Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Chapter 2: Drug action & Handling Lisa Mayo, RDH, BSDH Pharmacology

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Chapter 2: Drug action & Handling

Lisa Mayo, RDH, BSDHPharmacology DH206


THANK YOU LAURA!!


1. Pharmacodynamics2. Pharmacokinetics 3. Routes of drug administration4. Factors that alter the effect of a drug

LEARNING OBJECTIVES


Pharmacodynamics1) Definitions2) Dose-Response Relationships

(potency, effi cacy, ceiling effect, toxicity)

3) Drug-Receptor Interactions

OBJECTIVE #1


Pharmacodynamics: describes the actions of a drug on the body

Involves drug-receptor interaction, mechanism of action, drug response, dose-response relationship

Therapeutic effect: intended effect of the drug in the body

Drug Indication: therapeutic uses of the drug in the body

Contraindication: situation or circumstance when a drug should NOT be given

Undesirable effects: (CH3)1. Side Effects2. Adverse Effects3. Toxic Effects

PHARMACODYNAMICS1.) DEFINITIONS


Site of Action Location within the body where the drug exerts its

therapeutic effect Ex: aspirin’s site of action is on the hypothalamus

to reduce feverMechanism of Action

Explains how a drug produces its effects Drugs do NOT impact a new function in an organism Drugs either intensify same actions or block actions

in the body Drugs speed up or slow down reactions in the body

PHARMACODYNAMICS1.) DEFINITIONS


Dose response curveDetermine correct DOSE of drugs to give to patientsDetermines POTENCY & EFFICACY of a drug’s actionResponse of any drug depends on the amount given:

this is called dose-response relationship Dose: amt of drug given to produce a desired effect Response: the effect of that dosage A curve results when DOSE of a drug is plotted against

the INTENSITY of it’s effect ↑ dose = ↑ magnitude of response

Threshold dose: minimum dose of a drug needed to produce a therapeutic/measurable response

PHARMACODYNAMICS2.) DOSE-RESPONSE CURVE


PHARMACODYNAMICS2.) LOG-DOSE CURVE

Log dose-eff ect curve Therapeutic range of the drug is plotted where

the dose is increasing sharply Max response of a drug may exhibit is plotted

where the curve plateaus: also called ceiling effect

Max Response

Therapeutic Range


PHARMACODYNAMICS2.) LOG-DOSE CURVE

Log dose-eff ect curve Once ceiling effect attained: if give more drug,

no further effect will be observed Doses above ceiling effect usually result in

toxicity & adverse effects

Max Response

Therapeutic Range


Potency: measure of strength or concentration of a drug Potency is shown by the location of that drug’s curve

along the x-axisLess-potent drugs: need more to produce a

desired effect equivalent to that of a more potent drug

Determined by the affi nity of a drug for its receptors

Potency usually expressed in terms of median effective dose (ED50) – next slide

BEER VS JACK DANIELS

PHARMACODYNAMICS2.) POTENCY (P.13)


The dose that will produce an effect that is HALF of the maximal response is referred to as the EFFECTIVE DOSE 50 (ED50)

PHARMACODYNAMICS2.) POTENCY


Maximum intensity or effect of a drug that can be reached

Ability to produce a therapeutic effect regardless of the dose

Effi cacy & potency often describe the success of drug therapyDrugs may be equally efficacious, but differ in potency (see next slide)

PHARMACODYNAMICS 2.) EFFICACY (P.13)




The strength of a drug with regard to it’s ability to achieve a desired effect is termed

A. efficacyB. potencyC. therapeutic effectD. tolerance

BOARD REVIEW QUESTION


Potency of a drug is a function of the amount of the drug required to produce an effect

BOARD REVIEW ANSWER


In comparing two drugs, the dose-response curve for the drug that is more effi cacious would

A. Be closer to the Y axisB. Be farther from the Y axisC. Have a greater curve heightD. Have a higher median effective dose

BOARD REVIEW QUESTION


C: The effi cacy of a drug increases as the height of the curve increases

Effi cacy is an expression of maximal activity of a drugThe other choices all refer to indicators of drug potency, not effi cacy

BOARD REVIEW ANSWER


Therapeutic index (TI): ratio of a drug’s toxic dose to its therapeutic dose

Safe drugs = High TIToxic drugs = Lower/Smaller TI

Small changes in dose can kill you fasterLD50 term used to describe when 50% test subject

dieThe ratio LD50/ED50 is the therapeutic index (TI) of

a drugTI = LD50

ED50

PHARMACODYNAMICS2.) TOXICITY (CH3)

Median Effective DoseED50

Lethal Dose = Death

Dosage of Drug

“Sleep” curve never hits 400 on x-axis but if Dr prescribes a dose too high, will hit LD

TI=LD50

ED50


What does ED50 stand for?

What does LD50 stand for?

If a drug has a narrow TI, is the drug safer?

REVIEW


Drugs have an eff ect in the body by binding to a receptor

Drug receptor: protein located on all cell membranes

Drugs attach to specific receptors & produce an eff ect

Drug attachment done in 2 ways (next slide)1) Direct/Specific drug receptor2) Indirect/Nonspecific drug reaction

PHARMACODYNAMICS3.) DRUG-RECEPTOR INTERACTIONS


Drug attachment done in 2 ways:1) Direct/Specific drug receptor (most common)

Drugs directly binding to cell receptors Cells have 100s of receptors: only certain ones specific

for a drug Drugs bind & form Van der Waal bonds (weak,

reversible bonds)2) Indirect/Nonspecific drug reaction

Drugs do NOT bind to receptors but instead saturate the water or lipid parts of a cell – drug actions occur based on degree of saturation




Drug+Receptor → Drug-Receptor → Effect Complex

eventually efficacy can be measured (max drug action)

LOCK-AND-KEY FASHION OF DRUGS TO THEIR RECEPTORS


Different drugs often compete for the same receptor sites (morphine & acetaminophen)The drug with stronger affinity for the receptor will bind to more receptors than the drug with weaker affinity

Drugs with stronger affinity for receptor sites are more potent drugs


Receptor

Morphine Acetaminophen


3 classifications of drug-receptor complexes1. Agonist2. Partial Agonist3. Antagonist/Blocking Drugs


All 3 have an affinity for a receptor, they differ in what they cause the receptor to do!


1. Agonist Drug that rapidly combines with a receptor to

initiate a response Rapidly dissociates/releases from receptor High efficacy

2. Partial Agonist Binds to receptor, produces a mild therapeutic

response May inhibit action of agonist when given at the

same time (acts like antagonist sometimes)



3. Antagonist/Blocking Drugs Binds to receptor but does NOT dissociate Has NO positive response or efficacy Blocks reaction of the agonist Ex: naloxone – morphine antagonist – given if

have morphine OD 3 different types (next slide)

1) Competitive2) Noncompetitive3) Physiologic




3. Antagonist/Blocking Drugs1) Competitive: drug that occupies a significant

proportion of the receptors and thereby prevents them from reacting maximally with an agonist

2) Noncompetitive: can exert action 2 ways1. React with receptor to prevent an agonist-

receptor response2. Act to inhibit some event that leads to a

response3) Physiologic: Has affinity for a different receptor

site than the agonist but decreases the effect of the agonist by producing an opposite effect via different receptors





Which of the following terms is related to the amount of drug administered?

a. Doseb. Responsec. Agonistd. Toxicity

NBQ


Which of the following terms is related to the amount of drug administered?

a. Doseb. Responsec. Agonistd. Toxicity

NBQ


An individual has an overdose on oxycodone, a narcotic, and is administered a narcotic antagonist. Which of the following features describes antagonist drugs?

a. Binds to the same receptor sites as agonist drugsb. Binds to the receptor to reduce the actions of the agonistc. Have a greater affi nity to the receptor than agonistsd. Have a lesser affi nity to the receptor than agonists

NBQ


An individual has an overdose on oxycodone, a narcotic, and is administered a narcotic antagonist. Which of the following features describes antagonist drugs?

a. Binds to the same receptor sites as agonist drugsb. Binds to the receptor to reduce the actions of the agonistc. Have a greater affi nity tot eh receptor than agonistsd. Have a lesser affi nity to the receptor than agonists

NBQ


Pharmacokinetics1. Definition2. Absorption3. Distribution4. Metabolism5. Excretion6. Clinical Applications

OBJECTIVE #2


Describes what a drug does once inside human body

(ADME)AbsorptionDistributionMetabolismExcretion

Drugs usually enter body at a site distant from its intended target – must travel through bloodstream in the body

PHARMACOKINETICSDEFINITION


PHARMACOKINETICSABSORPTION

ADME


Entrance of a drug into the blood streamDrug must first be dissolved in body fluidsRequires the drug to pass through biologic

membranesThe rate of absorption of a drug influenced

by:1) Physicochemical factors (physical &

chemical conditions such as temperature, redux potential…)

2) Site of absorption (determined by route of administration: IV, oral, rectal….)

3) The drug’s solubility



Topics for Absorption1. Passage across cell membranes2. Effects of ionization: review of basic

chemistry, acid-base effects on drugs



1. Passage Across MembranesBefore a drug is absorbed = must pass through cell membrane to get to the organ that has the receptor for the drug

Drugs are best absorbed in small intestine & stomach

Site of drug action: final destination of the drug



1. Passage Across Membranes Cell membranes: composed of lipids, proteins, &

carbohydrates “Like dissolves like” Lipids: make up biphospholipid layer of cells

Drugs that are water soluble do NOT pass through this layer with ease

Lipid soluble drugs pass with ease (passive diffusion) LIPID SOLUBILITY OF A DRUG IS ONE OF THE MOST

IMPORTANT DETERMINANTS OF THE PHARMACOKINETIC PROPERTY OF THAT DRUG!!

Proteins: contain small water channels/pores Water soluble drugs can pass through this structure

easily (passive diffusion) Lipid soluble drugs do NOT pass through this structure

with ease




1. Passage Across Membranes IV drugs pass directly into bloodstreamOrally administered drug

↓

Pass down esophagus ↓

Small intestine ↓

Blood for distribution to its target organ



1. Passage Across MembranesMechanism of drug transfer across membranes occurs by one of the following:1) Passive diffusion2) Facilitate diffusion3) Active transport4) Pinocytosis



1. Passage Across Membranes1) Passive diffusion

Most drugs absorbed this way (water or lipid soluble) Movement from high to low concentration, along a

concentration gradient Lipid soluble a drugs pass directly through cell

membrane Water soluble drugs pass through water channels or

pores No energy is required for his form of diffusion Ex: General anesthetics pass blood-brain barrier

quickly due to being a lipid soluble drug – fast onset of action



1. Passage Across Membranes2) Facilitated diffusion/Passive-mediated

transportCarrier PRO transports drug that is too large to passively diffuse

No energy is needed for transportEx: penicillin, aspirin

3) Active transportCarrier PRO transports a drug against a concentration gradient

Requires use of ATP Not common in pharmacologyEx: vitamin B12, amino acids




1. Passage Across Membranes4) Pinocytosis

Involves engulfment of fluids or particles by a cell

Minor role in drug movementCell membrane traps the substance

↓Forms a vesicle

↓Detaches and moves to inside the cell


Requires LARGE amount ATP


ATPATP


2. Effects of ionization

READ PAGE 17: EFFECTS OF IONIZATION



2. Effects of ionizationMost all drugs are weak acids or bases Weak electrolytes dissociate in solution: Non-ionized + Ionized formUn-ionized/non-ionized/uncharged

Lipid soluble Cross lipid cell membranes easily

Ionized/charged Low lipid solubility Cannot easily cross lipid membranes



2. Effects of ionization The pH of tissues at the site of administration and

dissociation characteristics (acid dissociation constant, or pKa) of the drug will determine the amount of drug in the ionized vs non-ionized state (ex: aspirin absorption in stomach vs mouth) Portion in each state will determine the ease

with which the drug penetrates tissue Ex: acidic drugs (aspirin) are mostly un-ionized

when they are in an acidic fluid (gastric juices) so drug absorption is favored (same hold true for basic drugs)

Ex: acidic drugs (aspirin) is mostly ionized when in alkaline fluids so absorption occurs at a slower rate & to a lesser extent (same holds true for basic drugs)



2. Effects of ionizationMemorization Tricks

Unionized = mimic lipid = ↑ absorption, ↓ excretion

Ionized = mimic water = ↓ absorption, ↑ excretion

Acidic drugs in basic solution = ↑ excretion

Basic drugs in acidic solution = ↑ excretion

Acidic drugs in acidic solution = ↓excretion

Basic drugs in basic solution = ↓ excretion


↑ Absorption

↓ Absorption


2. Effects of ionizationpH of body fluids vary greatly

Low pH (high acid) = gastric juices (1.5pH which will dissolve metal)High pH (high base) = blood & plasma (facilitates the transport of O2)

PHARMACOKINETICSABSORPTION: CHEM REVIEW



2. Effects of ionization The acid-base nature of drugs is useful in treating

drug toxicity (OD) Drugs are excreted by kidneys in an ionized form To ↑ drug excretion = alter pH of urine Ex: increase renal excretion of an acid drug

(aspirin), the urine is alkalized (pH>7) Alkaline urine - acidic drugs are mostly ionized &

more rapidly excreted



2. Effects of ionization (not need to know for test) Example: stomach made of parietal cells

Interior of parietal cells protected from the acidic juices of stomach by their membrane

Membrane allows H2O & neutral molecules to pass in&out but blocks movement of ions like H+

H+ can cross membrane through ACTIVE TRANSPORT

(using ATP)

(cont’d next slide)



2. Effects of ionization (not need to know for test)Stomach: eating stimulates H+ SECRETION

If acid content excessively high = influx H+ through membrane by active transport & back to plasma

Causes muscle contraction, pain, swelling, bleeding, inflammation

Antacids will neutralize HCl and ↓ H+ concentration

In rxn = all those chemical breakdown into different molecules w/ CO2 and H2O (CO2 makes patient belch)



2. Effects of ionization Strong acid/bases = rxns will go to completion Weak acids/bases = rxns ionize only to a limited

extent in water (less than 100%) Degree to which a weak acid ionizes depends on

the concentration of the acid and the equilibrium constant for the ionization

All weak acid/bases vary in their strength of ionization Some weak acids are weaker than other weak

acids



2. Effects of ionization A symbol of Ka is used when discussing acids and

bases and their strength K=symbol used when a molecule breaks apart A=acid Ka is the acid dissociation (molecules breaking apart)

constant In Pharmacology, not use Ka, use pKa which is a

log-rhythm of Ka Ka= 2.0x103 so the pKa=2.0 Larger pKa = weaker the acid (see next slide)

pKa = acid dissociation constant (when 50% of the drug is ionized and 50% is unionized)



Smaller pKa Stronger acid

Larger pKa Weaker acid

Larger pKa Stronger base

Smaller pKa Weaker base


2. Effects of ionization Getting drugs into the body can be done 2 ways:

1) Hydrophilically: soluble in aqueous solutions Dissolves well in water molecules Polar molecules

2) Lipophically: fats, alkanes, oil Cell membranes made of lipids Non-polar molecules

General Rule for molecule solubility: LIKE-DISSOLVES-LIKE Hydrophilic like hydrophilic (polar dissolves

polar) Lipophilic likes lipophilic (non-polar dissolves

non-polar)



2. Effects of ionization (not on test) Generic Acid RXN

HA + H2O A- + H3O+

H will be donated eventually Anion Hydronium ion

A=any acid Conjugate base

*Acids will dissociate to form a conjugate base*



2. Effects of ionization (not on test)Strength of conjugate base in solution

HCl → H+ + Cl-

Strong acid Weak conjugate base

(Will not readily react w/H+ free ion)

HF → H+ + F-

Weak acid ← Strong conjugate base

(will readily react w/H+ free ion)




In pharmacology, we need to relate to pH of tissues to the pKa of drugs

RULES Acidic drugs become more non-ionized in acidic

pH Basic drugs become more non-ionized in basic pH


Acid pH (stomach)

Basic pH (Plasma)

Acidic Drug Basic Drug

Non-Ionized

Non-IonizedIonized

Ionized


Hydrophilic = Ionized molecules (charged)Lipophilic = Non-Ionized molecules (non-

charged)Lipophilic molecules penetrate cell membranes because they are made of lipids (LIKE-DISSOLVES-LIKE)


Cell Membrane

Ionized MoleculeWater soluble

Non-Ionized MoleculeFat soluble


Summary: 3 things need to know to find out if a drug is Hydrophilic or Lipophilic1.Whether drug is acid or base (will be

told)2.pKa of the drug (pH at which number

of ionized molecules = number of non-ionized molecules, next slide)

3.pH of tissue into which the drug is going to be placed



Acid drugs become more non-ionized in acidic pHWHAT IS THE PkA? When 50% ionized & 50% non- ionized which is 6


pH 2 pH 6 pH 8

Acid drugAcid tissue75% drug NI25% drug I

Acid drugNeutral tissue50% drug NI50% drug I

Acid drugBasic tissue25% drug NI75% drug I

Non-Ionized Ionized

(↑ absorption)

More absorption

Lessabsorption


Basic drugs become more non-ionized in basic pHWHAT IS THE PkA? When 50% ionized & 50% non- ionized which is 8


pH 2 pH 9 pH 8

Basic drugAcid tissue2% drug NI98% drug I

Basic drugBasic tissue75% drug NI25% drug I

Basic drugNeutral tissue50% drug NI50% drug I

Non-Ionized Ionized

Lessabsorption

More absorption


If know the pKa and pH of the tissues

Can fi gure out if drug mostly ionized or mostly non-ionized

Can then fi gure out if hydrophilic or lipophilic

Can then know if drug will cross the cell membrane or dissolve in water

Ex: drugs given by mouth have to dissolve across a membrane (lipophilic drugs)

Ex: drugs given by IM (intramuscular injection) have to be able to dissolve in water (hydrophilic drugs)



Read p.17 “weak acids”


2. Effects of ionization: Weak Acids If pH of the site absorption increases (becomes more basic), H+ concentration falls (pH ↑ = H+↓)

This results in an increase in the ionized form (A–) (hydrophilic), which cannot easily penetrate tissues

If the pH of the site absorption falls (more acidic), H+ concentration will rise (pH↓ = H+↑)

This results in an increase in the un-ionized form(HA) (lipophilic), which can more easily penetrate tissues

PHARMACOKINETICSABSORPTION: (BOOK)

HA + H2O → A- + H3O+


Read p.17 “weak acids”


2. Effects of ionization: Weak Bases If the pH of the site rises (more basic), the H+ concentration will fall

This results in an increase in the un-ionized form (lipophilic), which can more easily penetrate tissues

If the pH of the site falls (more acidic), the H+ concentration will rise

This results in an increase in the ionized form (hydrophilic), which cannot easily penetrate tissues

PHARMACOKINETICSABSORPTION (BOOK)


2. Effects of ionization Summary In the presence of infection, the acidity of the tissue ↑ (pH ↓)

Effectiveness of local anesthetics decrease In the presence of infection, the H+ increases because of accumulating waste products in the infected area

Low pH = acidic tissue = lots extra H+ loose & convert anesthetic into SALT form (RNH+) so it will not penetrate fatty tissues because is hydrophillic & will not mix with fatty tissue

Tissues also swollen, lots of fluid = dilutes anes

Big open dilated blood vessels carry anes away faster = wears off faster



2. Effects of ionization SummaryRegardless of pH & ionization, absorption usually occur in small intestine where there is more surface area due to presence of microvilli on the surface

Enteric-coated tablets (aspirin, erythromycin) have a layer (wax/cellulose polymer) on the outside to protect the stomach lining from exposure to these acidic drugs

Blood flow to the organ can affect absorption (Ex: nitroglycerin administered sublingual because will have faster absorption due to high vascularity of the organ)



A patient is taking clindamycin for prophylaxis against bacterial endocarditis. In order for the clindamycin to be absorbed into the blood, it must pass through

a. 3 barriers: epithelial cells + blood vessels + brainb. 2 barriers: epithelial cells + blood vesselc. 1 barrier: bloodd. No barrier: drug goes directly into blood

NBQ


A patient is taking clindamycin for prophylaxis against bacterial endocarditis. In order for the clindamycin to be absorbed into the blood, it must pass through

a. 3 barriers: epithelial cells + blood vessels + brainb. 2 barriers: epithelial cells + blood vesselc. 1 barrier: bloodd. No barrier: drug goes directly into blood

NBQ


All of the following statements are TRUE about lipid soluble drugs EXCEPT which one?

a. Readily absorbed through blood vessel wallb. Slowly absorbed through cell membranec. Goes through the blood-brain barrierd. Can be given by inhalation

NBQ


All of the following statements are TRUE about lipid soluble drugs EXCEPT which one?

a. Readily absorbed through blood vessel wallb. Slowly absorbed through cell membranec. Goes through the blood-brain barrierd. Can be given by inhalation

NBQ


Which of the following statements is TRUE regarding absorption of local anesthetics?

a. Lidocaine (pKa 4) is not absorbed easily through lipid membranes

b. Lidocaine (pKa 7.9) has a fast onset because the tissue pH is close to the pKa

c. Lidocaine (pKa 8.3) has a faster onset than lidocaine

d. Lidocaine (pKa 7.7) has a slow onset of action because it is highly ionized

NBQ


Which of the following statements is TRUE regarding absorption of local anesthetics?

a. Lidocaine (pKa 4) is not absorbed easily through lipid membranes

b. Lidocaine (pKa 7.9) has a fast onset because the tissue pH is close to the pKa

c. Lidocaine (pKa 8.3) has a faster onset than lidocaine

d. Lidocaine (pKa 7.7) has a slow onset of action because it is highly ionized

NBQ


What does pKa stand for?Acid drugs will be in greatest unionized state when

placed into ______ tissue. If a drug has a fast rate of excretion, what does this

mean for absorption? If pKa is small – is the acid strong or weak? If pKa is small – is the base strong or weak? Is H+ concentration high or low in acidic state?

REVIEW


PHARMACOKINETICSDISTRIBUTION

ADME


Once a drug in the bloodstream through absorption – then distribution will occur

Distribution phase: time is takes drug to get through lymph, blood, plasma to target organ

The manner in which a drug is distributed in the body will determine:

How rapidly it produces the desired response

Duration of that responseWhether a response will occur at all



Factors Aff ecting Drug Distribution1. Presence of specific tissue barriers

Blood-brain barrier & placenta are lipid barriers2. Blood flow

Greater blood flow = greater rate of distribution of the drug to that organ

Drugs distributed faster to the heart, kidney, brain than to skeletal muscle, adipose tissue, skin which have lower blood flow

3. Solubility of the drug Hydrophilic drugs like insulin – do not penetrate lipid cell

membranes, entirely distributed in the extracellular fluid Lipophilic drugs (general anesthetics, alcohol) do cross

lipid layer & are more evenly distributed in all fluids4. Plasma-PRO binding or free drug (next slide)



4. Plasma PRO binding or un-bound/free drug Many drugs are bound to plasma-PRO (esp albumin)

Degree of PRO-binding depends on concentration of drug in the blood & affi nity of that drug for the PRO

PRO-binding ↓ distribution of the drug from the plasma to intended receptor

Some drugs are highly bound to plasma PRO (99%), while other drugs are not bound to any significant degree

Binding is reversible Some drugs compete for PRO-binding sites: remember

drug with higher affi nity for the receptor wins – can cause problems if 2nd drugs knocks 1st drug from the PRO - ↑ levels of 1st drug in system

Only the un-bound/free drug can exert the pharmacologic effect (NBQ)

Only the free drug can pass across cell membranes



Blood-Brain BarrierThis barrier is an additional lipid barrier that protects the brain by restricting the passage of electrolytes & other water-soluble substances

Since brain composed of large amts of lipids, lipid-soluble drugs pass readily to the brain

To penetrate the central nervous system, a drug must cross the blood-brain barrier



PHARMACOKINETICSMETABOLISM

ADME


Whenever a drug is taken into the body – the body immediately starts trying to eliminate it Why you can smell alcohol on someone's breath – part of ethyl alcohol excreted via respiratory system

Metabolism is the chemical alteration of drugs & foreign compounds in the body



LIVER is the main organ involved in metabolismGrp of enzymes found in liver are called DMMS (drug microsomal metabolizing system)

DMMS uses cytochrome P-450 enzymes that are important in oxidation & reduction rxns that convert drugs into their metabolites (next slide)

Function of DMMS: convert lipid-soluble drugs into water-soluble so they can be excreted by kidneys & not reabsorbed into circulationRemember: lipid drugs more readily absorbed

Water-soluble form of drugs can be excreted



Metabolites will be formed during metabolismMetabolic product Is more ionized/polar/hydrophilic then the original drug Increase excretion of the drug

PHARMACOKINETICSMETABOLISM/BIOTRANSFORMATION


DRUG Ingested

Metabolic product formed (MP)

MP+

Less lipid soluble/More water soluble

Kidney absorption of MP+ increased, ↓ plasma-binding & fat storage

More easily excreted from the body


Metabolism begins (Liver)


Drug metabolism is an enzyme-dependent process

Drugs can be metabolized 3 ways1. Active to inactive

An inactive metabolite is formed from an active drug

Most common process2. Inactive to active

An inactive drug (also called prodrug) will be transformed to an active compound once ingested

Ex: vyvance used to tx ADHA is inactive – once ingested – changes composition in the GI tract – then active metabolite produced

Helps reduce abuse of ADHD drugs



Drugs can be metabolized 3 ways3. Active to active

An active parent drug may be converted to a second active compound, which is then converted to an inactive product

Ex: Valium is active anti-anxiety drug – metabolized into active metabolite desmethyldiazepam = Valium’s action prolonged because of its active component combining with metabolite active component

This is why Valium’s half-life can be 20 hours



2 phases of drug biotransformation1. Phase I: occurs in liver

Place drugs into the correct chemical state to be acted upon by Phase II conjugative mechanisms

Prepares chemicals for phase II metabolism and subsequent excretion

Drugs that are lipid soluble go through, if water form – can skip this phase

2. Phase II True “detoxification” step in the metabolism process

Turns drugs into highly water-soluble compounds



Faster Excretion

Slower Excretion


Phase I Liver uses enzymes to make lipid-soluble drugs more

water-soluble by adding or unmasking functional groups

(-OH, -SH, -NH2, -COOH, etc.) Cytochrome P450 enzymes located in liver

Concentration affected by drugs like ethanol, narcotics, barbiturates, smoking, etc…

When take these drugs repeatedly, P-450 enzyme concentrations will ↑ in the body = called enzyme induction

↑ P450 = ↑ rate of metabolism = thus a↓ in effects of meds taken

Ex: smoker/alcoholics have higher levels of P-450 = LA will not work as effectively and they will need higher levels of to achieve full anesthesia

TOLERANCE patients develop to drugs/meds explained in part by P-450 actions



Table 2-1 lists drugs that increase (induce) P-450 enzymes

List to know for boards: Alcohol, tobacco, antidepressants,

anticonvulsants, NSAIDs, antidepressants, antipsychotics, antiarrhythmics, erythromycin, antidepressants, benzos, calcium-channel blockers, opioids



Different P-450 enzymes1. CYP3A4

Most common enzyme that metabolizes drugs used in dentistry

Ex: lidocaine, erythromycin, clarithromycin2. CYP2D6

Codeine, Prozac, Propranolol3. CYP2C9

Ibuprofen


Certain drugs can decrease or increase action of these enzymesEx: grapefruit juice inhibits CYP3A4 metabolism of Xanax – results in elevation of drug in system


Phase I Lipid molecules are metabolized by the 3 processes

1. Oxidation: Causes the loss of part of the drug molecule by incorporating O2 into the drug. MOST COMMON

2. Reduction: occurring in liver with hepatic enzymes3. Hydrolysis: Adding water to molecules

Ex: ester compounds metabolized this way. Enzymes found in plasma = break up ester & add H2O. Ester anes inactivated by plasma cholinesterases



OXIDATION-REDUX RXNS: CHEM REVIEW


Phase II Involve conjugation with endogeneous

substrates to further increase water solubility of the drug Glucuronic acid, acetic acid, amino acid, sulfuric

acid The most common conjugation occurs with

glucuronic acid



Phase I and II - Summary:

Products are generally more water solubleThese reactions products are ready for renal excretionThere are many complementary, sequential and

competing pathwaysPhase I and Phase II metabolism are a coupled

interactive system interfacing with endogenous metabolic pathways



Displacement of a drug from plasma albumin binding sites would usually be expected to:

a. Decrease the amount of distributionb. Increase blood levels of the drugc. Decrease the metabolism of the drugd. Increase the metabolism of the drug

NBQ


Displacement of a drug from plasma albumin binding sites would usually be expected to:

a. Decrease the amount of distributionb. Increase blood levels of the drugc. Decrease the metabolism of the drugd. Increase the metabolism of the drug

NBQ


What is a prodrug?Do hydrophilic drugs have faster excretion?Name something that can induce enzyme induction.

REVIEW


PHARMACOKINETICSEXCRETION

ADME


Drugs may be excreted by any of several routes, but renal excretion is most important Lungs, bile, feces, skin, sweat, saliva, breast milk

Drugs may be excreted unchanged or as metabolites Need conversion into hydrophilic compounds first

& preferably in ionized form Acidic drugs mostly ionized by alkaline urine

Aspirin/barbiturate OD – will want patient to ingest sodium bicarb to alkaline the urine to allow for more rapid excretion of acidic drug



Drugs may be excreted by any of several routes, but renal excretion is most important1. Renal Route2. Extrarenal routes3. Biliary routes

Drugs may be excreted unchanged or as metabolites



1. Renal: Elimination of substances in the kidney can occur through 3 routes:1) Glomerular

filtration (most common)

2) Active tubular secretion

3) Passive resorption

PHARMACOKINETICSEXCRETION: RENAL


1. Renal1) Glomerular filtration (most common)

The unchanged drug or its metabolites are filtered through the glomeruli and concentrated in renal tubular fluid



1. Renal2) Active tubular secretion

When drug too large for glomerular filtration Requires energy Drug transported from bloodstream, across

renal cells, & into renal tubular fluid



1. Renal3) Passive tubular diffusion

Keeps drugs useful to the body such as water, glucose, salts

Resorbs those drugs and puts them back into blood stream



2. Extra-Renal RoutesGases used in general anesthesia are excreted across lung tissue by simple diffusion

Alcohol is partially excreted by the lungs (Breathalyzer)

PHARMACOKINETICSEXCRETION: EXTRARENAL ROUTES


3. BiliaryThe major route by which systemically absorbed drugs enter the GI tract and are eliminated in feces

Drugs excreted in bile may be reabsorbed from the intestines (enterohepatic circulation)

This enterohepatic circulation prolongs a drug’s action

Ex: tetracycline

PHARMACOKINETICSEXCRETION: BILIARY


1. Half-Life2. Kinetics3. Drug Dose

PHARMACOKINETICSCLINICAL APPLICATIONS


READ P.18 “HALF-LIFE”

PHARMACOKINETICS1.) HALF-LIFE


The amount of time that passes for the concentration of a drug to fall to 1/2 of its original level

Indicator of how long a drug will produce its effect in the body

Helps define time intervals between dosesWhen the half-life is short = duration of

action is shortWhen the half-life is long = duration of action

is long



Uusally need 4-5 half-lives for drug to be completely eliminatedPen VK given 4x/day but Amox only given 3x/day Due to difference in half-lives of 2 drugs

Half-life of 2% Lidocaine w 1:100,000 is 90-120 minutes

Why many patients need more anesthetic during long procedures?



The mathematical representation of the way in which drugs are removed from the body

First & Zero Oder Kinetics/Eliminationhttp://www.youtube.com/watch?v=iwVqXeSIOEc

PHARMACOKINETICS2.) KINETICS

http://www.youtube.com/watch?v=iwVqXeSIOEc

http://www.youtube.com/watch?v=iwVqXeSIOEc



1. Kinetics: First-order kinetics Most drug elimination follows 1st-order Rate of drug metabolism is proportional to drug

concentration Constant % of drug eliminated from body per unit of

time In = Out Effect: half life of drug is constant and predictable

Half life is the amount of time it takes to eliminate 50% of the drug

Clinician knows exactly what will happen and when Decrease chances of toxicity ↑ drug concentration = ↑ rate of metabolism



1. Kinetics: Zero-Oder Kinetics Clinicians do not want to be at zero order

kinetics/elimination because the drug plasma is increasing but the body is not eliminating it

In = Out Effect: drug will build-up and can lead to toxicity Clinician cannot predict when body will eliminate

the drug Drug elimination is at a constant rate in spite of

the amt of drug present Ex: aspirin, alcohol, phenytoin(anti-seizure)

Too many beers = can lead to high blood plasma concentrations as enter into zero-order kinetics = toxicity = death



Drug dose: quantity of a drug administeredDrug w/high rate of absorption = smaller doses neededDrug w/high rate of elimination = larger doses neededLoading dose: large initial dose to rapidly establish a

therapeutic plasma drug concentration May need to establish a rapid response in life-

threatening situationsMaintenance dose: subsequent doses that are smaller

than loading dose Maintained for a desired stead-state plasma drug

concentration

PHARMACOKINETICS3.) DRUG DOSING

Ex: Pen VK for dental infections1,000mg immediately (loading dose)500mg 4x/day doses (maintenance dose)


What is half-life?What is a loading dose?What is a maintenance dose?

REVIEW


OBJECTIVE #3ROUTE OF DRUG ADMINISTRATION


Routes of AdministrationEnteral: Drugs absorbed from GI system

Oral, sublingual, buccal, rectalSlower onset of action than parenterally administered agents

Parental: Bypass GI system IV, IM, Subcutaneous, Intradermal, Intrathecal

Topical

OBJECTIVE #3ROUTE OF DRUG ADMINISTRATION


Oral PO: written Rx directions, means oral route Most common, convenient route

Sublingual & Buccal (between cheek & tongue) Absorption through mucosa

Rectal Suppository used when a drug is too irritating to

stomach, patient nauseous, cannot swallow, pt unconscious

Common route for infants, children, older adults

ROUTE OF DRUG ADMINISTRATIONENTERAL


Deliver drugs under skin, subcutaneous tissue. Muscle, cerebral spinal fluid, veins

Needle at different degree depth and anglesFast absorption, rapid onsetUseful for emergencies, unconsciousness,

lack of cooperation, or nauseaSome drugs must be administered by

injection to remain active (insulin)Need good asepsis

ROUTE OF DRUG ADMINISTRATIONPARENTAL



IVAdministered via veinUsed for emergencyProduces the most rapid drug

responseThe absorption phase is bypassed

More predictable drug response because easy to control drug dose



INTRAMUSCULARAbsorption of drugs injected into the muscle

occurs as a result of high blood flow through skeletal muscle

Useful for irritating drugsRapid absorption: many blood vessels in

musclesSite: deltoid, gluteus muscleHep B vaccine



SUBCUTANEOUS (SC OR SQ)Injection of liquid into connective tissue

under skinDental anesthetics, insulin



INTRADERMALInjection into dermisTB. Allergy testing

INTRATHECALLess commonSpinal anesthesia



Application to body surfacesMajor barrier is stratum corneum

(outermost layer of skin)Some absorption systemicallyCan be done through

1) Sublingual administration: Oraquix, dental antibiotics (Arestin, Atridox, PerioChip) admin through GCF

2) Nasal passages or trachea: rapid absorption due to presence many capillaries in resp tract, dosing difficult

3) Transdermal: nitroglycerine, smoking cessation

ROUTE OF DRUG ADMINISTRATIONTOPICAL


Which of the following routes will a drug follow after intravenous administration?

a. Vein, general circulation, liver, kidneyb. Esophagus, stomach, small intestine, liver, kidneyc. Liver, small intestine, kidneyd. Vein, liver, general circulation, kidney

NBQ


Which of the following routes will a drug follow after intravenous administration?

a. Vein, general circulation, liver, kidneyb. Esophagus, stomach, small intestine, liver, kidneyc. Liver, small intestine, kidneyd. Vein, liver, general circulation, kidney

NBQ


Which of the following reasons explains why an IV drug achieves very high initial blood concentration levels?

a. Drugs made of small moleculesb. Drugs have a higher pHc. No barrier to absorptiond. Expensive to give

NBQ


Which of the following reasons explains why an IV drug achieves very high initial blood concentration levels?

a. Drugs made of small moleculesb. Drugs have a higher pHc. No barrier to absorptiond. Expensive to give

NBQ


Which of the following routes of drug administration bypasses the GI tract?

a. Intravenousb. Oralc. Buccald. Sublingual

NBQ


Which of the following routes of drug administration bypasses the GI tract?

a. Intravenousb. Oralc. Buccald. Sublingual

NBQ


A patient had an injection of lidocaine with epi. Which of the following types of injections was given?

a. Subcutaneousb. Intravenousc. Intramusculard. Sublingual

NBQ


A patient had an injection of lidocaine with epi. Which of the following types of injections was given?

a. Subcutaneousb. Intravenousc. Intramusculard. Sublingual

NBQ

Documents

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Chapter 2: Drug action & Handling Lisa Mayo, RDH, BSDH Pharmacology