lecture 3

Question 1

Pharmacokinetics

Answer 1

Describes the movement of a drug from “consumption” (entry) to “elimination” (removal).

What the body does with the drug.

Question 2

Pharmacodynamics

Answer 2

Describes how the drug works at the target tissue.
What the drug does to the body.

(see image)

Question 3

Four processes of pharmacokinetics

Answer 3

ADME
Drug Absorption
Drug Distribution
Drug Metabolism
Drug Excretion

Question 4

Routes of administration

Answer 4

The route of administration is determined primarily by the properties of the drug and the therapeutic objective.

There are two major routes of administration: enteral (oral, sublingual, rectal) & parenteral (IV, IM, subcutaneous)

Question 5

Enteral: Oral

Answer 5

The most common route, by mouth (aka. per os).

While the easiest (and safest? - not necessarily - e.g., can’t swallow) this pathway is the most COMPLICATED and exhibits the most variability (stomach vs. small intestine (duodenum), “FIRST-PASS METABOLISM” in both the intestine and liver, gastric emptying variability, acid lability, enteric coating, etc.)

Question 6

Enteral: Sublingual

Answer 6

Absorption directly into the systemic circulation, rapid onset and AVOIDS first-pass metabolism in the liver and intestine and the acidic stomach.

Question 7

Enteral: Rectal

Answer 7

Venous drainage of the distal rectum enters the systemic circulation (just like sublingual) this route is also useful in patients with nausea & vomiting. (avoids first pass initially?)

Question 8

Parenteral: IV

Answer 8

This avoids first pass effects, it allows the most control over the circulating level of agent; it is invasive, requires intravenous access once given IV drugs are difficult to remove (emesis, charcoal).

Question 9

Parenteral: IM

Answer 9

Intramuscular administration allows for administration of drugs without IV access, aqueous solutions are ~rapidly absorbed some drugs are given in depot preparation which promote slow absorption over prolonged time periods (depot anti-psychotics can be given once a month).

Question 10

Parenteral: Subcutaneous

Answer 10

Like IM this allows for absorption into the plasma, this can be RAPID (insulin, epinephrine) OR slow (contraceptives). This can also help to localize a drug effect (local anesthetics).

Question 11

Pharmacokinetics: Absorption

Answer 11

Movement of drug from the site of administration that allows the agent access to the plasma.

Depends on drug’s ability to cross cell membranes and resist presystemic metabolism (enzymes in GI tract begin to break down drug before it is absorbed).

PRESYSTEMIC METABOLISM (think this means breakdown of drugs in GI tract which could include destruction of drug by GI acids and also referring to first pass metabolism) affects drug’s BIOAVAILABILITY— amount of drug that reaches systemic circulation intact

*taking meds with food reduces the speed of absorption

Question 12

Absorption: Movement across the membrane

Answer 12

For drugs to move throughout the body they need to cross plasma membranes via DIFFUSION (passive transport) or ACTIVE TRANSPORT

Facilitated diffusion is also possible.

can go inside cell: small, nonionized (not charged), lipophilic

can’t go inside cell: large, ionized (charged), hydrophilic

Question 13

Absorption: Bioavailability

Answer 13

Bioavailability is the fraction of administered drug that reaches the SYSTEMIC CIRCULATION; this is expressed as the FRACTION of drug in the systemic circulation to drug administered.

Bioavailability is determined by COMPARING plasma levels of drug after administration (via whatever route) compared to IV injection (~100% bioavailability)!!!

-Administration by any other avenue except IV usually results in <100% bioavailability.

dose –> destroyed in gut –> not absorbed –> destroyed by gut wall –> destroyed by liver –> to systemic circulation

*Some of it is destroyed in these places, and what’s left goes into systemic circulation to have its effect
*Something in grapefruit inhibits p450 enzyme, so people are told to not take grapefruit with meds

Question 14

Factors That Affect Absorption: Related to the drug

Answer 14

Lipid vs water solubility
Molecular size
Particle size
Degree of ionization (charged or not)
Dissolution (dissolving)
Physical form (solid/liquid/gas)
Chemical nature
Concentration
Formulation

Question 15

Factors That Affect Absorption: Related to the body

Answer 15

Area of absorptive surface (how big of an area it is absorbed)
Functional integrity of absorptive surface
Vascularity/blood flow
pH of stomach (meds are designed for low pH of stomach)
Presence of other substances (food)
GI motility (ex. how food goes down the digestive tract)
Route of administration
Diseases

Question 16

Pharmacokinetics: Distribution

Answer 16

Passage of agent through blood or lymph to various body sites and into the interstitial tissue and intracellular fluids; presented to the cells.

Many drugs are BOUND to circulating proteins, affecting their ability to bind to receptors; cross tissue membranes; and be distributed, metabolized, and excreted.

Question 17

Factors which affect Drug Distribution
(4)

Answer 17

1. blood flow
2. capillary permeability
3. drug structure
4. binding to plasma proteins

Question 18

Factors which affect Drug Distribution: Blood Flow

Answer 18

Tissue distribution of a drug is dependent on transport in the bloodstream, HIGH FLOW TISSUES (brain, liver & kidney) RECEIVE DRUGS IN LARGE VOLUMES prior to muscle & adipose tissue.

Some tissues have such low blood flow that drug delivery is a major concern (cartilage, connective tissue, abscess). - less vascularized

Question 19

Factors which affect Drug Distribution: Capillary permeability

Answer 19

Capillary permeability is determined by capillary structure which varies widely in terms of the fraction of basement membrane exposed to the SLIT junctions between the capillary endothelium.

Most capillaries allow large molecules to pass with little impedance, permeability is responsive to both local & systemic factors (inflammation).

The CNS blood brain barrier is created by TIGHT junctions between endothelial cells and a basement membrane supported by astrocytic foot processes; this presents a formidable barrier to drug penetration. Lipid soluble agents or drugs with specific transport mechanisms can penetrate rapidly.

A) endothelial cells in liver:
- large fenestrations allow drugs to exchange freely between blood and interstitium in the liver (slit junctions)

B) brain capillary
- at tight junctions, two adjoining ceclls merge so that the cells are physically joined and form a continuous wall that prevents many substances from entering the brain (tight junctions) (astrocyte foot processes)

C) permeability of brain capillary
- charged drug stays in, lipid-soluble drugs and carrier mediated transport go out

Question 20

Factors which affect Drug Distribution: Drug structure

Answer 20

Has a major influence on a drug’s ability to penetrate membranes, hydrophobic, nonpolar drugs with uniform electron distribution and no net charge (but still soluble in an aqueous state) move directly through endothelial membranes to reach targets.

Polar, hydrophilic, charged molecules must pass through endothelial slit junctions.

Question 21

Factors which affect Drug Distribution: Binding to plasma proteins

Answer 21

Drugs BOUND to plasma proteins are UNABLE to diffuse to active sites.

Irreversibly bound drugs are lost, reversibility bound drugs will respond to the concentration gradient in plasma as free drug is sequestered.

It is the FREE drug that is ACTIVE!!

This binding tends to be non-specific, drugs and endogenous substances can compete for binding sites.

ALBUMIN is the major drug binding entity and acts as a reservoir of drug.

Question 22

Pharmacokinetics: binding to plasma proteins

Answer 22

Binding of Drugs to Plasma Proteins
- Drugs BOUND to plasma proteins, usually ALBUMIN, are INACTIVE… only FREE drug (active) can exert its EFFECT and be ELIMINATED.

Binding capacity of Albumin
- Drugs bind reversibly to albumin (can bind and unbind), binding capacity may be low (1:1) or high.

-The AVIDITY of binding also varies from drug to drug; weak acids & hydrophobic drugs bind the STRONGEST, and hydrophilic & neutral drugs bind WEAKLY or not at all.

(SEE IMAGE)

Question 23

Plasma Protein Binding

Answer 23

Drugs may be categorized into two groups with respect to albumin binding:

class I and class II

Question 24

Plasma Protein Binding: Class I

Answer 24

Drugs that have a LOW dose/albumin binding ratio.

Albumin binding sites exceed the availability of the drug.

The bound fraction consists of a significant proportion of the total drug.

Many clinically useful drugs are Class I types.

*Albumin has plenty of unoccupied binding sites, so most of the drug can bind to albumin.
**A large proportion of the drug is bound, leaving only a small fraction in the free (active) state.

Question 25

Plasma Protein Binding: Class II

Answer 25

Drugs that have a HIGH dose/albumin capacity ratio. The majority of the drug exists in the free state, bound drug is a small proportion of the total drug. Class II drugs can DISPLACE Class I drugs from albumin dramatically increasing the amount of free (active) drug. When two drugs are given each with an affinity for albumin there is COMPETITION for binding sites; one drug can displace the other. *Albumin binding sites become saturated, so the majority of the drug remains in the free (active) state. **The bound fraction is relatively small compared to the free drug.

Question 26

Class I and II overview

Answer 26

Class I: Dose is less than available binding sites Most drug molecules are bound to albumin, and concentration of free drug is low Most of the drug is bound to protein, so most of it is not available to act with other things Class II: Dose is greater than available binding sites Most albumin molecules contain a bound drug, and the concentration of free drug is significant There is extra drug leftover and they are active Administration of Class I and Class II drug Displacement of Class I drug occurs when a Class II drug is administered simultaneously Taking both at the same time… if green dots (Class II) have more affinity than red (Class I), then the green dots bind and red don’t, making class I more free and active and having greater effects?

Question 27

Pharmacokinetics: Metabolism

Answer 27

Most drug metabolism occurs in the LIVER First-pass effect (metabolism of drug by liver enzymes before it reaches systemic circulation) influences metabolism. Substances that are absorbed across the intestinal wall enter blood vessels and are carried directly to the liver (HEPATIC PORTAL CIRCULATION). (SEE IMAGE)

Question 28

Phase I and II reactions

Answer 28

Phase I reactions are generally reactions which modify the chemical by adding a functional structure. This allows the substrate to “fit” into the phase II enzyme so that it can become conjugated with another substance. The conjugated products are larger molecules than the substrate and generally polar in nature (water soluble). Thus they have a poor ability to cross the membranes but can more easily be excreted from the body.

Question 29

Biotransformation

Answer 29

Biotransformation is the conversion of drugs in two stages: Phase I Oxidation: combining with oxygen Reduction: gaining electrons Hydrolysis: cleaving into simpler compounds Phase II Conjugation: combining with glucuronic or sulfuric acid, terminating biologic activity (phase I --> phase II) oxidation --> sulfate conjugation reduction --> glucuronide conjugation hydrolysis --> glutathione conjugation acetylation --> amino acid conjugation

Question 30

Cytochrome P450 Enzymes

Answer 30

The P450 system is involved in the metabolism of many endogenous and exogenous substances Cytochrome P450 (CYP) is composed of families of ISOENZYMES (a different molecular form of an enzyme that catalyzes the same chemical reaction but has slightly different chemical structures and kinetic properties) present in many cells but located mainly in the liver & GI tract. SIX isoenzymes are responsible for the vast majority of P450 catabolism (CYP3A4, CYP2D6, CYP 2C9/10, CYP2C19, CYP2E1 & CYP 1A2) A drug may be a SUBSTRATE for MORE than one isoenzyme. These isoenzymes exhibit considerable genetic variability, the specific repertoire of CYPs influences all aspects of drug action. Various medications and nutrients can either induce or inhibit the function or expression of cytochrome P450 enzymes. *We all have them, but how much we have varies from person to person depending on age, what we eat, our genetics, etc… (SEE IMAGE)

Question 31

Metabolism of Acetaminophen- Example

Answer 31

Occasionally the biotransformation product is HAZARDOUS. A good example is the biotransformation of acetaminophen (TYLENOL). At high doses, the normal level of enzymes may be depleted and the acetaminophen is available to undergo reaction by an additional biosynthetic pathway, which produces a REACTIVE METABOLITE that is toxic to the liver. (this is why you can overdose and have liver toxicity!), when you have too much, you make products that shouldn’t be made???) (SEE IMAGE) *You can make 5 different things depending on which enzyme is reacting interacting with the acetaminophen (Tylenol). Different cytochromes make different products! **Inhibitors and inducers: Inhibitors of CYP enzyme… if you take another med that’s supposed to be metabolized by the CYP, it won’t because the one med is inhibiting its function so the one med will creep up to a higher dose Inducers… if you take a med that is an inducer, the CYP will work faster, so the other med you take will be metabolized quicker

Question 32

Modifiers of biotransformation

Answer 32

The RELATIVE EFFECTIVENESS of biotransformation depends on several factors, including species, age, gender, genetic variability, nutrition, disease, exposure to other chemicals that can inhibit or induce enzymes, and dose levels. Age: may affect the efficiency of biotransformation. In general the fetus and neonates have limited abilities for xenobiotic biotransformation. It also decreased in the elderly. Body weight: Generally based on a 150 pound person with average body size and composition. Gender: This is usually limited to hormone-related differences in the oxidizing cytochrome P450 enzymes and in body composition (intramuscular injections) Race: Drug responses are influenced by variations and psychosocial factors. Genetic variability: may account for differences in humans. Some people are rapid and some slow acetylators. Body rhythms: Some are more effective with circadian rhythms (Ex. Sedatives, cortisol). Poor nutrition: such as inadequate levels of protein, vitamins or minerals can decrease the ability to synthesize biotransformation enzymes. Acid-Base, fluid and electrolyte balance: Conditions such respiratory acidosis or alkalosis or metabolic acidosis or alkalosis. Altered electrolyte balances Enzyme induction is when prior exposure to a chemical or drug results in an enhanced capability to biotransform a xenobiotic (any chemical foreign to an organism) Dose level can affect the nature of biotransformation. At high doses a pathway may be saturated and the excess is metabolized by other enzymes which generate more toxic metabolites (acetaminophen) Diseases: Liver or kidney diseases and affect metabolism and excretion. Immunology: Drug allergies Psychology: The placebo effect Environment: Sedatives work better in quiet environments, antihypertensive medications work more in warm climates. Tolerance: Some patients develop a decreased responsiveness to a drug after repeated administration.

Question 33

Urinary excretion

Answer 33

Elimination of substances by the kidneys into the urine is the primary route of excretion of drugs and toxicants. (SEE ALL IMAGES, MIGHT NEED TO KNOW THE PARTS OF THE KIDNEY!!) *Blood comes in afferent, fluid and small molecules flow out along the purple tubules (but not blood cells), and out efferent **Good things are absorbed by tubules and bad metabolites and other bad things stay in the tubule and become part of the urine ***If damaged, blood cells can come out and you can get blood in urine

Question 34

Pharmacokinetics: Excretion

Answer 34

The main route of excretion is via the kidneys. Kidney DISEASES can PROLONG the duration of drug action. Other routes of excretion include: -Lungs -Breast milk (combination of fatty and aqueous substances) -Sweat, tears, urine, feces -Bile - feces -Saliva

Question 35

Renal excretion

Answer 35

Renal excretion is the result of 3 processes: 1. Passive glomerular filtration 2. Active tubular secretion in the proximal tubules 3. Passive distal tubular reabsorption

Question 36

Factors affecting renal excretion

Answer 36

Glomerular filtration rate: -Only free unbound water soluble drugs with low molecular weight are filtered. -If it’s slow, it’ll take longer to get rid of stuff Change in urinary pH affect excretion of weak acid and base drugs: -Alkalinization (basicity) of urine by sodium bicarbonate increases excretion of acidic drugs, Ex. aspirin. -Acidification (acidity) of urine with Vit C increases excretion of basic drugs Ex. amphetamine (SEE 4 IMPORTANT STEPS AND PARTS IN DIAGRAM)

Question 37

Drug Half-Life

Answer 37

Half-life (t1/2): time taken for the drug’s blood or plasma concentration to decrease from full to one-half (50%). The longer the half-life, the longer the drug remains in the body. If the half life is 6 hours, it won’t be gone in another 6 hours, it keeps multiplying over and over

Question 38

Plasma concentration of a drug vs time

Answer 38

The onset of action occurs at 2 hours; the duration of action is 6 hours; peak plasma concentration is 10 mcg/mL; and the time to reach peak drug effect is 5 hours. (see image to go with this) *If you take a pill, the blood concentration will slowly go up *Therapeutic range: drug has an effect on what you’re taking it for *At some point you need to take another dose because you want to be in the therapeutic range (but it’s important to get the timing right so you stay in therapeutic as much as possible and don’t go into the toxic concentration) *You can go into toxic range from your body not metabolizing or excreting as it should… it’s not always from taking too much (overdosing) (see images that come after)

Question 39

Pharmacodynamics

Answer 39

Dose-effect relationship Frequency distribution curve (It illustrates the relationship between the dose of a drug and the proportion of individuals in a population who experience a particular response) Therapeutic index and drug safety Cellular receptors and drug action Drug-receptor interactions

Question 40

Pharmacodynamics describes...

Answer 40

Describes all matters concerned with the pharmacologic actions of a drug - therapeutic or adverse. Describes how a medication changes the body. Looks at the biochemical and physiologic effects of the drug as well as the molecular mechanisms.

Question 41

In pharmacodynamics, the majority of drugs either;

Answer 41

a) Mimic or inhibit normal physiological/biochemical processes or inhibit pathological processes… or b) Inhibit vital processes of microbial organisms.

Question 42

There are 4 main drug actions:

Answer 42

1. Depressing (slow things down) 2. Stimulating (speed things up) 3. Destroying cells (toxic) 4. Replacing substances (ex. insulin)

Question 43

Dose-effect (response) relationship

Answer 43

The relationship between the dose of the drug that produces therapeutic effects and the potency of the effects on individual person. (MUST SEE THE IMAGES X2 AND NOTES FOR THIS)

Question 44

Potency

Answer 44

amount of drug required to produce a given effect. A more potent drug achieves the desired effect at a lower dose. ex. Drug A is more potent than Drug B because it produces a higher response at a smaller dose (requires a smaller dose to have the same effect)

Question 45

Efficacy

Answer 45

maximum effect a drug can produce, regardless of dose. It indicates the drug's ability to activate its target receptors fully. ex. Drug A has higher efficacy than Drug B because it reaches 100% of the maximum drug response, while Drug B plateaus at a lower percentage.

Question 46

Frequency distribution curve

Answer 46

Number of patients that respond to a drug’s action at different doses. (median effective dose)

Question 47

median effective dose (ED)

Answer 47

Medication needed to produce a specific response in 50% of patients ED = median effective dose (Dose of a drug that produces a specific beneficial therapeutic response in 50% of cases)

Question 48

Therapeutic index and drug safety

Answer 48

Used to predict whether a certain dosage is safe for a specific patient. The LD50 cannot be tested in humans therefore the median toxicity dose (TD50) is used. YOU WANT A LARGE therapeutic index!!! (not narrow, we don't want ED and TD (toxic dose) to be too close!!) TD50 = median toxic dose (dose at which toxicity occurs in 50% of cases) LD50 = median lethal dose (dose at which a substance is lethal for 50% of cases) (we don’t use this anymore) Large therapeutic index: If you take too much of the drug, you should be okay (left image) Narrow therapeutic index: Much more risky because the dose at which it works is very close to the dose at which they kill you!! (right image) (SEE BOTH IMAGES) DRUG X: TI = LD50/ED50 (toxic dose/ effective dose)

Question 49

Therapeutic Index formula

Answer 49

Drug X: TI = LD50/ED50 (toxic dose/ effective dose)

Question 50

Cellular receptors and drug action

Answer 50

Drugs produce their effect by altering the function of the cells and tissues of the body or of organisms. Each drug has a specific AFFINITY (attractive force) for its target. Recipients are usually receptors on the cell surface (proteins) but some interact with intracellular receptors. (sometimes the med goes inside the cell to interact) (MUST SEE IMAGE FOR IMPORTANT DETAILS) - Transmembrane pores A) voltage-gated channel B) chemical-gated channel C) G-protein-linked channel

Question 51

Cellular receptors and drug action cont...

Answer 51

Once bound, a drug may trigger second messenger events inside the cell. There are two basic receptor types ALPHA (α) and BETA (β) Some medications only interact with one subtype (specific) Some medications act independently of the receptors and generate NON-SPECIFIC CELLULAR RESPONSES (Ex. anesthetics, osmotic diuretics (draw water in), alcohol) -Change cell permeability -Change the function of cellular pumps -Depresses membrane excitability

Question 52

Types of drug receptors

Answer 52

Ligand-gated ion channels (ex. cholinergic nicotinic receptors) - changes in membrane potential or ionic concentration within cell G-protein-coupled receptor systems (ex. a and B adrenoceptors) - protein phosphorylation Enzyme embedded in the cell membrane (ex. insulin receptors) - protein and receptor phosphorylation Transcription factors (ex. steroid receptors) - protein phosphorylation and altered gene expression *intracellular effects!!! (SEE IMAGE TO UNDERSTAND THIS!!)

Question 53

Basics of Pharmacology

Answer 53

Chemical Shape and Properties of Drug -Complimentary to receptor binding site -Very important in determining if drug will be an agonist or antagonist -Paradigm is requirement of at least THREE POINTS OF CONTACT for specific interaction of drug to receptor (to be bound well enough) -Chiral vs. non-chiral (need to twist a certain way, S and R… non chiral = symmetrical) -Flexibility and rotation of internal bonds

Question 54

Drug-receptor interactions

Answer 54

Drug-receptor interactions are explained in the following: D + R ←→ D-R complex → Response

Question 55

Drug-receptor interactions: Agonist

Answer 55

a drug that binds to a receptor and produces a stimulatory response simile the endogenous substance. (high intrinsic activity) A drug is said to be an agonist when it binds to a receptor and causes a response or effect. It has INTRINSIC ACTIVITY = 1 (SEE IMPORTANT IMAGE) - (once the blue drug is bound, you can let ions through)

Question 56

Drug-receptor interactions: Agonist-Antagonist

Answer 56

(partial agonist): only SLIGHT INTRINSIC ACTIVITY Can act as both agonist (alone) or antagonist (competes with other drug) Ex. Can be in the same class but be an agonist on one receptor and an antagonist on another receptor

Question 57

Drug-receptor interactions: Antagonist

Answer 57

Blocks or antagonizes the effects of another substance or function. They can be competitive or non-competitive A drug is said to be an antagonist when it binds to a receptor and prevents (blocks or inhibits) a natural compound or a drug to have an effect on the receptor. An antagonist has NO activity. Its INTRINSIC ACTIVITY is = 0 COMPETITIVE: -They compete for the binding site Reversible Irreversible NON-COMPETITIVE: -Bind elsewhere in the receptor (Channel Blockers) (SEE IMPORTANT IMAGE)

Question 58

Model of Drug/Receptor Binding

Answer 58

*Left image shows the 3 points of contact for binding *Right image shows you don’t always need a 100% fit for a response (SEE IMAGES!!)