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1. PHARMACOTHERAPEUTICS
DNP 608- Summer 2021
Arizona State University
Edson College of Nursing and Health
Innovation

2. Important Principles of Drug Action
• Drugs modify existing functions within the body
Drugs do not create function
• No drug has a single action
• Drug effects are determined by the drug's interaction with the
body
• Drugs are formulated in such a way as to either produce local
or systemic effects
• A drug is made up of one or more active ingredients and
various additives
Active ingredients are responsible for producing desired effects
and vary considerably in chemical structure
• Factors to be taken into consideration when deciding on the
best drug dosage for a patient include age, gender, weight,
ethnic background, other concurrent disease states, and other
drug therapy

3. Pharmacokinetics/Pharmacodynamics
Pharmacokinetics
• What the body does to
the drug
• Actions of the biologic
system on the drug
• Process of absorption,
distribution, metabolism, and
elimination
• Calculation of loading and
maintenance doses
Pharmacodynamics
• What a drug does to the
body
• The effects of drugs on
biological systems
• Receptors, effectors, dose
response relationships,
efficacy, potency, agonists,
partial agonists, antagonists,
therapeutic index

4. Pharmacokinetics
• The study of the effect the body has on drugs
Absorption, distribution, metabolism (aka biotransformation),
elimination
• Combined with a knowledge of disease states and conditions
that influence the disposition of a particular drug, kinetic
concepts can be used to modify doses to produce serum
concentrations that result in desirable pharmacologic effects
without unwanted side effects
• Administration-Unless a drug is given at its site of action it
needs to be absorbed into the blood and transported to its site
of action
• Various routes of administration exist
• The formulation chosen depends on many factors;
Barriers and the drugs' ability to pass through them
Setting of use (inpatient vs. outpatient)
Urgency of administration (emergent vs. chronic)
First Pass effect

5. General Info
• Before drug can elicit physiologic response, it must be
absorbed into the body from a site of administration
• In most cases the drug interacts with a specific target or
receptor
• Several different types of receptors many of which are located
on the cell membrane
• For drug to possess ability to produce benefits it must have the
appropriate size, electrical charge, shape and composition to
interact with a receptor and produce an effect
• Drugs used for pharmacologic purposes often have similarities
to chemicals made naturally within the body
• Physical nature of the chemical (drug) often determines the
best route

6. Drug-Dose Relationship
• Dose–response curve: depicts the relationship between
drug dose and magnitude of effect
• Doses below the curve do not produce a pharmacological
response.
• Doses above the curve do not produce much additional
pharmacological response.
• May have unwanted effects → toxicity

7. Receptors
• Ion channel receptors
• Receptors Coupled to
G Proteins
• Transmembrane
receptors
• Intracellular receptors
regulating gene
expression
• Enzymes
• Drug action at
receptors
• Disease states and
receptors
• Non-receptor
mechanisms

8. Drug-Receptor Binding
• Drug–receptor binding is reversible.
• Drug–receptor binding is selective.
• Drug–receptor binding is graded.
• The more receptors filled, the greater the pharmacological
response.
• Drugs that bind to receptors may be agonists, partial
agonists, or antagonists.

9. Routes of Administration
• Oral (PO)
Easiest to administer
Must withstand environment of the stomach and be
absorbed
Must survive first pass
• Sublingual (SL)
Good absorption through capillary bed under tongue
Easy for self-administration
Bypasses stomach and hepatic first pass does not effect
Direct access to systemic circulation
Good for drugs in need of quick absorption
• Inhalation
Rapid administration
Metered dosing allows self administration

10. Routes of Administration Cont.
• Rectal
Useful for unconscious, pediatrics, vomiting patients
Unreliable absorption
Useful for local administration
Only 50% of rectal dose assumed to bypass liver
• Topical
Local administration
Good for agents with systemic toxicity
Useful for dermatology and ophthalmic disorders
• Transdermal
Patch systems
Convenient for self administration
Useful for agents that need to bypass the GI system
Provide long term consistent exposure to the agent

11. Routes of Administration Requiring Skin Puncture
• Intravenous (IV)
Injected into the vein
Rapid onset
Used in emergency, unconscious and hospitalized pt.
Bypass GI and first pass metabolism
Used for systemic exposure
• Subcutaneous (SQ)
Injected into fat beneath the skin
Permeates capillary walls to enter blood
Absorption can be controlled by drug formulation
May be self administered
• Intramuscular
Administered into muscle
Passes through capillary walls to enter blood
Formulation dictates absorption
Aqueous preparations are absorbed quickly
Oil based are absorbed slowly
Some patients may self administer

12. Routes of Administration Table
From: Whalen,K.,(2015)Pharmacology6th ed.,WoltersKluwer:Philadelphia.

13. Four Pharmacokinetic Properties
• Absorption
Absorption from the site permits entry into plasma (either
directly or indirectly)
• Distribution
Drug may then reversibly leave the bloodstream and distribute
into the interstitial and intracellular fluids
• Metabolism
Drug may be biotransformed by the liver or other tissues
• Elimination (Excretion)
Drug and its metabolites are eliminated from the body in urine,
bile, or feces

14. Absorption of Drugs
• Mechanisms of absorption of drugs from the GI tract
Passive diffusion
• Driving force is concentration gradient across a membrane separating body
components
• Drug moves from an area of high concentration to area of lower
concentration
Facilitated diffusion
• Agents enter cell through specialized transmembrane carrier proteins
• These carrier proteins undergo conformational changes allowing passage of
drugs
Active Transport
• When drug has structure similar to physiologic compound that moves across
cell membrane
• Involves specific carrier proteins that span the membrane
• Is energy dependent and able to move drugs against a concentration
gradient
Endocytosis and Exocytosis
• Used to transport drugs of very large size across cell membrane
Ex. Insulin and drugs made of large proteins

15. Absorption
• Once administered the drug must pass from administration site
through body membranes into systemic circulation
• Factors that impact absorption
Drug factors- ionization, molecular weight, solubility (lipophilicity),
and formulation
Small, non-ionized lipophilic drugs permeate plasma membranes
first
Remember
• Small, non-ionized (uncharged) molecules are lipid soluble and readily cross cell membranes
• Large, ionized (charged) molecules are water-soluble and do not readily cross cell
membranes
• Patient factors
Depend on route
Presence of food, stomach acidity, blood flow to GI tract, presence
of GI infection (oral meds), temperature (topical)

16. Factors Influencing Absorption
• Effects of pH on drug absorption
Most drugs are weak acids or weak bases
Acidic drugs in ionized form
A drug passes through membranes more readily if it is
uncharged
• Blood flow to the absorption site
Ex. Intestines receive more blood flow than the stomach, so
absorption from the intestine is favored over the stomach
• Total surface available for absorption
Again, the intestine with its microvilli has a surface area about
1000X’s that of the stomach, making absorption of the drug
across the intestine more efficient
• Contact time at the absorption site
• Expression of P-glycoprotein

17. P-glycoprotein
• Importance of membrane transport proteins in drug
bioavailability, elimination, and distribution is better understood
• Membrane transporters are protein molecules concerned with
the active transport of drugs across cell membranes
• P-glycoprotein is a transmembrane transporter protein
responsible for transporting various molecules- including drugs
across cell membranes
• Expressed in tissues throughout the body (liver, kidneys,
placenta, intestines, brain capillaries)
• Involved in transportation of drugs from tissue to blood
• Pumps drugs out of cells, thus in areas of high expression of P-
glycoprotein drug absorption is reduced
• Associated with multidrug resistance

18. Barriers and DrugsAbility to Pass Through Them
• Drug’s biological properties are a function of physiochemical
parameters
Solubility
Lipophilicity
• The ability of a chemical compound to dissolve in fats and lipids
• Lipid soluble drugs have enhanced absorption because they pass through the lipid bilayer
that makes up the cell membrane
• State of ionization
Drugs exist in equilibrium between ionized and non-ionized forms, where
the degree of ionization depends in part on the pH of the surrounding area
A non-ionized form of the drug that is lipid soluble and can diffuse across
cell membranes, has access to produce biological effect
• To reach site of action a drug may need to pass various barriers,
including skin, mucous membranes, GI tract etc.
Drug absorption determined in part by ionization state of the drug and the
pH of the surrounding fluid

19. To review-
• Most drugs are weak acids or bases that exist in either
ionized or non-ionized form
• Acidic drugs are in an non-ionized form that is lipid
soluble or lipophilic- thus they diffuse easily across the
phospholipid cell membrane
• Basic drugs are in an ionized form and are water soluble
or hydrophilic- thus they can’t pass the cell membrane
into the intracellular compartment easily
• pH of the GI also affects this process because the
proportion of the drug that is non-ionized or lipophilic
depends on the pH of the environment
Stomach→acidic→ ↓pH→drugs that are acids are mostly in non-ionized
forms in acidic environment and weak acids such as ASA are readily
absorbed in the stomach

20. Bioavailability
• The rate and extent an administered drug reaches the systemic
circulation
• Determining bioavailability is important for calculating drug
dosages for non-IV routes of administration
• Determined by comparing plasma levels of a drug after a
particular route of administration
• After IV 100% rapidly enters the circulation
• When drug given orally only part of the dose reaches the plasma
• Plotting plasma concentrations of the drug versus time, the area
under the curve (AUC) can be measured
• Bioavailability of a drug given orally is the ratio of the AUC
following oral administration to the AUC following IV administration
• The AUC represents the body’s total exposure to the drug and is a
function of the fraction of the drug dose that enters systemic
circulation via the administered route and clearance

21. Bioavailability contd.
• The fraction of the dose which reaches the systemic
circulation as intact drug is what is bioavailable
• Depends on the absorption and how much reaches the
systemic circulation
• Factors affecting bioavailability
Gut lumen, portal circulation, drug absorbed intact, and drug escaping first
pass metabolism (more on this later)
• IV drugs have bioavailability of 100%
• Bioavailability is calculated as a comparison of dosing
form’s preferably studied formulation (e.g. PO) to IV

22. Factors Influencing Bioavailability
• First pass hepatic metabolism
• The first pass clearance is the extent of the drugs removal by the liver during its first
passage in the portal blood through the liver to systemic circulation
• A fraction or all of drug can be metabolized by the initial metabolism in the gut wall or
the liver, this may limit bioavailability (amount of drug available to produce a biological
effect)
• Limits efficacy of many oral meds
• Ex. Nearly 90% of nitroglycerin (NTG) is cleared in first-pass metabolism
• When given sublingually nitroglycerin is very active because it is absorbed directly through the
oral mucosa into the system circulation bypassing the portal circulation
• Drugs with high first-pass should be given in doses sufficient to ensure that enough
drug reaches desired site of action

23. Factors Influencing Bioavailability contd.
• Solubility
Very hydrophilic drugs are poorly absorbed because of their
inability to cross lipid-rich cell membranes
Drugs that are extremely lipophilic are also poorly absorbed
because they are totally insoluble in aqueous body fluids and can’t
gain access to the surface of the cells
For a drug to be readily absorbed it must be largely lipophilic,
yet have some solubility in aqueous solutions
Thus, many drugs are weak acids or weak bases
• Chemical Instability
Some drugs like penicillin G are unstable in pH of gastric contents
and some like insulin are destroyed in the GI tract
• Nature of drug formulation
Particle size, salt form, enteric coatings and presence of binders
and dispersing agents can influence the ease of dissolution and
thus alter absorption

24. In review:
• Once drug administered it passes through the intestinal
wall to the portal circulation and liver before it enters
systemic circulation
• Most drugs undergo metabolic changes via interactions
with bacterial enzymes, permeability glycoprotein (P-gp),
cytochrome 450 enzyme (CYP 450) in GI cells and CYP
450 enzyme in the liver (more on this later)
• The biotransformation that occurs before the drug enters
the systemic circulation is referred to as 1st pass
metabolism or 1st pass effect
This results in some of the drug not entering the systemic
circulation and thus decreased drug bioavailability
Ex. Estrogen is extensively metabolized in the liver via 1st pass

25. Bioequivalence and Therapeutic Equivalence
• Bioequivalence
Two drug formulations are bioequivalent if they show comparable
bioavailability and similar times to achieve peak blood concentrations
• Therapeutic equivalence
Two drug formulations are therapeutically equivalent if they are
pharmaceutically equivalent (have the same dosage form, same active
ingredient and use same route of administration) with similar clinical and
safety profiles
• Clinical effectiveness frequently depends on both
maximum serum drug concentration and the time required
to reach peak concentration
Therefore- 2 drugs that are bioequivalent may not be therapeutically
equivalent

26. Distribution
• Process by which a drug reversibly leaves the blood
stream and enters the interstitium (extracellular fluid) and
tissues
• Distribution of a drug from the plasma to the interstitium
depends on cardiac output and local blood flow, capillary
permeability, tissue volume, degree of binding of the drug
to the plasma and tissue proteins and relative lipophilicity
of the drug
• Blood flow to tissue capillaries varies widely
Vessel rich organs (brain, liver, kidneys) greater blood
Skeletal, adipose, skin, viscera lower rates of blood flow
• Capillary/membrane permeability- determined by
capillary/membrane structure and chemical nature of the drug
Membrane permeability- must cross all membranes between the administration
site and site of action
Blood-brain-barrier- lipophilic small drugs pass through
Blood-placenta barrier- protects fetus

27. Distribution contd.
• Binding of drugs to plasma proteins and tissues
• Binding to plasma proteins - reversible binding to plasma proteins
sequesters drugs in a nondiffusable form and slows their transfer out of the
vascular compartment
Drugs bound to plasma proteins are not available to reach the site of action and unable to
produce biological effect
Drug will reach an equilibrium between free and bound drug
Albumin is the major drug-binding plasma protein and may act as a drug reservoir (as the
concentration of free drug decreases due to elimination, the bound drug dissociates from the
protein)
This is a common cause of drug-drug interaction where 2 drugs compete for binding to these
inert protein binding sites the drug with higher affinity (binding potential) will displace the other
drug, increasing the free drug concentration of this drug to levels that may cause adverse
effects
• Binding to tissue proteins - drugs may accumulate as a result of binding of
lipids, proteins, or nucleic acids
Tissue reservoirs may serve as a major source of the drug and prolong its actions or cause
local drug toxicity

28. Distribution Contd.
• Lipophilicity - chemical nature of drug strongly influences its ability to
cross cell membrane
Lipophilic drugs readily move across most biologic membranes
These drugs dissolve in the lipid membranes and penetrate the entire cell surface
Major factor influencing the distribution of lipophilic drugs is blood flow in the area
Hydrophilic drugs do not readily penetrate cell membranes and must pass thru slit
junctions
• Lipophilic drugs are slowly released from fat (obese patients may have
different effects)
• Properties that affect distribution
• Water or lipid solubility
• Size of molecule
• Acid vs basic environment
• Henderson–Hasselbalch relationship
• Protein binding
• Transporters
• Volume of distribution

29. Protein Binding
• Drugs exist in bound and unbound states
• Travel when bound; cross membranes when unbound
• “Highly” protein bound
• Ratio of bound drug usually remains stable
• Low plasma proteins (low albumen) will result in more free
drug in circulation

30. Competition for Protein-Binding Sites
• Finite number of plasma proteins
• Compete and displace each other → more free drug
• Higher risk for toxicity
• More drug may be eliminated

31. In review:
• Distribution depends on size of drug molecule, drugs
affinity for aqueous and lipid tissues, tissue permeability,
systemic circulation, protein binding and pH
• All these factors determine rate of delivery and potential
amount of drug distributed into the tissue

32. Volume of Distribution
• Volume of distribution (VD) defined as the fluid volume that is required
to contain the entire drug in the body at the same concentration
measured in the plasma
• Useful to compare the distribution of a drug with the volumes of water
compartments in the body
• Distribution into the water compartments- once drug enters body it has
potential to distribute into any one of 3 distinct compartments
• Plasma compartment- if drug has high molecular weight or is protein bound it is too
large to pass through the slit junctions of the capillaries and therefore is effectively
trapped in the plasma (vascular) compartment- it therefore has a low VD- basically it
approximates the plasma
• Extracellular Compartment- if drug is low molecular weight but is hydrophilic it can
pass through the slit junctions of capillaries into the interstitial fluid. But—hydrophilic
drugs can’t move across the lipid membranes of the cells and enter the intracellular
fluid. These drugs distribute into a volume that is the sum of the plasma volume and
the interstitial fluid- thus the extracellular fluid or about 20% of body weight
• Total body water- if drug low molecular weight and is lipophilic it can move into the
interstitium through the slit junctions and also pass through the cell membranes into
the intracellular fluid- these drugs distribute into a volume of about 60% of body weight

33. Volume of Distribution Contd.
• VD is a useful pharmacokinetic parameter for
calculating loading dose of a drug
• Effect of VD on drug half-life- Drug elimination depends on
the amount of drug delivered to the liver or kidney (or
other organs where metabolism occurs) per unit of time
Delivery of a drug to the organs of elimination depends not only on blood
flow but also on the fraction of the drug in the plasma
If a drug has a large VD most of the drug is in the extraplasmic space and
is unavailable to the excretory organs
Any factor that increases the VD can increase half-life and extend the
duration of action of the drug

34. Metabolism/Elimination
• Some call metabolism biotransformation
• Once a drug enters the body the process of elimination begins
• Sites of metabolism
Liver (hepatic metabolism)- major site of metabolism due to cytochrome P450
(CYP 450) enzymes
Biliary elimination
Urinary elimination
• Together these processes decrease the plasma concentration
• Most drugs eliminated by first-order kinetics
• Metabolism leads to production of products with increased
polarity which allows the drug to be eliminated
• Clearance (CL) estimates the amount of drug cleared from the
body per unit of time

35. Kinetics of Metabolism/Elimination
• First-order kinetics
Referred to as linear kinetics
The rate of drug metabolism and elimination is directly proportional to the
concentration of free drug
A constant fraction of drug is metabolized per unit of time
With each half-life the concentration decreases by 50%
Most drugs
• Zero-order kinetics
Nonlinear kinetics
A constant amount of drug is metabolized per unit of time
The rate of elimination is constant and doesn't not depend on the drug
concentration
Aspirin, ethanol, and phenytoin

36. Metabolism/Elimination contd.
• Together these metabolic/elimination processes decrease
the plasma concentration exponentially
• Most drugs are metabolized and thus eliminated
according to first-order kinetics
Some like Aspirin in high doses are eliminated according to zero-order or
nonlinear kinetics.
Metabolism leads to production of products with increased polarity which
allows the drug to be eliminated
Clearance (CL) estimates the amount of drug cleared from the body in a
unit of time
Total CL is an estimate reflecting all mechanisms of drug elimination-
including half-life and VD (see text for equation and detailed explanation)

37. Reactions of Drug Metabolism
• The kidney can’t efficiently eliminate lipophilic drugs
• Lipid soluble agents are first metabolized into more polar
(hydrophilic) substances in the liver by 2 general sets of
reactions- phase l and phase II
Phase I- Lipophilic drugs are metabolized to make them less active or
inactivate them and to make them more polar and water-soluble to ease
secretion
Phase II- Conjugation reactions that alter many phase I metabolites that
are still too lipophilic to be excreted into more water-soluble compounds
that are therapeutically inactive.
Enzymatic alteration of the structure of a drug to an inactive metabolite
form

38. Metabolism
• Phase I and Phase II metabolism
• Phase I: nonsynthetic reactions
• Phase II: synthetic or conjugation reactions
• Cytochrome P450 (CYP450)
• Organized into numbered families
• CYP1, CYP2, CYP3
• Metabolism and half-life

39. Cytochrome (CYP) P450 System
• The phase I reactions most frequently involved in drug metabolism
are catalyzed by cytochrome P450 system
• CYP 450 describes the group of enzymes responsible for oxidation of
many drugs. Drug metabolism occurs in intestine and liver
• The family name is indicated by the number that follows CYP, the
capital letter designates the subfamily and the second number
indicates the specific isozyme
• Most commonly CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A4
Understanding which CYP 450 isozyme is responsible for the metabolism of a drug is
useful in predicting and understanding drug reactions
• CYP 3A4 is the workhouse- major form CYP450 system, greatest
proportion of drugs
• There is considerable genetic variability among individuals and racial
groups
• Enzyme function may change due to induction or inhibition of the
enzymes, thus altering the drugs that are acted on by these enzymes
• Drugs can be inhibitors, inducers or substrates
A drug can be a substrate and inhibitor at the same time

40. CYP 450 Continued
• Drug interactions in the CYP system can result from 2
processes
• Inhibition/Inhibitor- drugs competing for the same binding site- results
in drug metabolism being diminished→ decreased clearance- with
increased serum concentrations
Inhibition of metabolism increases drug concentrations
Important source of drug interactions that lead to serious adverse events
Natural substances may also inhibit drug metabolism
• Induction/Inducer- enhances the enzymes metabolizing capacity-
increases rate of metabolism→ substrate clears faster- decreases
pharmacologic action
Induction of metabolism decreases drug concentrations
Decreases therapeutic drug effect
• Substrate
The agent or drug that is metabolized by an enzyme into an end product
Usually in preparation for elimination from the body

41. Factors Affecting Drug Metabolism
• Diet
• Induction of CYP
Brussel sprouts, cabbage, cruciferous vegetables (broccoli), charcoal
broiled beef, low protein diets and malnutrition
• Inhibition of CYP
Grapefruit juice, high protein diet, alcohol, increased hepatotoxicity,
acetaminophen, isoniazid, cocaine, methotrexate, Vit. A
• Other drugs
Use of 2 or more drugs may either inhibit or enhance another
drug’s metabolism
• Age
Overall reduction in CYP activity may occur with increasing age
Reduced albumin may lead to increased free drug availability

42. Therapeutic Consequences of Drug Metabolism
1. Accelerated renal excretion
Most important consequence of drug metabolism
Kidney is major organ for drug excretion and is unable to excrete drugs
that are highly lipid soluble
By converting lipid-soluble drugs to less lipid soluble (more polar)
compounds drug metabolism makes it possible for the kidney to excrete
many drugs
2. Drug Inactivation
Drug metabolism can convert pharmacologically active compounds to
inactive forms
3. Increased therapeutic action
 Metabolism can increase the effectiveness of some drugs ( e.g.
analgesic activity of morphine is greater than cocaine)

43. Therapeutic Consequences of Drug Metabolism Contd.
4. Activation of Pro-drug
 Agent must undergo chemical or enzymatic transformation to the
active drug so that the metabolic product can exhibit the desired
response
 Compound is pharmacologically inactive as administered and
then converted to its active form within the body
5. Increased or decreased toxicity
 By converting drugs into inactive forms, metabolism can
decrease toxicity
 Conversely metabolism can increase the potential for harm by
converting relatively safe compounds into toxic forms (e.g. it is
the product of metabolism of acetaminophen that causes
hepatic injury when acetaminophen is taken in overdose)

44. Elimination (Excretion)
• Removal of drug from body
 Drugs must by sufficiently polar to be eliminated from the body
• Some drugs excreted after they have been metabolized and others
are excreted unchanged
• 2 major sites kidneys and liver
• Elimination via kidneys accounts for the majority of drug excretion
 Clearance of unchanged drug in urine represents renal clearance
 Adjustments made for renal insufficiency (if GFR drops by 50% drug
clearance drops by 50%)
 People with renal dysfunction may be unable to excrete drugs and are at risk
for drug accumulation and adverse events
• May be excreted via liver via biotransformation of parent drug to 1
or more metabolites
• May be concentrated in the bile and reabsorbed into portal
bloodstream (enterohepatic circulation)
• May be excreted into expired air
• May be excreted in feces

45. Factors That Modify Renal Drug Excretion
• Competition for active tubular transport
 Active transport systems of renal tubules can carry limited number of drug
molecules
 If there are too many present renal excretion of this drug is delayed causing
prolonged drug action
 If you administer 2 drugs at same time that use the same transport system
excretion of each can be delayed by the presence of the other
• pH Dependent Ionization
 Lipid soluble compounds are reabsorbed by kidney tubules
 Drugs that are ionized (not lipid soluble) at the pH of tubular urine will
remain in the kidney tubule and be excreted
 You can therefore manipulate urinary pH to promote ionization of a drug and effect
its elimination
• Renal clearance is affected by renal disease or decreased cardiac
output which often decreases drug clearance
• Age related changes
 Kidney loses up to 20-25% of its mass with aging from 30-80 y/o.
 GFR decreases 10% /decade from age 30
 GFR decreases 1 ml/min/yr

46. Renal Function Assessment
• When deciding on initial doses for drugs that are
eliminated renally the patient's renal function should be
assessed
• Common useful way to do this is to measure the patient's
serum creatinine concentration and convert this value into
a creatinine clearance- CLcr
• Serum creatinine values alone should not be used to
assess renal function because they don’t include age,
weight, or gender
• Cockcroft - Gault equation is a widely used method to
estimate creatinine clearance (CLcr)

47. Time Course of Drug Response
• Most of the time the time course of a drugs action is directly related to the
concentration of the drug in the blood
• Two plasma drug levels are important
 Minimum effective concentration- plasma drug level below which therapeutic effects will
occur
 Toxic concentration- plasma level of a drug at which toxic effects begin to appear
• Therapeutic range- the range of plasma drug levels between the minimum
effective concentration and the toxic concentration
• The goal of drug dosing is to maintain plasma drug levels within the
therapeutic range-
 Achieve and maintain concentrations within a therapeutic response window while
minimizing toxicity and/or side effects
 Narrow therapeutic window- extra caution in selecting dosage regimen and monitoring
of drug levels may help ensure attainment of therapeutic range (digoxin, warfarin,
cyclosporine)
• Because responses don’t occur until plasma drug levels have reached the
minimum effective concentration, there is a period of latency between drug
administration and onset of effects
 The extent of this delay is determined by rate of absorption
• The duration of effects is largely determined by the combination of
metabolism and excretion because they determine how long the plasma
levels remain in the therapeutic range

48. Half-Life (t ½)
• Time required for serum concentrations to decrease by one-half
after absorption and distribution are complete
• Measures how rapidly drug levels decrease due to metabolism and
excretion
• Important because it determines the time required to reach steady
state and dosage interval
• Time required for amount of drug in the body to be decreased by
half
One t1/2= 50% of the drug eliminated
Two t1/2= 75% of drug is eliminated
Three t1/2= 87.5% of drug is eliminated
Four t1/2= 93.75% of drug is eliminated
• The half-life of a drug does not depend on the size of the dose
administered.
• It takes the same amount of time from the serum concentrations to
drop from 200-100 mg/L as it does for 2 to1mg/L

49. Half-life Altered by Clinical Situations
• When a patient has an abnormality that alters the half-life of a
drug a dosage adjustment needs to be made
• Increased half-life seen in
Diminished renal or hepatic blood flow (cardiogenic shock, heart
failure, hemorrhage)
Decreased ability to extract drug from plasma (renal disease)
Decreased metabolism (when another drug inhibits metabolism or in
hepatic insufficiency as seen in cirrhosis)
These folks would require a decrease in dosage or less frequent
intervals
• Half-life a drug decreased
Increased hepatic blood flow
Decreased protein binding
Increased metabolism
May necessitate higher doses of more frequent dosing intervals

50. Steady State
• Reached when the rate of drug elimination is equal to the rate
of drug administration such that the plasma and tissue levels
remain relatively constant
Continuous or repeated administration results in accumulation of the
drug until a steady state is reached
• Important concept related to elimination
• Because the rate of elimination and accumulation is
proportional to the concentration, at some point a steady state
is reached
• With repeated dosing, drugs accumulate in the body until they
reach a steady state or until dosing stops
• Drug absorption then equals drug elimination during the dose
interval
• The sole determinant of the rate that a drug achieves steady
state is the half-life (t ½ )
It takes about 3-5 half lives for plasma drug levels to reach a
steady state with peak and valley (trough) levels remaining
constant after each dosing

51. Clearance
• Clearance (CL)
• Ratio of the rate of elimination of a drug to its concentration in the
plasma or blood
Dependent on the integrity of glomerular filtration
• Volume of fluid that would be completely cleared of drug per unit of
time if all the drug being excreted/metabolized were removed from
that volume
• Clearance is a calculated value that can’t be measured directly
Total clearance= renal clearance + metabolic clearance + all other
clearance
• Clearance is an important pharmacokinetic parameter because it
determines steady state concentration for a given dosage rate

52. Drug Interactions
• Drugs can interact at each of the phases of
pharmacokinetics
• Just a few examples:
• Absorption- interferes with absorption site
Calcium binding of tetracycline in gut
• Distribution- compete for binding site on plasma or tissue protein
Valproic acid displaces phenytoin from protein binding sites
• Metabolism- compete for, induce or inhibit metabolism
Probenecid competes for sulfonamides increasing concentration and
decreasing elimination rate

53. In Review:
• Pharmacokinetic processes occur as drug is distributed
• Steady state- concentration of drug in systemic circulation
that will eventually be achieved when rate of drug
elimination equals rate of drug availability
Usually reached in 3-5 half lives
• Half-life - time it takes for the plasma concentration or
amount of drug in the body to be reduced by 50% or ½
Important because it determines time required to reach a steady state
and dosage interval
• Loading dose - one or a series of doses that may be given
at onset of therapy with aim of reaching the target plasma
concentration rapidly
Used to rapidly attain steady state when need a quick therapeutic dose

54. In Review Contd.
• Volume of distribution- VD the apparent volume in which
the drug is dissolved-
Relates to concentration of drug in plasma and amount of drug in
the body
Often used to calculate loading dose of a drug that will immediately
achieve a desired steady state drug level because it refers to the
relationship between dose of drug administered and serum
concentration after administration
• Plasma protein binding - important factor when drug is in
systemic circulation
Refers to the fraction of the total drug in the plasma that is bound to
proteins in plasma

55. Pharmacodynamics
• Pharmacodynamics describes how drugs act on the body to
produce physiologic changes.
• To produce these effects, drugs commonly bind to receptors
and modulate their functions.
Pharmacodynamics is based on the concept of drug-receptor binding
Receptors are specialized target macromolecules
Drugs act as signals and the receptors act as signal detectors
• Important to describe drug effects quantitatively in order to
determine appropriate dose ranges for patients and to be able
to compare potency, efficacy, and safety of one drug to another

56. Basic Definitions
• Receptor- Molecules in the biological system with which the
drug interacts to bring about the biological effect
• Agonist- Drug that activates its receptor upon binding
 Drug binds to a receptor and produces a maximal biologic response
• Partial Agonist- Drugs that bind to and activate a given
receptor but have only partial efficacy at the receptor relative to
a full agonist
• Antagonist- Drugs that bind to a receptor without eliciting a
response
• Drugs can bind with inert binding sites. These inert binding
sites are often components of endogenous molecules that bind
the drug without leading to any of the drug effects
Plasma proteins (such as albumin)
Only drug that is free to reach the site of action will have a
biological effect
Interaction with plasma proteins lowers the concentration of free
drug and decreases the bioavailability of the drug

57. Dose Response Curve
• The basic currency of pharmacodynamics is the dose-
response curve view of the observed drug effect as a
function of drug concentration
• Two types of dose-response relationships
Graded - dose of a drug is described in terms of a percentage of
the maximal response
Quantal - dose of a drug is described in terms of the cumulative
percentage of subjects exhibiting a defined all or none effect
• Determines the therapeutic index (TI) and safety factors

58. Dose Curve Response Contd.
• Using a dose response curve you can plot the response
of an affected system to different doses of a drug
• By plotting these dose response curves, you can identify
two important values
1) EC50- Effective concentration that produces a 50% response
2) Emax- maximum effect observed
• These values are important because they translate to two
observable properties of drugs: potency and efficacy

59. Potency and Efficacy
• Potency- drug concentration (EC50) required to produce
50% of the drug’s maximal effect.
The lower the EC50 of a drug, the greater the potency
This is true because less drug is required to produce 50% of the
maximal response
• Efficacy- strength of the drug-receptor interaction which
invokes a maximal effect- i.e. the maximum possible
effect achieved
Corresponds to the Emax which is measured on the dose response
curve
The greater the Emax the greater the efficacy of the drug

60. Therapeutic Pharmacodynamics
• This is population pharmacodynamics
Allows you to determine the median effective (ED50) and median
lethal (LD50) doses of a drug by measuring percentage response to
various concentrations of drug in a given population
Term ED50 is synonymous with EC50 (effective dose and effective
concentration)
Important because while drugs have an effective range of
concentrations that produce the desired physiological effect, higher
levels of drug often produce serious side effects.
Goal is to achieve therapeutic levels of a drug while minimizing
adverse effects- the indication of this is the therapeutic index

61. Therapeutic Index
• Ratio of LD50 to ED50
• The larger the therapeutic index, the safer the drug
• Therapeutic index (TI)= LD50/ED50
• Some use TD (toxic dose) instead of LD (lethal dose)
TI= TD50/ED50

62. Definitions for Review-
• Absorption - movement of drug from the GI tract to the
systemic circulation
• Agonist - drugs that activate a receptor when bound to receptor
• Agonist-antagonist - drugs that have agonist properties for one
opioid receptor and antagonist properties for a different type of
opioid receptor
• Antagonist - drug that prevents receptor from being activated
when bound to that receptor
• Bioavailability - amount of administered drug that is available to
the target tissues
• Bioequivalence - state in which a products bioavailability falls
within 80-120% of the bioavailability of the reference drug
If the two products are bioequivalent one can usually be substituted for
the other

63. Definitions contd.
• Biotransformation - changes a substance undergoes in the
body
• Clearance - measure of bodies ability to eliminate a drug
• Cytochrome P-450 - (CYP 450) name for a family of enzymes
that are responsible for most drug metabolism reactions
• Distribution - process by which a drug becomes available to
body fluids and tissues
• Dose response curve - change in the response to a drug
caused by different doses of that drug
Dose response curves help determine safe doses for drugs
• Drug-drug interaction - alteration in drugs effect that occurs
when another drug is administered at the same time or in close
proximity to the original drug administration time

64. Definitions contd.
• Efficacy - ability to induce a therapeutic response
• Effectiveness - ability of a drug to induce a therapeutic
response in real life conditions
• Excretion - elimination of a drug from the body
• First pass effect - drug metabolism that occurs as the drug
passes through the intestine, portal vein, and liver prior to
entering the systemic circulation
Also know as hepatic first pass
• Half-life - time it takes for half of the drug concentration to
be eliminated from the body (t ½ )
• Hydrophilic - drug that is water soluble
A drug or drug metabolite must be hydrophilic to be eliminated in
the urine

65. Definitions contd.
• Inducers - drugs that stimulate production of one of the
CPY 450 enzymes which rapidly metabolizes the
substrate drug.
This can result in a decreased therapeutic effect of the substrate
drug
• Inhibitors - drugs that prevent production of a CYP 450
enzyme which decreases metabolism of the substrate
drug
Results in increased plasma level of drug and increases
therapeutic effect, adverse drug reaction and/or toxic effect
• Lipophilic - drug that has a high affinity for fat
Lipophilic drugs transfer readily across the cell membrane which is
a phospholipid

66. Definitions contd.
• Loading dose - administration of a large initial drug dose
• Maximum effect - the maximum drug effect
• Metabolism - change of a drug, primarily in the liver by
CYP 450 enzymes into metabolites that may be
pharmacologically active or inactive
Drug metabolism alters a drug so that it may be eliminated
• Minimum effective concentration - minimum concentration
of a drug in serum required to produce the desired
pharmacologic effect
• Narrow therapeutic index - defined by FDA as less than a
2 fold difference between the median effective dose and
the median lethal dose

67. Definitions contd.
• Partial agonist - drug molecule that elicits a partial
pharmacologic effect
• P-glycoprotein (P-gp) - permeability glycoprotein- a
transmembrane protein that serves as a drug transporter
and moves drugs out of cells (efflux pump)
• Pharmacodynamics - study of drug effects- including
duration and magnitude of the response relationship to
the drug dose
• Pharmacokinetics - process of drug absorption,
distribution, metabolism, and elimination
• Phase I reaction - first half of enzymatic metabolism which
makes drug water soluble so it can be excreted
• Phase II reaction - second half of drug metabolism
process which makes drug polar and finalizes the
changes that make it water soluble

68. Definitions contd.
• Potency - concentration at which a drug elicits 50% of its
maximal response
• Prodrugs - biologically inactive or partially active drugs that are
changed as a result of the body's metabolism into active drugs
• Protein binding - fraction of total drug in the plasma that is
bound to plasma proteins
• Receptor - protein or molecular complex that when bound to a
ligand (drug) either initiates a physiologic response or blocks
the specific response that the receptor normally stimulates
• Steady state - occurs when drug elimination equals drug
availability
Concentration of drug remains constant when SS is reached

69. Definitions contd.
• Therapeutic effect - desired physiological or psychological
response to a drug
• Therapeutic equivalence - state when 2 different drugs contain
the same active ingredient at the same dose (pharmaceutically
equivalent) and have the same clinical effect with regard to
safety and efficacy
• Therapeutic index - guideline that estimates the margin of
safety of a drug
Uses a ratio that measures the effective dose in 50% of the population
and the lethal dose in 50% of the population
• Therapeutic range (therapeutic window) - plasma drug
concentration between the minimum effective concentration in
the serum for obtaining the desired drug action and the mean
toxic concentration
• Volume of Distribution (VD) - relationship between the dose of
drug administered and the serum concentration after
administration

70. The End