP biotransformation, and vitamin/ mineral deficiencies may also impact other metabolizing enzymes  alcohol: acute alcohol ingestion inhibits CYP2E1; chronic consumption can induce CYP2E1 and ↑ risk of hepatocellular damage from acetaminophen by ↑ generation of acetaminophen’s toxic metabolite (NAPQI ) smoking can induce CYP1A2, thus  ↑ metabolism of some drugs (e.g. theophylline, antipsychotic) Marc Imhotep Cray, M.D.

Elimination definition: removal of drug from body Routes of Drug Elimination  kidney (main organ of elimination): two mechanisms 1. glomerular filtration  a passive process, so that only free drug fraction can be eliminated  drug filtration rate depends on GFR, degree of protein binding of drug, and size of drug o Remember from physiology we can use CrCl to estimate GFR

2. tubular secretion  an active process that is saturable allowing both protein-bound and free drug fractions to be excreted  distinct transport mechanisms for weak acids (e.g. penicillin, salicylic acid, probenecid, chlorothiazide) and weak bases (e.g. quinine, quaternary ammonium compounds such as choline)  drugs may competitively block mutual secretion if both use same secretion system (e.g. probenecid can reduce excretion of penicillin) Marc Imhotep Cray, M.D.

Elimination cont’d. tubular reabsorption: drugs can be passively reabsorbed back to the systemic circulation, countering elimination mechanisms renal function (assessed using serum Cr levels) ↓ w age and is affected by many disease states such as diabetes lungs: elimination of anesthetic gases and vapors by exhalation saliva: saliva concentrations of some drugs parallel their plasma levels (e.g. rifampin)

Marc Imhotep Cray, M.D.

Elimination cont’d. stool: some drugs and metabolites are actively excreted in bile or directly into GI tract 

enterohepatic reabsorption counteracts stool elimination, and can prolong drug’s duration in body



some glucuronic acid conjugates that are excreted in bile may be hydrolyzed in intestines by bacteria back to their original form and can be systemically reabsorbed

Marc Imhotep Cray, M.D.

Cockcroft-Gault Equation  Cockcroft-Gault Equation can Estimate CrCl in Adults 20 yrs. of Age and Older 

For males

CrCl (mL/min) = [(140 – age in yrs.) x Weight (kg)] x 1.2 serum Cr (μmol/L) 

For females, multiply above equation x 0.85

NB: Only applies when renal function is at steady state

Marc Imhotep Cray, M.D.

Pharmacokinetic Calculation  definition: quantitative description of rates of various steps of drug disposition (i.e. how drugs move through body)  pharmacokinetic principles of ADME (absorption, distribution, metabolism, and elimination) can be graphically represented on a concentration vs. time graph NB: Principles of Pharmacokinetics   

Vd = amount of drug in body/ plasma drug conc. Cl = rate of elimination of drug/plasma drug conc. Half-life (t1/2) = 0.7 x Vd/ Cl

Marc Imhotep Cray, M.D.

Time Course of Drug Action many kinetic parameters are measured using IV dosing, such that absorption is immediate and distribution for most drugs is rapid, thus elimination is main process being measured

1. Absorption Phase 2. Peak Absorption 3. Post-Absorption Distribution Phase 4. Elimination Phase (half-life based on this)

concentration axis is converted to a log10 conc. to allow for easier mathematical calculations drugs such as warfarin can exhibit hysteresis (for a single drug conc., there may be two different response levels) Marc Imhotep Cray, M.D.

Leung P, Voruganti T. Clinical Pharmacology. Toronto Notes, 2017.

Half-Life ď ądefinition: time taken for serum drug level to fall 50% during elimination ď ądrugs w first order kinetics (most drugs) require five half-lives to reach steady state w repeated dosing or for complete drug elimination once dosing is stopped # of Half-Lives % of Steady State Conc.

Marc Imhotep Cray, M.D.

1 50

2 75

3 75

4 90

5 96.9

Steady State drug conc. remains constant when amt. of drug entering system is eliminated from system drug levels in therapeutic drug monitoring are of greatest utility when steady state has been reached special situations  use a loading dose for drugs w a long half-life and when there is clinical need to rapidly achieve therapeutic levels (e.g. amiodarone, digoxin, phenytoin)  use continuous infusion for drugs w very short half-life and when there is need for a long-term effect and multiple or frequently repeated doses are too inconvenient (e.g. nitroprusside, insulin, unfractionated heparin) Marc Imhotep Cray, M.D.

Steady state of a drug displaying first-order kinetics ď&#x201A;§ Steady state of a drug w t1/2 of 3 h ď&#x201A;§ It takes about 15 h (5 x t1/2) to reach steady state

Leung P, Voruganti T. Clinical Pharmacology. Toronto Notes, 2017.

Marc Imhotep Cray, M.D.

Clearance a quantitative measurement of body fluid volume from which a substance is removed per unit time Cl = rate of elimination of drug ÷ plasma drug concentration 

b/c Cl is removal of drug from circulation, clearance is related to elimination rate constant and apparent volume into which drug is dissolved → Cl= 0.693 x Vd ÷ t1/2 or t1/2=0.693 x Vd ÷Cl

must consider Cl from a specific part of body and total body Cl

Marc Imhotep Cray, M.D.

Clearance cont'd. ď ą Rather than describing amount of drug eliminated, clearance describes volume of plasma from which drug would be totally removed per unit time ď ą Having an idea of how much plasma is cleared of drug over time allows estimation of how much drug must be given to maintain a constant plasma conc.= maintenance dose

Marc Imhotep Cray, M.D.

Elimination Kinetics first-order kinetics (most common type)  constant fraction of drug eliminated per unit time  some drugs can follow first-order kinetics until elimination is saturated (usually at large doses) at which point Cl decreases becomes linear relationship when plotted on a log (conc.) vs. time graph

zero-order kinetics (less common, assoc. w overdose, e.g. alcohol)  drug is eliminated at a constant rate regardless of conc. concept of half-life does not apply  conc. axis is converted to a log (conc.) to allow for easier mathematical calculations Marc Imhotep Cray, M.D.

First and zero order kinetics ď ą In first order kinetics (solid line), a constant fraction of drug is eliminated per unit time ď ą In zero order kinetics (dashed line), a constant amount of drug is eliminated per unit time Leung P, Voruganti T. Clinical Pharmacology. Toronto Notes, 2017.

Marc Imhotep Cray, M.D.

Loading vs. Maintenance Dosing A loading dose is an initial higher dose of a drug that may be given at beginning of a course of treatment before dropping down to a lower maintenance dose A loading dose is most useful for drugs eliminated from body relatively slowly, i.e. have a long systemic half-life  Such drugs need only a low maintenance dose in order to keep amt. of drug in body at appropriate therapeutic level, but  Also means, without an initial higher dose, it would take a long time for amt. of drug in body to reach that level o Drugs which may be started w initial loading dose include digoxin, teicoplanin, voriconazole and procainamide Marc Imhotep Cray, M.D.

Calculating loading dose Four variables are used to calculate loading dose:  Cp = desired peak concentration of drug  Vd = volume of distribution of drug in body  F = bioavailability  S = fraction of drug salt form which is active drug Required loading dose may then be calculated as LD=Cp Vd ÷ FS  For an IV admin. drug, bioavailability (F) will equal 1 since drug is directly introduced to bloodstream  If pt. requires an PO, F will be less than 1 (depending on absorption, first pass metabolism etc.), requiring a larger loading dose See: Worked example of loading dose. pdf Marc Imhotep Cray, M.D.

Loading vs. Maintenance Dosing cont’d.  A maintenance dose is maintenance rate [mg/h] of drug admin. equal to rate of elimination at steady state

 Continuing maintenance dose for about 5 half lives (t½) of drug will approximate steady state level  One or more doses higher than maintenance dose can be given together at beginning of therapy with a loading dose

Marc Imhotep Cray, M.D.

Calculating maintenance dose Required maintenance dose may be calculated as: MD=Cp Cl÷ F Where:  MD is maintenance dose rate [mg/h]  Cp = desired peak concentration of drug [mg/L]  CL = clearance of drug in body [L/h]  F = bioavailability

 For an IV admin. drug, bioavailability will equal 1, since drug is directly introduced to bloodstream  If pt. requires an PO, F will be less than 1 (depending on absorption, first pass metabolism etc.), requiring a larger loading dose Marc Imhotep Cray, M.D.

LD vs. MD Summary Table Loading Dose

Maintenance Dose

Use when you need an IMMEDIATE effect After a loading dose OR beginning with maintenance doses Often parenteral medication

Steady-state levels achieved after ~5 half-lives

Rationale: give large dose of medication to “fill up” the volume of distribution

Can be given as either a continuous infusion (relatively rare, short half-life drug) OR much more commonly as intermittent doses

Vd determines LD (LD=Cp Vd ÷ FS)

Cl determines MD (MD=Cp Cl ÷ F)

Marc Imhotep Cray, M.D.

Pharmacodynamics study of “what the drug does to the body” Dose-Response Relationship graded dose-response relationships: relates dose to intensity of effect Efficacy  maximum biological response produced by a drug  measured by Emax (maximal response that a drug can elicit in a RCT or under optimal circumstances) Potency  measured by EC50 (the concentration of a drug needed to produce 50% of Emax)  a drug that reaches its EC50 at a lower dose is more potent

Marc Imhotep Cray, M.D.

Log(dose)-response curve illustrating efficacy and potency

Leung P, Voruganti T. Clinical Pharmacology. Toronto Notes, 2017.

Efficacy vs. Potency â&#x20AC;˘ Efficacy measures maximal effect of a drug (vertical axis) â&#x20AC;˘ Potency measures conc. of a drug needed to produce a certain effect (horizontal axis) Marc Imhotep Cray, M.D.

Effects of Drugs on Receptors  Agonists: drugs that mimic effects of endogenous ligand and evoke a response when bound to receptor (has affinity and intrinsic activity)  affinity: ability of agonist to bind to receptor, e.g. β2-agonist salbutamol has greater affinity for β2-receptors than β1-receptors  efficacy: ability to recapitulate endogenous response via receptor interaction, e.g. binding of salbutamol to β2-receptors results in smooth muscle relaxation

 full agonists: can elicit a maximal effect at a receptor  partial agonists: can only elicit a partial effect, no matter conc. at receptor, i.e. reduced efficacy compared to full agonists) Marc Imhotep Cray, M.D.

Effects of Drugs on Receptors cont’d. Antagonists drugs that block action of an agonist or of an endogenous ligand  chemical antagonism: direct chemical interaction betw. agonist and antagonist prevents agonist receptor binding, e.g. chelating agents for removal of heavy metals  functional antagonism: two agonists that act independently at different receptors and have opposite physiological effects, e.g. acetylcholine at muscarinic receptor compared to epinephrine at adrenergic receptor

Marc Imhotep Cray, M.D.

Effects of Drugs on Receptors cont’d.  reversible and irreversible competitive antagonism o drugs that exert no direct effect upon binding to a given receptor o reversible competitive antagonists reversibly bind to same receptor as agonist, thus displacing it (e.g. naloxone is an antagonist to morphine or heroin) o irreversible antagonists form a covalent bond w receptor thus irreversibly blocking substrates from binding (e.g. phenoxybenzamine forms a covalent bond w adrenergic receptors preventing Epi and NE from binding)

 non-competitive antagonism o antagonist binds to an alternate site near agonist binding site, producing allosteric effects that change ability of agonist to bind (e.g. organophosphates irreversibly bind acetylcholinesterase) Marc Imhotep Cray, M.D.

Mechanism of agonists and antagonists

Agonist Binding

ÂŠ Adrian Yen 2006

Marc Imhotep Cray, M.D.

Mechanism of agonists and antagonists

Antagonist Binding 1) Competitive reversible binding

ÂŠ Adrian Yen 2006

2) Competitive irreversible binding

ÂŠ Adrian Yen 2006

Marc Imhotep Cray, M.D.

Mechanism of agonists and antagonists

Antagonist Binding 3) Non-competitive irreversible binding

ÂŠ Adrian Yen 2006

Marc Imhotep Cray, M.D.

Effectiveness and Safety Effectiveness  ED (effective dose): dose of a drug needed to cause a therapeutic effect in 50% of a test population of subjects 50

Safety  LD (lethal dose): dose of a drug needed to cause death in 50% of a test population of subjects  TD (toxic dose): dose needed to cause a harmful effect in 50% of a test population of subjects 50

NB: Two most clinically relevant properties of any drug are effectiveness and safety Marc Imhotep Cray, M.D.

Therapeutic Indices Therapeutic Index: TD /ED 50

 reflects “margin of safety” for a drug likelihood of a therapeutic dose to cause serious toxicity or death  larger TI, safer a drug (e.g. warfarin has a low TI (=narrow therapeutic window or low safety margin )requires drug monitoring  factors that can change TI o presence of interacting drugs o changes in drug ADME

Certain Safety Factor: TD /ED 1

 >1 translates to a dose effective in at least 99% of population and toxic in less than 1% of population Marc Imhotep Cray, M.D.

ED50, TD50 and TI Leung P, Voruganti T. Clinical Pharmacology. Toronto Notes, 2017.

TI (TD50/ED50) is a measure of margin of safety of a given drug

Marc Imhotep Cray, M.D.

Drug A has a much narrower TI than Drug B. Dose of Drug A required to achieve a 100% therapeutic response will be toxic in 50% of patients For Drug B, this is only 10% 65

Therapeutic Drug Monitoring Adverse Drug Reactions Approach to Suspected ADRs

Variability in Drug Response Drug Interactions

Therapeutic Drug Monitoring definition: using serum drug concentration data to optimize drug , e.g.→ dose adjustment, monitor compliance  serum drug samples are usually taken when drug has reached steady state (after approx. 5 half-lives)

TDM is often used for drugs that have:    

narrow TIs unpredictable dose-response relationships significant consequences assoc. w therapeutic failure or toxicity, and wide inter-patient PK variability

Examples of drugs whose levels need to be monitored include warfarin (via INR levels), digoxin, lithium, anti-epileptics (e.g. phenytoin, carbamazepine) Marc Imhotep Cray, M.D.

Adverse Drug Reactions (ADRs)  An ADR is an injury caused by taking a medication  ADRs may occur following a single dose or prolonged admin. of a drug or result from combination of two or more  Meaning ADR differs from meaning of "side effect", as → side effect might also imply that effects can be beneficial  Study of ADRs is concern of field known as pharmacovigilance  An adverse drug event (ADE) refers to any injury occurring at time a drug is used, whether or not it is identified as a cause of injury  An ADR is a special type of ADE in which a causative relationship can be shown Marc Imhotep Cray, M.D.

Classification ADRs  ADRs may be classified by e.g. cause and severity

Cause Type A: Augmented pharmacologic effects→ dose dependent and predictable  Type A reactions, constitute approximately 80% of ADRs→ usually a consequence of drug’s primary pharmacological effect (e.g. bleeding when using anticoagulant warfarin) or a low therapeutic index of drug (e.g. nausea from digoxin) = predictable  They are dose-related and usually mild, although may be serious or even fatal (e.g. intracranial bleeding from warfarin)  Such reactions are usually due to inappropriate dosage, especially when drug elimination is impaired o term ‘side effects’ is often applied to minor type A reactions

 Type B: Idiosyncratic (Bizarre) NB: Types A and B proposed in 1970s, other types were proposed subsequently when found to be insufficient to classify all types of ADRs (see next slide) Marc Imhotep Cray, M.D.

Characteristics of Type A-E ADRs Classification

Definition

Characteristics

A (Augmented)

Dose related

Predictable extension of drugâ&#x20AC;&#x2122;s pharmacologic effect (e.g. Î˛blockers causing bradycardia), >80% of all ADRs

B (Bizarre)

Non-dose related

Reactions unrelated to known pharmacological actions of drug Examples include: drug hypersensitivity syndromes, immunologic reactions (penicillin hypersensitivity), and idiosyncratic reactions (malignant hyperthermia)

C (Chronic)

Dose and time related

Related to cumulative doses Effects are well-known and can be anticipated (e.g. atypical femoral fracture from bisphosphonates)

D (Delayed)

Time related

Occurs some time after use of drug (e.g. carcinogen) May also be dose-related

E (End of use)

Withdrawal

Occurs after cessation of drug use (e.g. opiate withdrawal)

Redrawn after Leung P, Voruganti T. Clinical Pharmacology. Toronto Notes, 2017.

Marc Imhotep Cray, M.D.

Sample of Clinically Relevant ADRs Classification Drug(s) ADR A Î˛-blockers Bradycardia A ACEIs Cough A NSAIDs GI bleeding A Opiates GI upset, constipation, urinary retention, respiratory depression A Acetaminophen Hepatotoxicity A Vancomycin Red Man syndrome A Aminoglycosides Ototoxicity and nephrotoxicity B Sulfa Drugs Stevens-Johnson syndrome Toxic epidermal necrolysis B Penicillins Rash B Valproic acid, Chinese herbs Hepatotoxicity Marc Imhotep Cray, M.D.

Approach to Suspected ADRs history and physical exam: signs and symptoms of reaction (e.g. rash, fever, hepatitis, anaphylaxis), timing, risk factors, detailed medication history including all drugs and timing, dechallenge (response when drug is removed), and re-challenge (response when drug is given again) differentiate drug therapy vs. disease pathophysiology treatment: stop the drug, supportive care, symptomatic relief

Marc Imhotep Cray, M.D.

Approach to Suspected ADRs cont'd. ď ąresources: check recent literature, FDA; contact pharmaceutical company; call Poison Control if overdose or poisoning suspected; check with Motherisk (www.motherisk.org ) in cases involving pregnant or breastfeeding women ď ą report all suspected ADRs that are: 1) Unexpected 2) serious, or 3) reactions to recently marketed drugs (on market <5 yrs.) regardless of nature or severity Marc Imhotep Cray, M.D.

Variability in Drug Response recommended patient dosing is based on clinical research and represents mean values for a select population, but each person may be unique in their dosing requirements possible causes of individual variability in drug response include problems with:  intake: patient adherence  PK  PD

Marc Imhotep Cray, M.D.

Variability in Drug Response cont'd. PK causes of individual variability in drug response:  absorption: vomiting, diarrhea, or steatorrhea; first pass effect increased due to enzyme induction or decreased due to liver disease  drug interactions (e.g. calcium carbonate complexes with iron, thyroxine, and fluoroquinolones)  distribution: very high or low percentage body fat; intact or disrupted BBB; patient is elderly or a neonate, or has liver dysfunction  biotransformation and elimination: certain genetic polymorphisms or enzyme deficiencies related to drug metabolism (e.g. acetylcholinesterase deficiency, CYP polymorphism); kidney or liver dysfunction PD: genetic variability in drug response (e.g. immune-mediated reactions); diseases that affect drug PD; drug tolerance or cross-tolerance Marc Imhotep Cray, M.D.

Drug Interactions concomitant prescriptions: one drug alters effect of another by changing its PK and/or PD PK interactions involve changes in drug conc.  absorption: alterations in gastrointestinal pH, gastric emptying, intestinal motility, gut mucosal function  biotransformation: alterations in drug metabolizing enzymes  excretion: alterations in renal elimination

PD interactions are due to two drugs that exert similar effects (additive) or opposing effects (subtractive) drug interactions can also involve herbal medications (e.g. St. John’s wort) and food (e.g. grapefruit) Marc Imhotep Cray, M.D.

Drug Interactions contâ&#x20AC;&#x2122;d. Examples of Clinically Relevant Drug Interactions Interaction

Potential Effect

Warfarin plus ciprofloxacin, clarithromycin, erythromycin, metronidazole or TMP-SMX

Increased effect of warfarin

OCPs plus rifampin, antibiotics

Decreased effectiveness of PO contraception

Sildenafil plus nitrates

Hypotension

SSRI plus St. Johnâ&#x20AC;&#x2122;s wort, naratriptan, rizatriptan, sumatriptan, zolmitriptan

Serotonin syndrome

SSRI plus selegiline or nonselective MAO-I

Serotonin syndrome

Some HMG-CoA reductase inhibitors plus niacin, gemfibrozil, erythromycin or itraconazole

Possible rhabdomyolysis

Redrawn after Leung P, Voruganti T. Clinical Pharmacology. Toronto Notes, 2017.

Marc Imhotep Cray, M.D.

Autonomic Pharmacology

Marc Imhotep Cray, M.D.

Subdivisions of peripheral nervous system Peripheral Nervous System

Somatic

Autonomic (ANS)

Sympathetic (SNS) Fight or Flight

Marc Imhotep Cray, M.D.

Parasympathetic (PNS) Rest and Digest

Autonomic Pharmacology  most organs are innervated by both sympathetic and parasympathetic nerves, which have opposing effects  ACh and NE are main neurotransmitters of ANS  ACh binds to cholinergic receptors include nicotinic and muscarinic receptors  NE binds to adrenergic receptors, principally include β1, β2, α1, and α2

Marc Imhotep Cray, M.D.

ANS Pharm cont’d.  ACh action is terminated by  metabolism in synaptic cleft by acetylcholinesterase and in plasma by pseudocholinesterase o acetylcholinesterase inhibitors (pyridostigmine, donepezil, galantamine, rivastigmine) can be used to ↑ ACh levels in conditions such as myasthenia gravis or Alzheimer’s disease

 NE action is terminated by   

reuptake at presynaptic membrane diffusion from synaptic cleft, and degradation at monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT)

Marc Imhotep Cray, M.D.

Parasympathetic Nervous System blood vessels, adrenals, sweat glands, spleen capsule, and adrenal medulla do NOT have parasympathetic innervation parasympathetic pre-ganglionic fibers originate in lower brainstem from cranial nerves III, VII, IX, X, and in sacral spinal cord at levels S2-S4connect w post-ganglionic fibers via nicotinic receptors in ganglionic cells located near or within target organ post-ganglionic fibers connect with effector tissues via:  M1 muscarinic receptors located in the CNS  M2 muscarinic receptors located in smooth muscle, cardiac muscle, and glandular epithelium Marc Imhotep Cray, M.D.

Sympathetic Nervous System sympathetic pre-ganglionic fibers originate in spinal cord at spinal levels T1-L2/L3 pre-ganglionic fibers connect w post-ganglionic fibers via nicotinic receptors located in one of two groups of ganglia 1. paravertebral ganglia (i.e. the sympathetic trunk) that lie in a chain close to vertebral column 2. pre-vertebral ganglia (i.e. celiac and mesenteric ganglia) that lie within abdomen post-ganglionic fibers connect w effector tissues via:  β1 receptors in cardiac tissue  β2 receptors in smooth muscle of bronchi and GI tract  α1 receptors in vascular smooth muscle  α2 receptors in vascular smooth muscle  M.D. M3 muscarinic receptors located in sweat glands Marc Imhotep Cray,

ANS summary schematic

Le T., Bhushan V. First Aid for the USMLE Step 1 2017. New York, NY: M-H. 2017.

Marc Imhotep Cray, M.D.

Direct Effects of Autonomic Innervation on Cardiorespiratory System Organ Heart 1. Sinoatrial 2.Atrioventricular node 3. Atria 4. Ventricles Blood Vessels 1. Skin, splanchnic 2. Skeletal muscle 3. Coronary

Sympathetic NS

Parasympathetic NS

Receptor Action

β1 β1 β1 β1

↑ HR ↑ conduction ↑ contractility ↑ contractility

M M M M

↓conduction ↓ conduction ↓ conduction ↓ HR

α1, β2 α β2 (lg m) α1, β2 β2

Constriction Constriction Dilatation Constriction Dilatation

M M M M M

Dilatation Dilatation Dilatation Dilatation Dilatation

Relaxation ↑secretion

M M

Constriction Stimulation

Lungs 1. Bronchiolar sm. Mm. β2 2. Bronchiolar glands α1, β2 Marc Imhotep Cray, M.D.

Common Drug Endings

Marc Imhotep Cray, M.D.

Ending