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1

Define Pharmacology

study of substances that interact with living systems
beneficial therapeutic effect
toxic effects--parasites infecting the patient.

2

Define Toxicology

deals with the undesirable effects of chemicals on living systems

3

Define Pharmacotherapeutics

study of the therapeutic uses and effects of drugs

4

Define Pharmacodynamics

What the drug does to the body
Study of the relationship between the concentration of a drug and the response obtained in a patient

5

Define Pharmacokinetics

What the body does to the drug: how it moves
Describes the absorption, distribution, metabolism (biotransformation) elimination of drugs
ADME

6

What form of drug has an effect on the body?

Free drug only!

7

What organ is the most likely to transform a drug?

Liver

8

Define Bioavailability

Fraction (F) of the administered dose that reaches the systemic circulation
Bioavailability is defined as 100% for intravenous administration

9

Bioavailability through methods other than IV

(less than 100%), bioavailability is generally reduced
by incomplete absorption (and in the intestine, expulsion of drug by intestinal transporters)
first-pass metabolism, and any distribution into other tissues that occurs before the drug enters the systemic circulation

10

Intravenous route: available, absorption and limitations/precautions

100% available

Absorption circumvented

Increased risk of adverse effects

11

Subcutaneous: available, absorption and limitations/precautions

75-100%
Prompt from aqueous solution slow and sustained from repository preparations

not suitable for large volumes possible pain or necrosis from irritating substances

12

Intramusclular: available, absorption and limitations/precautions

75-100% slide 10
prompt from aqueous solution slow and sustained from repository preparations

Precluded during anticoagulant therapy
may interfere with interpretation of certain diagnostic tests(creatine kinase)

13

Oral ingestion: available, absorption and limitations/precautions

5-100%
variable depends on many factors

requires pt compliance bioavailability potentially erratic and incomplete

14

Oral administration

Offers maximal convenience; absorption is often slower. Subject to the first-pass effect, in which a significant amount of the agent is metabolized in the gut wall, portal circulation, and liver before it reaches the systemic circulation

15

Buccal and sublingual administration

Direct absorption into the systemic venous circulation, bypassing the hepatic portal circuit and first-pass metabolism

16

Inhalation administration

Route offers delivery closest to respiratory tissues (eg, for asthma). Usually very rapid absorption (eg, for anesthetic gases)

17

Topical administration

The topical route includes application to the skin or to the mucous membrane of the eye, ear, nose, throat, airway, or vagina for local effect

18

Transdermal administration

The transdermal route involves application to the skin for systemic effect. Absorption usually occurs very slowly (because of the thickness of the skin), but the first-pass effect is avoided

19

What factors may change the bioavailability of a drug for the various routes of administration?

-liver function
-IBS

Not finished

20

Pediatric absorptions: Oral, skin and IM

Oral:
gastric pH ranges from 6 to 8 at birth but declines to 1 to 3 within 24 hours
gastric pH remains elevated in premature infants because of immature acid secretion
Skin
may be increased substantially in newborns because of an underdeveloped stratum corneum and increased skin hydration
IM
Drug absorption is impossible to predict

21

Pregnant absorption: Oral

Oral
Nausea and vomiting
Delayed gastric emptying
Increase in gastric pH may affect the absorption of weak acids and bases

22

Geriatric absorption

-Most drugs are absorbed via passive diffusion
age-related physiologic changes appear to have little influence on drug bioavailability
-Nutrients absorbed by active transport
vitamin B12, iron, calcium, magnesium, and leucine, may have impaired absorption in older adults
-Evidence for a decreased first-pass effect on hepatic or gut wall metabolism
results in increased bioavailability and higher plasma concentrations of drugs

23

Define first-pass effect and examples

-Concentration of a drug is greatly reduced before it reaches the systemic circulation
-Fraction of lost drug during the process of absorption which is generally related to the liver and gut wall
-Example: propranolol (F of ~25%)
Oral dose-- 10mg
IV dose-- 1mg

24

What can alter the fraction unbound in protein binding?

-concentration of drug in the body(higher drug concentration leads to higher fraction unbound)
-amount and quality of plasma protein(decreased=higher fraction unbound)
-other drugs that bind to plasma proteins(generally clearance increases because displacing drug is an inhibitor of clearance)

25

Do protein bound molecules exert any pharmacological effects?

No they are not available to do so

26

Protein binding distribution warfarin example

-Narrow margin of safety or narrow therapeutic window
Little difference between therapeutic effect and toxicity
-98% protein bound
-Addition of second highly protein bound drug such as aspirin competes for the protein resulting in more free drug for both warfarin and aspirin through inhibition of clearance of warfarin.

27

Are drugs dosed on protein bound amount?

Yes. you have to give enough to make it work. Think of musical chairs: more kids/chair=more free drug(has an effect)

28

List drug movement exampes

Passive transport: paracellular transport and diffusion
Active transport: facilitated diffusion and drug transporters
Ion Channels: voltage activated Na channel and ligand gated Na channel

29

What is volume of distribution?

-relates the amount of drug in the body to the serum concentration
-determined by the physiologic volume of blood and tissues and how the drug binds in blood and tissues
-used to calculate the loading dose of a drug that will immediately achieve a desired steady-state concentration
gentamicin

30

Where is most of our volume as humans?

Total body water and then fat

31

Changes in distribution in pediatric pt. List an example

-more total body water
94%fetus
85%preemies
78% full term baby
60%adult
-more extracellular fluid
50%preemies
35%4-6month
25%1year
19%adult
Example: gentamicin distribution volumes of 0.48 L/kg in neonates and 0.2 L/kg in adults
-decreased binding of drugs to plasma proteins: lower plasma protein concentration, binding capacity, affinity of proteins, competition
ex: phenobarbital, salicylates, phenytoin
-decreased body fat

32

Changes in distribution during pregnancy

-increased body fat: volume of dist. of fat soluble drugs may increase
-decreased plasma albumin: increase vol of dist. of drugs that are highly protein bound

33

Changes in distribution in geriatric pts

-decreased total body water
-decreased lean body mass
-↑ body fat
-decreased serum albumin
-increased α1-Acid glycoprotein (↔ or ↑ by several disease states)
-↓ cardiac output

34

Define receptors

specific molecules in a biologic system with which drugs interact to produce changes in the function of the system

35

Define Agonist

drugs bind to and activate the receptor in some fashion, which directly or indirectly brings about the effect

36

Define partial agonist

binds to its receptor but produces a smaller effect at full dosage than a full agonist

37

Define antagonist

drugs, by binding to a receptor, compete with and prevent binding by other molecules

38

Define allosteric

drugs bind to the same receptor molecule but do not prevent binding of the agonist
-may enhance or inhibit the action of the agonist molecule
-not overcome by increasing the dose of agonist

39

Define irreversible antagonist

is an antagonist that cannot be overcome by increasing the agonist

40

What is the best example of a competitive inhibitor?

Narcotics and Narcan

41

Allosteric binding

Look at slide 36 for diagram

42

Metabolism(biotransformation)

-Unchanged—excreted as is
-Changed through metabolism:
-Active drug
-Inactive drug

43

Sites of drug metabolism

-Most important: liver
-Kidneys important in some drugs met.
-Few drugs(esters) are metabolized in many tissues(liver, blood, intestinal wall) because of the wide distribution of their enzymes

44

What are Phase I reactions?

-convert the parent drug to a more polar (water-soluble) or more reactive product by unmasking or inserting a polar functional group such as —OH, —SH, or —NH2
-Cytochrome P450 enzyme species (eg, CYP2D and CYP3A4) that are responsible for much of drug metabolism. Many isoforms of CYP have been recognized

*50% of drug reactions go through cytochrome P450: problem is that a lot of other drugs can rev it up or inhibit it

45

What are Phase II reactions?

increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate, or sulfate

46

What is P-glycoprotein, MDR-1?

An ATP-dependent transport molecule found in many epithelial and cancer cells. The transporter expels drug molecules from the cytoplasm into the extracellular space. In epithelial cells, expulsion is via the external or luminal face

47

What usually happens during a Phase I reaction?

-Usually convert the parent drug to a more polar metabolite
Introduce or mask a functional group
=OH, -NH₂. –SH
-Usually changed to inactive
May be modified or even enhanced
-Polar metabolite generally more easily excreted

48

Cytochrome P450 (CYP450)

-Generic name for the group of enzymes that are responsible for most drug metabolism oxidation reactions. (Phase I)
-Several P450 isozymes have been identified
CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4

49

What are the most common CYP450?

2D6 and 3A4

50

Define Substrate and give an example

-drug which is metabolized by one of the CYP450 enzymes
-Example
Acetaminophen is metabolized by CYP1A2

51

Define Inducer and give an example

-drug which can increase the activity of a CYP450 enzyme

Example
Smoking increases the activity of CYP1A2
What happens to acetaminophen then? decreases due to increased enzyme activity (metabolism increases)

*a second drug that comes into the system and increases the activity of that particular cytochrome

52

Define Inhibitor and give an example

-drug which can decrease the activity of a CYP450 enzyme

Example
Fluvoxamine decreases the activity of CYP1A2
What happens to acetaminophen then? Increased due to decreased enzyme activity(metabolism decreases)

53

Application question:
Cocaine is metabolized by the CYP3A4 enzyme
In this situation cocaine is a substrate

You prescribe erythromycin and you look up that this drug is an inhibitor of CYP3A4
What happens to cocaine?

At the next visit you prescribe a glucocorticoid which again you look up and know it is an inducer of CYP 3A4.What happens to cocaine?

-Increases(cyp3a4 blocks cocaine metabolism, so more cocaine stays in the body)

-Cocaine is metabolized at a higher rate, is out of system faster

54

What happens during a Phase II reaction? Give examples

-Often the subsequent reaction (to Phase I)
-Form a highly polar conjugate:
Glucuronic acid (glucuronidation UDP)
Sulfuric acid (sulfation SULTs)
Acetic acid (Acetylation NAT)
Amino acid
Glutathione conjugation (GST)
Glycine conjugation
Methylation (TPMT, SAMe MT)

55

Inhibitors of Intestinal P-glycoprotein

List some complications if P-gp is inhibited

P-gp inhibitors include verapamil, and furanocoumarin components of grapefruit juice(not all grapefruit juices are equally potent)

Important drugs that are normally expelled by P-gp (and are therefore potentially more toxic when given with a P-gp inhibitor) include digoxin, cyclosporine, and saquinavir.

56

What metabolism changes are seen in pediatric pts? List examples

-Drug metabolism is substantially slower in infants than in older children and adults.
Example: Higher serum concentrations of morphine are required to achieve efficacy in premature infants than in adults
Infants are not able to metabolize morphine adequately to its 6-glucuronide metabolite (20 times more active than morphine
-Sulfation pathway is well developed in infants
-Glucuronidation pathway is undeveloped in infants
Example: acetaminophen metabolism by glucuronidation is impaired in infants compared with adults
partly compensated for by increase through the sulfation pathway
balanced to some degree because clearance of morphine quadruples between 27 and 40 weeks of postconceptional age

57

Metabolism changes during pregnancy

Hepatic perfusion increases:
theoretically increases the hepatic extraction of drugs

58

Metabolism changes in geriatric pts

↓ Hepatic size
↓ Hepatic blood flow
↓ Phase I (oxidation, reduction, hydrolysis) metabolism (therefore includes the CYP450 enzymes)

59

Define Steady state

Condition in which the average total amount of drug in the body does not change over multiple dosing cycles
ie, the condition in which the rate of drug elimination equals the rate of administration

60

Do most drugs follow linear pharmacokinetics?

YES.
Linear pharmacokinetics: steady-state serum drug concentrations change proportionally with long-term daily dosing.

61

What is nonlinear pharmacokinetics?

serum concentration changes more or less than expected. (does not change proportionally like in linear)

62

What is a half life?

-Time required for serum concentrations to decrease by one-half after absorption -and distribution are complete
-Determines the time required to reach steady state and the dosage interval

63

What can effect half life?

-Dependent kinetic variable because its value depends on the values of clearance and volume of distribution

-Disease, age, and other variables usually alter the clearance of a drug much more than they alter its Vd

64

What is clearance?

*Most important pharmacokinetic parameter
-Determines the steady-state concentration for a given dosage rate
-Determined by blood flow to the organ that metabolizes or eliminates the drug
-Efficiency of the organ in extracting the drug from the bloodstream. Can increase or decrease open/close spigot analogy

65

First order vs zero order elimination

First order: time to remove drug is a percentage: cuts down by half each half life 50-->25-->12.5
Zero order: same amount each time 50-->47.5-->45

66

Organs involved in elimination

-Primary:
Kidney
-Others:
Lungs
Skin
GI
Biliary
Salivary
Mammary

67

Adjustment of Dosage When Elimination Is Altered by Disease: examples

-Renal disease or reduced cardiac output often reduces the clearance of drugs that depend on renal function.
-Alteration of clearance by liver disease is less common but may also occur.
-Impairment of hepatic clearance occurs (for high extraction drugs) when liver blood flow is reduced, as in heart failure, and in severe cirrhosis and other forms of liver failure.

68

Glomerular filtration rate(GFR)

-Total filtration rates of functioning nephrons of kidney
-GFR cannot be measured directly
-Variables: gender, age, weight, and race
-Used for the detection, severity, and treatment of kidney disease

69

What changes in excretion are seen with pediatric pts

-Efficiency of renal excretion is determined by:
glomerular filtration
tubular secretion
tubular reabsorption
-Processes may not develop fully for several weeks to 1 year after birth

70

What changes in excretion are seen during pregnancy

-Maternal plasma volume, cardiac output, and glomerular filtration increase by 30% to 50% or higher:
potentially lowering the concentration of renally cleared drugs
-Higher levels of estrogen and progesterone alter liver enzyme activity:
increase the elimination of some drugs but result in accumulation of others

71

What changes in excretion are seen in the geriatric pop?

↓ GFR
↓ Renal blood flow
↓ Filtration fraction
↓ Tubular secretory function
↓ Renal mass

72

What are some equations used to determine medication dosage?

-Modification of Diet in Renal Disease (MDRD) equation
Estimates GFR adjusted for BSA
More accurate than ----Cockroft-Gault
Used by most laboratories as eGFR

Cockroft-Gault equation
Uses body weight
Is the standard for drug dosing

73

Factors to be taken into consideration when deciding on the best drug dose for a patient include

Age
Gender
Weight
Ethnic background
Concurrent disease states
Other drug therapy

74

Pharmacodynamics (PD)

-Deals with the effects of drugs on biologic systems
Potency denotes the amount of drug needed to produce a given effect
Efficacy is the greatest effect (Emax) an agonist can produce if the dose is taken to the highest tolerated level
partial agonists have lower maximal efficacy than full agonists

75

Define potency

measure of dose required to produce a response
slide 76

76

Define efficacy:

Maximal response a drug can produce
slide 77 figure