2Drug EffectivenessDose-response (DR) curve: Depicts the relation between drug dose and magnitude of drug effectDrugs can have more than one effectDrugs vary in effectivenessDifferent sites of actionDifferent affinities for receptorsThe effectiveness of a drug is considered relative to its safety (therapeutic index)
5Therapeutic IndexThis is a figure of two different dose response curves. You can obtain a different dose response curve for any system that the drug effects. When you vary the drug, this is the Independent variable, what you are measuring is the % of individuals responding to the drug. Here we see the drugs effects on hypnosis and death. Notice that the effective dose for 50 % of the people is 100 mg and if you double the dose to 200 mg then 1 % of your subjects die. Thus, if you want to use this drug to hypnotize 99 % of your subjects, in the process you will kill 2-3 % of your subjects.
6Drug Safety and Effectiveness Not all people respond to a similar dose of a drug in the exact same manner, this variability is based upon individual differences and is associated with toxicity. This variability is thought to be caused by:Pharmacokinetic factors contribute to differing concentrations of the drug at the target area.Pharmacodynamic factors contribute to differing physiological responses to the same drug concentration.Unusual, idiosyncratic, genetically determined or allergic, immunologically sensitized responses.
7PharmacokineticsDrug molecules interact with target sites to effect the nervous systemThe drug must be absorbed into the bloodstream and then carried to the target site(s)Pharmacokinetics is the study of drug absorption, distribution within body, and drug elimination over time.Absorption depends on the route of administrationDrug distribution depends on how soluble the drug molecule is in fat (to pass through membranes) and on the extent to which the drug binds to blood proteins (albumin)Drug elimination is accomplished by excretion into urine and/or by inactivation by enzymes in the liver
14Drug Delivery Systems Tablets Injections (Syringe) Cigarettes BeveragesPatchesSuppositoriesCandyGumImplantsGasCreamsOthers?StampsBandana
15Membranes Types of Membranes: Cell Membranes: This barrier is permeable to many drug molecules but not to others, depending on their lipid solubility. Small pores, 8 angstroms, permit small molecules such as alcohol and water to pass through.Walls of Capillaries: Pores between the cells are larger than most drug molecules, allowing them to pass freely, without lipid solubility being a factor.Blood/Brain Barrier: This barrier provides a protective environment for the brain. Speed of transport across this barrier is limited by the lipid solubility of the psychoactive molecule.Placental Barrier: This barrier separates two distinct human beings but is very permeable to lipid soluble drugs.
16Drug DistributionDependent upon its route of administration and target area, every drug has to be absorbed, by diffusion, through a variety of bodily tissue.Tissue is composed of cells which are encompassed within membranes, consisting of 3 layers, 2 layers of water-soluble complex lipid molecules (phospholipid) and a layer of liquid lipid, sandwiched within these layers. Suspended within the layers are large proteins, with some, such as receptors, transversing all 3 layers.The permeability of a cell membrane, for a specific drug, depends on a ratio of its water to lipid solubility. Within the body, drugs may exist as a mixture of two interchangeable forms, either water (ionized-charged) or lipid (non-ionized) soluble. The concentration of two forms depends on characteristics of the drug molecule (pKa, pH at which 50% of the drug is ionized) and the pH of fluid in which it is dissolved.In water soluble form, drugs cannot pass through lipid membranes, but to reach their target area, they must permeate a variety of types of membranes.
17Pharmacokinetics vs Pharmacodynamics…concept Fluoxetine increases plasma concentrations of amitriptyline. This is a pharmacokinetic drug interaction.Fluoxetine inhibits the metabolism of amitriptyline and increases the plasma concentration of amitriptytline.
18Pharmacokinetics vs Pharmacodynamics…concept If fluoxetine is given with tramadol serotonin syndrom can result. This is a pharmacodynamic drug interaction.Fluoxetine and tramadol both increase availability of serotonin leading to the possibility of “serotonin overload” This happens without a change in the concentration of either drug.
19Basic ParametersIn the next few slides the basic concepts and paramaters will be described and explained.In pharmacokinetics the body is represented as a single or multiple compartments in to which the drug is distributed.Some of the parameters are therefore a little abstract as we know the body is much more complicated !
20Volume of Distribution, Clearance and Elimination Rate Constant Volume 100 LClearance10 L/hr
21Volume of Distribution, Clearance and Elimination Rate Constant Volume 100 L (Vi)V2Cardiac andSkeletal MuscleClearance10 L/hr
22Volume of Distribution = Cardiac andSkeletal MuscleVolume 100 L (Vi)VClearance10 L/hrVolume of Distribution =Dose_______Plasma Concentration
23Volume of blood cleared of drug per unit time Cardiac andSkeletal MuscleVolume 100 L (Vi)VClearance10 L/hrClearance =Volume of blood cleared of drug per unit time
24Volume 100 L (Vi) Clearance = 10 L/hr Volume of Distribution = 100 L Cardiac andSkeletal MuscleVolume 100 L (Vi)VClearance10 L/hrClearance = 10 L/hrVolume of Distribution = 100 LWhat is the Elimination Rate Constant (k) ?
25CL = kVk = 10 Lhr -1 = 0.1 hr -1100 L10 % of the “Volume” is cleared (of drug) per hourk = Fraction of drug in the body removed per hour
26CL = kVIf V increases then k must decrease as CL is constant
27Important ConceptsVD is a theoretical Volume and determines the loading dose.Clearance is a constant and determines the maintenance dose.CL = kVD.CL and VD are independent variables.k is a dependent variable.
28Volume of Distribution (Vd) Apparent volume of distribution is the theoretical volume that would have to be available for drug to disperse in if the concentration everywhere in the body were the same as that in the plasma or serum, the place where drug concentration sampling generally occurs.
29Volume of Distribution An abstract conceptGives information on HOW the drug is distributed in the bodyUsed to calculate a loading dose
31Question What is the loading dose required for drug A if; Target concentration is 10 mg/LVd is 0.75 L/kgPatients weight is 75 kgAnswer is on the next slide
32Answer: Loading Dose of Drug A Dose = Target Concentration x VDVd = 0.75 L/kg x 75 kg = LTarget Conc. = 10 mg/LDose = 10 mg/L x L= 565 mgThis would probably be rounded to 560 or even 500 mg.
33Clearance (CL)Ability of organs of elimination (e.g. kidney, liver) to “clear” drug from the bloodstream.Volume of fluid which is completely cleared of drug per unit time.Units are in L/hr or L/hr/kgPharmacokinetic term used in determination of maintenance doses.
34ClearanceVolume of blood in a defined region of the body that is cleared of a drug in a unit time.Clearance is a more useful concept in reality than t 1/2 or kel since it takes into account blood flow rate.Clearance varies with body weight.Also varies with degree of protein binding.
35Clearance Rate of elimination = kel D, Remembering that C = D/Vd And therefore D= C VdRate of elimination = kel C VdRate of elimination for whole body = CLT CCombining the two,CLT C = kel C Vd and simplifying gives:CLT = kel Vd
36Maintenance Dose Calculation Maintenance Dose = CL x CpSSavCpSSav is the target average steady state drug concentrationThe units of CL are in L/hr or L/hr/kgMaintenance dose will be in mg/hr so for total daily dose will need multiplying by 24
37Question What maintenance dose is required for drug A if; Target average SS concentration is 10 mg/LCL of drug A is L/kg/hrPatient weighs 75 kgAnswer on next slide.
38Answer Maintenance Dose = CL x CpSSav CL = L/hr/kg x 75 = L/hrDose = L/hr x 10 mg/L = mg/hrSo will need x 24 mg per day = 270 mg
39Half-Life and kHalf-life is the time taken for the drug concentration to fall to half its original valueThe elimination rate constant (k) is the fraction of drug in the body which is removed per unit time.
47Steady-StateSteady-state occurs after a drug has been given for approximately five elimination half-lives.At steady-state the rate of drug administration equals the rate of elimination and plasma concentration - time curves found after each dose should be approximately superimposable.
48Accumulation to Steady State 100 mg given every half-life …200194187.5175150100…971009487.57550
50What is Steady State (SS) ? Why is it important ? Rate in = Rate OutReached in 4 – 5 half-lives (linear kinetics)Important when interpreting drug concentrations in time-dependent manner or assessing clinical response
52Therapeutic Index Therapeutic index = toxic dose/effective dose This is a measure of a drug’s safetyA large number = a wide margin of safetyA small number = a small margin of safety
53Drug Concentrations may be Useful when there is: An established relationship between concentration and response or toxicityA sensitive and specific assayAn assay that is relatively easy to performA narrow therapeutic rangeA need to enhance response/prevent toxicity
54Why Measure Drug Concentrations? Lack of therapeutic responseToxic effects evidentPotential for non-complianceVariability in relationship of dose and concentrationTherapeutic/toxic actions not easily quantified by clinical endpoints
55Potential for Error when using TDM Assuming patient is at steady-stateAssuming patient is actually taking the drug as prescribedAssuming patient is receiving drug as prescribedNot knowing when the [drug] was measured in relation to dose administrationAssuming the patient is static and that changes in condition don’t affect clearanceNot considering drug interactions
57Elimination by the Kidney Excretion - major1) glomerular filtrationglomerular structure, size constraints, protein binding2) tubular reabsorption/secretion- acidification/alkalinization,- active transport, competitive/saturable, organic acids/bases protein bindingMetabolism - minor
58Elimination by the Liver Metabolism - major1) Phase I and II reactions2) Function: change a lipid soluble to more water soluble molecule to excrete in kidney3) Possibility of active metabolites with same or different properties as parent moleculeBiliary Secretion – active transport, 4 categories
60Liver P450 systems Liver enzymes inactivate some drug molecules First pass effect (induces enzyme activity)P450 activity is genetically determined:Some persons lack such activity leads to higher drug plasma levels (adverse actions)Some persons have high levels leads to lower plasma levels (and reduced drug action)Other drugs can interact with the P450 systemsEither induce activity (apparent tolerance)Inactivate an enzyme system
64Therapeutic WindowUseful range of concentration over which a drug is therapeutically beneficial. Therapeutic window may vary from patient to patientDrugs with narrow therapeutic windows require smaller and more frequent doses or a different method of administrationDrugs with slow elimination rates may rapidly accumulate to toxic levels….can choose to give one large initial dose, following only with small doses
66Distribution Rate & Extent depend upon Chemical structure of drug Rate of blood flowEase of transport through membraneBinding of drug to proteins in bloodElimination processes
67Partition Coefficients: ratio of solubility of a drug in water or in an aqueous buffer to its solubility in a lipophilic, non-polar solventpH and ionization: Ion Trapping
68The Compartment ModelWe can generally think of the body as a series of interconnected well-stirred compartments within which the [drug] remains fairly constant. BUT movement BETWEEN compartments important in determining when and for how long a drug will be present in body.
69Partitioning into body fat and other tissues · A large, nonpolar compartment. Fat has low blood supply—less than 2% of cardiac output, so drugs are delivered to fat relatively slowlyFor practical purposes: partition into body fat important following acute dosing only for a few highly lipid-soluble drugs and environmental contaminants which are poorly metabolized and remain in body for long period of time
70IMPORTANT EFFECTS OF pH PARTITIONING: · urinary acidification will accelerate the excretion of weak bases and retard that of weak acids; alkalination has the opposite effects· increasing plasma pH (by addition of NaHCO3) will cause weakly acidic drugs to be extracted from the CNS into the plasma; reducing plasma pH (by administering a carbonic anhydrase inhibitor) will cause weakly acidic drugs to be concentrated in the CNS, increasing their toxicity
71Renal EliminationGlomerular filtration: molecules below 20 kDa pass into filtrate. Drug must be free, not protein bound.Tubular secretion/reabsorption: Active transport. Followed by passive and active. DP=D + P. As D transported, shift in equilibrium to release more free D. Drugs with high lipid solubility are reabsorbed passively and therefore slowly excreted. Idea of ion trapping can be used to increase excretion rate---traps drug in filtrate.
72Plasma Proteins that Bind Drugs albumin: binds many acidic drugs and a few basic drugsb-globulin and an a1acid glycoprotein have also been found to bind certain basic drugs
73A bound drug has no effect! Amount bound depends on:1) free drug concentration2) the protein concentration3) affinity for binding sites% bound: __[bound drug]__________ x 100[bound drug] + [free drug]
74% BoundRenal failure, inflammation, fasting, malnutrition can have effect on plasma protein binding.Competition from other drugs can also affect % bound.
75An Example Warfarin (anticoagulant) protein bound ~98% Therefore, for a 5 mg dose, only 0.1 mg of drug is free in the body to work!If patient takes normal dose of aspirin at same time (normally occupies 50% of binding sites), the aspirin displaces warfarin so that 96% of the warfarin dose is protein-bound; thus, 0.2 mg warfarin free; thus, doubles the injested dose
76Volume of Distribution C = D/VVd is the apparent volume of distributionC= [drug] in plasma at some timeD= total [drug] in systemVd gives one as estimate of how well the drug is distributed. Vd < L/kg indicate the drug is mainly in the circulatory system.Vd > L/kg indicate the drug has entered specific tissues.
77Conc. vs. time plotsC = Co - kt ln C = ln Co - kt
78Types of Kinetics Commonly Seen First Order KineticsRate = k CC = Co e-ktRate of elimination proportional to plasma concentration. Constant fraction of drug eliminated per unit time.C vs. t graph is NOT linear, decaying exponential. Log C vs. t graph is linear.Zero Order KineticsRate = kC = Co - ktConstant rate of elimination regardless of [D]plasmaC vs. t graph is LINEAR
79Example of Zero Order Elimination: Pharmacokinetics of Ethanol Ethanol is distributed in total body water.Mild intoxication at 1 mg/ml in plasma.How much should be ingested to reach it?Answer: 42 g or 56 ml of pure ethanol (VdxC)Or 120 ml of a strong alcoholic drink like whiskeyEthanol has a constant elimination rate = 10 ml/hTo maintain mild intoxication, at what rate must ethanol be taken now?at 10 ml/h of pure ethanol, or 20 ml/h of drink.
81To reiterate: Comparison Zero Order Elimination[drug] decreases linearly with timeRate of elimination is constantRate of elimination is independent of [drug]No true t 1/2First Order Elimination[drug] decreases exponentially w/ timeRate of elimination is proportional to [drug]Plot of log [drug] or ln[drug] vs. time are lineart 1/2 is constant regardless of [drug]
82Route of Administration Determines Bioavailability (AUC)
83AUC: An Indicator of Bioavailability Dose is proportional to [drug] in tissues.[drug], in turn, is proportional to the Area Under the Curve in a Concentration-decay curve.Thus, we have k = dose/AUCBecause oral administration is full of barriers, the fraction, F, that is available by entering the general circulation, may not be significant.Thus, FD = k(AUC)or k = FD/AUC
84Combining these 2 equations gives us: FDpo/AUCpo = Div/AUCivAnd thus, F = AUCpoDivAUCivDpoMore generally, the relative bioavailability, F = AUCADoseBAUCBDoseA
88BioavailabilityThe fraction of the dose of a drug (F) that enters the general circulatory system,F= amt. of drug that enters systemic circul.Dose administeredF = AUC/Dose
89Bioavailability A concept for oral administration Useful to compare two different drugs or different dosage forms of same drugRate of absorption depends, in part, on rate of dissolution (which in turn is dependent on chemical structure, pH, partition coefficient, surface area of absorbing region, etc.) Also first-pass metabolism is a determining factor
90The Effect of the Liver First Pass F = 1-E, where E is fraction of the dose elim via the liver.Cltot = D/AUCClhep = Cltot-ClrenClhep = E × LBF, which is liver blood flow or E = Clhep/LBFCombining the 1st eq with the last givesF = 1-E = 1-ClhepLBF
91Rowland’s Equation F = 1-E = 1-Clhep LBF This very useful equation calculates the magnitude of the effect of the liver’s 1st pass of an oral dose and, more precisely, to predict it from and i.v. test.Thus, if E < 0.10, then, clearly, bioavailability F > 0.90.
92P450 InteractionsSubstrate: Is the drug metabolized via a specific hepatic isoenzyme?Inhibitor: does a specific drug inhibit a specific hepatic isoenzyme?Would expect this to interfere with drug inactivationInducer: does a specific drug enhance a specific hepatic isoenzyme?Would expect this to speed up drug inactivation
94Drug EnantionersA drug molecule may be organized in such a way that the same atoms are mirror imagesEnantioners represent drug molecules that are structurally different (spatial configutation)Different physical propertiesLight rotation (levo = left; dextro = right)Melting pointsDifferent biological activities (typically: dextro > levo)Fenfluramine = racemic mix ofdextro-fenfluraminelevo-fenfluramineEnantiomers often have different affinity for receptors