Pharmacology Test 1

Front 1

drug

Back 1

a chem substance that acts often by interaction w/regulatory molecules to stimulate or inhibit normal physiologic processes

substance that interacts with a receptor to produce a physiological efect

Front 2

receptors

Back 2

molecules w/which a drug or endogenous substance first interacts to eventually affect biological fn

drug targets = receptors for endogenous subs - nt, hormones, etc
enzymes, transport proteins and ion chanels

Front 3

agonist

Back 3

drug that binds to a receptor and triggers a response by the cell

drug that activates cellular signaling pathways to alter physiological activity - often mimicking endogenous substances

Front 4

antagonist

Back 4

chem substance that interferes with the physiologicalaction of another

esp by combining with and blocking its receptor

bind but cannot initiate a change in cellular fn 0

blocks agonists from binding

Front 5

signal transduction

Back 5

how a ccell responds to substances in enviro

basic oricess involving the conversion of a signal from outside the cell to a fnal change w/in the cell

usually a cascade process - extracellular sgnal (hormone, nt) interacts w/receptor at cell surface - chauses a change in the level of a second messanger (calcium or cAMP)
= ultimately effects a change in the cells fning for example - triggering glucose uptake

Front 6

structure-activity relationship

Back 6

relationship between chem structure and pharmacological activity for a series of compounds

Front 7

Ion channels

Back 7

ligand gated
voltage gated or second messenger regulated

agonist is transported into cell w/Na
Na rises inside cell
activation of conduction

miliseconds

Front 8

G-[rpteon coupled receptors

Back 8

agonist binds to outside cell
confromational change causes G-protein activation
--> generation of second messenger --> activation of second messangeer

seconds

Front 9

cell-surface protein kinase

Back 9

tyrosine kinases

agonist binds to each receptor
dimerization
phosphorylation of tyrosines on key signaling molecules
activation of cell signaling

minutes

Front 10

transcription factors

Back 10

intracellular steroid hormone receptors

diffuses into cell where it binds to receptor
which is then transported into the nucleus
activation of transcription and translation

hours

Front 11

competitive antagonists

Back 11

drugs that bind in a reversible manner to the active binding site on receptors but lack intrinsic activity

cannot initiate a conformational change in the receptor resulting in signal transduction

if agonists given in high enough concentrations can displace the antagonist from receptor and still produce same max effect

produces a parallel shift to the right on an agonist dose-response curve

Front 12

noncompetitive antagonistts

Back 12

irrereversible (covalent) or pseudo-irreversible bonds w/receptors

reducing the number of fning receptors available to agonist = decreasing the max response in concentration dependent mannor

Front 13

antagonist that binds to the allosteric site

Back 13

causes a shift to the left in the agonist dose response curve ( called potentiation)

or to the right = antagonism
also alters the shape of the curves

Front 14

physiological antagonism

Back 14

when pharmacological response of one drug via its receptor is reduced by an opposing action of another agonist acting through a different receptor

ex = autonomic control of heart rate - parasymp agonists slow heart rate (actinga at muscarinic receptors) while symp agonists acting at beta adrenergic receptors case tachycaqrdia_

Front 15

chemical antagonism

Back 15

drug effect is antagonized by the fofrmation of a complex with another drug
only imp example is the neutralization of heparin an acidic mucopolysaccharide by protamine ( a basic protein)

Front 16

drug selectivity

Back 16

conferred by the cell's expression of specific receptor subtypes and by the cell-type specificity of signal transduction systems that mediate the receptor-effector coupling

Front 17

how do cells integrate the inhibitory and stimulatory signals to produce a coherent response

Back 17

Gproteins
intracellular ions
second messangerss

Front 18

affinity

Back 18

measure of how tight a drug binds to the receptor

sum of all molecular forces that connect a drug to its binding site on a receptor

depends on the molecular interaction

drugs can bind to many diff receptors w/diff affinities for each
more tightly = high affinity
loosely bound = low affinity

both agonists and antagonists

to compare must have same receptor = parallel dose response curves

higher affinity closer to Left on dose-response graph

Front 19

efficacy

Back 19

aka intrinsic activity

the ability of an agonist to bind to a receptor and generate an activating stimulus (conformational change in the drug receptor) producing a change in cellular activity (drug response

agonists but NOT antagonists

comparing does not require common receptor

height on y axis

Front 20

law of mass action

Back 20

predicts magnituded of drug response is proportional to the occupancy of the receptor bya drug forming a drug receptor complex

[DR]/[RT] = [D]/([D]+Kd)

RT = total number of receptors available

Front 21

Kd

Back 21

equilibrium dissociation constant = K2/k1

inverse relationship between drugs affinity and idissociation constant
higher affinity drugs have lower Kd (1pM -1nM range)
drugs with lower affinity have higher Kd (1microM-1mMm

Kd = [D][R]/[DR] = k2/k1 = 1/affinity

Front 22

occupancy theory

Back 22

asusmes drug ressponse is proportional to the fraction occupancy (f) of receptors by agonist

f= [drug receptor complexes]/[total receptors] = [DR]/{R]+[DR]

f= Ka[D]/1+Ka[D] = [D]/[D]+kd

Front 23

simplest model for drug receptor iinteractions

Back 23

when[D]=kd a drug will occupy 50% of the receptors present

relate drugs potency

Front 24

potency

Back 24

potent - elicit a response by binding to a criticle number of receptors at low conc = high affinity
compared t other drugs acting on same system having lower affinity (req higher conc of drug to bind to same number of receptors)

on graph the sooner it reaches max = higher relative potency= higher affinity

influenced by both its affinity for receptors and its efficacy (state at which receptor mediated signal is max)

det by 4 factors
1. 2 relate to receptors - density and efficacy of stimulase -response mech of tis
2. 2 relate to interaction of drug and receptor - affinity and efficacy

Front 25

dose response relationships

Back 25

represented by plotting a drugs observed graded effect vs iths conc at the receptor

conc = x axis
effect = y- axis

drug conc vs effect (%max response E/e,ax)
= rectangular hyperbola
--- E is measured pharmacological effect Emax- max effect possible

usually constructed w/log of conc on x axis = sigmoidal shape
- w/ threshold,slope and max response (asymptope

Front 26

threshold

Back 26

smalles t amt of drug to see a physiological respoonse

Front 27

EC50

Back 27

aka ED50

conc at which 50% of max effect is observed

Front 28

full agonists

Back 28

each drug is capable of eliciting max response in the same system

one may be more potent than the other- reaching max sooner = higher affinity

Front 29

partial agonist

Back 29

a drug that acts on the same system but has lower relative efficacy - less intrinsic activity
-> occupy receptor but cannot produce a max response - can reduce pharmacological response of full agnoists

can act as an agonist or antagonist depending on the level of drug response (or endogenous tone) exerted by full agonists

one drug doesn't reach the same level of max response as the other

EC50 produces 50% of max effect for that drug = 1/2 its efficacy

Front 30

e/emax =

Back 30

E/emax= e[DR]/[RT]= e[D]/([D]+Kd)

DR= active form of receptor

Front 31

spare receptors

Back 31

receptors in excess of those required to produce a full agonist effect

amplification or receptor-initiated signal transduction doesn't require all receptors to be occupied in order to achhieve max drug response

Front 32

constituatively active receptors

Back 32

over-expression of wild type or gen modified receptors - measurable pharm activity in absence of agonist activating receptor

receptors adopt active conformations that produce cellular response spontaneously

G-prot receptors - changing of a single AA

Front 33

inverse agonists

Back 33

competitive antagonists that reduce the spontaneous actions of constitiuatively active receptors

intrinsic activity (efficacy) = -1 to <0

full inverse agonists = e= -1

drug decrease the basallevel of signaling after binding to receptor

selectively bind to inactive form of receptor and shift the conformational equilibrium toward the inactive state

reduce affinity of full agonist

competitive antagonist has no effect in absence of agonist

drugs used to treat asthma diabetes and CHF
chemo

Front 34

neutral or inactive agonists

Back 34

competitive antagonists w/ intrisic activity = 0

Front 35

quantal response

Back 35

dose response curves in a populationof subjects by measuring an all or none response

plotting cumulative frequency of the observed response = sigmoid dose response curve

characteristics sim to graded dose response curve

dose of drug producing an effect 50% of the population = median effective dose E50

Front 36

median lethal dose

Back 36

det in experimental animals LD50

toxic effect measured other than death - TD50

Front 37

therapeutic index

Back 37

ration of LD50/ED50

how selective the drug is in producing desired effects compared to adverse effects

higher therapeutic index= safer drug is

Front 38

idiosyncratic

Back 38

rare or unexpected drug effect

immune -mediated
w/some causing severe organ toxicity via reactive metabolites

- ex hypersensitivity rxn

- acetaminophen (Tylenol)-induced hepatotoxicity appears to be caused by a reactive imidoquinone metab

Front 39

hypersensitivity reactions

Back 39

allergic rxns such as:
- skin rashes
- hematological rxn
- generalized hypersensitivity syndromes
- autoimmune - lupus like syndromes

Front 40

pts sensitivity to beneficial of toxic pharmacological effects

Back 40

altered by:
- gender
- age
- dx states
- genetics
- prior exposure to drugs

polymorphisms in enzymes for drug disposition can produce major alterations in drug conc at its receptor

Front 41

tolerance

Back 41

chronic admin of some drugs produces this

Front 42

tachyphylaxis

Back 42

decreased responsiveness to drugs that occurs very rapidly ( nitrate)

repeated admin of same dose of drug over a short time results rapidly in a reduced drug affect

Front 43

down - regulation

Back 43

excessive levels of an endogenous hormone/transmitter or direct-acting agonist drug may cause compensatory decrease in receptor number

repeated or persistent drug-receptor interactions results in removal of the receptor from sites where subsequent drug receptorinteractions could take place (intracellular sequestration

Front 44

desensitization

Back 44

reduced coupling efficacy w/excessive levels of endogenous hormone

decreased ability of a receptor to respond to stimulation by a drug or ligand
- homologous - decreased response at a single type of receptor
- heterologous - decreased response at two or more types of receptor

Front 45

supersensitivity

Back 45

loss of endogenous input (denervation) or continuous exposure to an antagonist drug can lead to receptor
UP-regulation

in attempts to restore homeostasis

Front 46

additive effects

Back 46

if both drugs are full agonists and similiar acting at same receptor =

REDUCED effects if one drug is a partial agonist or antagonist

AKA synergistic effects
- drugs acting at different receptors to activate same transduction pathway -

Front 47

inactivation

Back 47

loss of ability of a receptor to respond to stimulation by a drug or ligand

Front 48

refractory

Back 48

after a receptor is stimulated a period of time that is required before the next drug-receptor interaction can produce an effect

esp true for ion channels

Front 49

tachyphylaxis

Back 49

decreased responsiveness to drugs that occurs very rapidly ( nitrate)

repeated admin of same dose of drug over a short time results rapidly in a reduced drug affect

Front 50

down - regulation

Back 50

excessive levels of an endogenous hormone/transmitter or direct-acting agonist drug may cause compensatory decrease in receptor number

repeated or persistent drug-receptor interactions results in removal of the receptor from sites where subsequent drug receptorinteractions could take place (intracellular sequestration

Front 51

desensitization

Back 51

reduced coupling efficacy w/excessive levels of endogenous hormone

decreased ability of a receptor to respond to stimulation by a drug or ligand
- homologous - decreased response at a single type of receptor
- heterologous - decreased response at two or more types of receptor

Front 52

supersensitivity

Back 52

loss of endogenous input (denervation) or continuous exposure to an antagonist drug can lead to receptor
UP-regulation

in attempts to restore homeostasis

Front 53

additive effects

Back 53

if both drugs are full agonists and similiar acting at same receptor =

REDUCED effects if one drug is a partial agonist or antagonist

AKA synergistic effects
- drugs acting at different receptors to activate same transduction pathway -

Front 54

inactivation

Back 54

loss of ability of a receptor to respond to stimulation by a drug or ligand

Front 55

refractory

Back 55

after a receptor is stimulated a period of time that is required before the next drug-receptor interaction can produce an effect

esp true for ion channels

Front 56

tachyphylaxis

Back 56

decreased responsiveness to drugs that occurs very rapidly ( nitrate)

repeated admin of same dose of drug over a short time results rapidly in a reduced drug affect

Front 57

down - regulation

Back 57

excessive levels of an endogenous hormone/transmitter or direct-acting agonist drug may cause compensatory decrease in receptor number

repeated or persistent drug-receptor interactions results in removal of the receptor from sites where subsequent drug receptorinteractions could take place (intracellular sequestration

Front 58

desensitization

Back 58

reduced coupling efficacy w/excessive levels of endogenous hormone

decreased ability of a receptor to respond to stimulation by a drug or ligand
- homologous - decreased response at a single type of receptor
- heterologous - decreased response at two or more types of receptor

Front 59

supersensitivity

Back 59

loss of endogenous input (denervation) or continuous exposure to an antagonist drug can lead to receptor
UP-regulation

in attempts to restore homeostasis

Front 60

additive effects

Back 60

if both drugs are full agonists and similiar acting at same receptor =

REDUCED effects if one drug is a partial agonist or antagonist

AKA synergistic effects
- drugs acting at different receptors to activate same transduction pathway -

Front 61

inactivation

Back 61

loss of ability of a receptor to respond to stimulation by a drug or ligand

Front 62

refractory

Back 62

after a receptor is stimulated a period of time that is required before the next drug-receptor interaction can produce an effect

esp true for ion channels

Front 63

effective concentration

Back 63

at receptors is determined by
- how it is abs
- distributed throughout the body
localized in tis
eliminated

Front 64

pharmacodynamics

Back 64

relates how the drug affects the body

Front 65

pharmacokinetics

Back 65

describes how the body handles the drug after it is administered

Front 66

5 factors that influence the relationship btw dose of drug and effective conc at site of action

Back 66

1. liberation
2. absorption
3. distribution
4. metabolism (biotransformation
5. excretion - elimination - hepatic metab or renal excretion - expired air
LADME

Front 67

drugs with a narrow therapeutic window

Back 67

1. digitalis
2. vancomycin
3. lithium
4. phenytoin
5.procainamide
6. quinidine
7. theophylline
8. inhalation anesthetics

Front 68

drug absorption

Back 68

influenced by physiochem properties of drug
- solubility
-particle size
- chem form

orally - rate of abs is det byhow fast the drug dissolves in GI fluids

blood flow to site of admin = RATE LIMITING STEP

admin to large surface area = rapid abs

Front 69

drug mvmt through membranes

Back 69

passive diffusion - surface area and permeability characteristics of the membrane

passive facilitated diffusion- saturable carrier subject to competition
- abs of B12
- levodopa - only drug that uses facilitated diffusion

active transport - against conc gradient req energy
- affected by metabolic inhibitors
- specific, saturable, competitive inhibition
-ex- multi-drug resistance pump = pumps chemotherapeutic drugs, some HIV drugs, other agents
- acidic drugs - asprin, penicillin, certain diruretics actively transported into urine via Organic acid transporter OAT = norm transports uric acid

Front 70

drug's pKa

Back 70

the pH where unionized and ionized conc are equal

50% unionized and 50% ionized

weak acids are ionized at a pH above the pKa

weak bases are ionized at a pH below their pKa

Front 71

ion trapping

Back 71

acidic drugs will accumulate on the more basic side of the membrane

basic drug accumulates on the more acidic side of the membrane

can affect renal extraction of drugs - facilitating renal elimination of weak acid or bases
- beneficial in treating acute drug intoxication or drug overdose = increase drug ionization in urine

urien pH norm 6.3 should be alkalinized usingsodium bicarb to enhance elimination of weak acids or acidified using ammonium chloride or vit C to enhance elimination of weak bases

Front 72

pH of the stomach

Back 72

1-3

Front 73

pH of small intestines

Back 73

5-7

Front 74

pH of large intestines

Back 74

7-8

Front 75

gastrointestinal abs of acids

Back 75

acidic drugs unionized at low pH of gastric fluids = better abs by stomach

but predom abs through sml int bc much larger surface area
- laon residence time
- existence of some of the drug in unionized stage

ketaconazle - req low gastric pH to be abs

Front 76

gastrointestinal abs of bases

Back 76

weak bases poorly abs from stomach where they are primarily in ionized form

Front 77

other factors on gastrointestinal abs

Back 77

1. presence of food or other substances
2. gastric emptying time
3. drugs / dx process that affects GI motility

Front 78

first pass effect

Back 78

metabolism of much of the drug by the liver before it ever reaches systemic circulation

accounts for low bioavailability of rapidly metabolized drugs given orally

Front 79

bioavailability

Back 79

describes the fraction of the dose which reaches systemic circulation

of IV drug = 1 = 100% reaches systemic circulation

Front 80

bioequivalent

Back 80

2 drugs (generic vs name brand) w/same active ingredient and identical bioavailability

Front 81

amount of drug that reaches systemic circulation

Back 81

= dose*F
F= fraction of administered dose which reaches systemic circulation

F is determind by the amt reached orally/amt of IV

Front 82

pH of small intestines

Back 82

5-7

Front 83

pH of large intestines

Back 83

7-8

Front 84

gastrointestinal abs of acids

Back 84

acidic drugs unionized at low pH of gastric fluids = better abs by stomach

but predom abs through sml int bc much larger surface area
- laon residence time
- existence of some of the drug in unionized stage

ketaconazle - req low gastric pH to be abs

Front 85

gastrointestinal abs of bases

Back 85

weak bases poorly abs from stomach where they are primarily in ionized form

Front 86

other factors on gastrointestinal abs

Back 86

1. presence of food or other substances
2. gastric emptying time
3. drugs / dx process that affects GI motility

Front 87

first pass effect

Back 87

metabolism of much of the drug by the liver before it ever reaches systemic circulation

accounts for low bioavailability of rapidly metabolized drugs given orally

Front 88

bioavailability

Back 88

describes the fraction of the dose which reaches systemic circulation

of IV drug = 1 = 100% reaches systemic circulation

Front 89

bioequivalent

Back 89

2 drugs (generic vs name brand) w/same active ingredient and identical bioavailability

Front 90

amount of drug that reaches systemic circulation

Back 90

= dose*F
F= fraction of administered dose which reaches systemic circulation

F is determind by the amt reached orally/amt of IV

Front 91

intravenous administration

Back 91

adsorption pattern:
- circumbented
- potentially immediated effects
- suitavle for large volumes and irritating substances or complex mixtures

special utility -
- valuable for emergency use
- permits titration of dosage
- usually required for high0molecular wt protein and peptide drug

limitations - cautions -
- increased risk of adverse effects
- must inject solutions slowly
- not suitable for oily secretions or poorly soluble substances

Front 92

subcutaneous

Back 92

absorption pattern
-prompt from aqueous solution
- slow and sustained from repository preps

special utility
- suitable for some poorly soluble suspensions and for instillation of slow release implaints

limitations, cautions
- not suitable for larte volumes
- possible pain or necrosis from irritating substances

Front 93

intramuscular

Back 93

abs pattern:
- prompt from aqueous solution
- slow and sustained from repository preps

special utility:
- suitable for moderate volumes
- oily vehicles
- some irritating substances
- appropriate for self admin = insulin

limitations, cautions
- precluded during anticoag therapy
- may interfere w/interpretation of certain diagnostic tests (creatinine kinase)

Front 94

oral ingestion

Back 94

abs pattern:
- variable depends on many factors

special utility:
- most convienent and economical
- usually more safe

limitations, cautions
- req pt compliance
- bioavailability potenitially erratic and incomplete

Front 95

distribution

Back 95

reversible transfer of drug from one location to another within the body

once enters the blood stream depends on:
- physiochem properties of drug
- molecular size
- polarity
- solubility
- ability of drug to traverse various types of membranes
- organ blood flow
- binding of dtrug to plasma proteins or tissues

well perfused organs recieve the most drug - liver, kidney , and brain

delivery to skin, mm, viscera,and fat is slower

Front 96

second distribution phase

Back 96

requires several min - several hours before conc of drug in tis is in eq w/blood

involves far larger fraction of body mass than initial phase which onlly accounts fir most extravascularly distributed drug

Front 97

plasma protein binding

Back 97

influences distribution of the drug

only unbound drug capable of diffusing out of the vascular system to sites of pharm activity as well as biotransformation or elimination

Doesn't limit renal excretion or hepatic metab

acidic drugs bind to albumin
basic drugs bind to alpha1-acid glycoprotien

non linear saturable process

extent - affected by disease related factors - hypoalbuinemia - severe liver dx, or nephrotic syndrome - displacement of unconj bilirubin by sulfonamides and other organic anions = increase risk ofbilirubin encephalopathy

altered by age, pregnancy and pathophysiology

Front 98

redistribution

Back 98

factor in terminating drug effect priarily when a high lipid-soluble drug that acts on brain or cardivascular system is admin IV rapidly

Front 99

drugs that cross the BBB

Back 99

must be sufficiently small and hydrophobic to cross the lipid membranes easily
use existing transport proteins in the BBB

Front 100

intravenous administration

Back 100

adsorption pattern:
- circumbented
- potentially immediated effects
- suitavle for large volumes and irritating substances or complex mixtures

special utility -
- valuable for emergency use
- permits titration of dosage
- usually required for high0molecular wt protein and peptide drug

limitations - cautions -
- increased risk of adverse effects
- must inject solutions slowly
- not suitable for oily secretions or poorly soluble substances

Front 101

subcutaneous

Back 101

absorption pattern
-prompt from aqueous solution
- slow and sustained from repository preps

special utility
- suitable for some poorly soluble suspensions and for instillation of slow release implaints

limitations, cautions
- not suitable for larte volumes
- possible pain or necrosis from irritating substances

Front 102

intramuscular

Back 102

abs pattern:
- prompt from aqueous solution
- slow and sustained from repository preps

special utility:
- suitable for moderate volumes
- oily vehicles
- some irritating substances
- appropriate for self admin = insulin

limitations, cautions
- precluded during anticoag therapy
- may interfere w/interpretation of certain diagnostic tests (creatinine kinase)

Front 103

oral ingestion

Back 103

abs pattern:
- variable depends on many factors

special utility:
- most convienent and economical
- usually more safe

limitations, cautions
- req pt compliance
- bioavailability potenitially erratic and incomplete

Front 104

distribution

Back 104

reversible transfer of drug from one location to another within the body

once enters the blood stream depends on:
- physiochem properties of drug
- molecular size
- polarity
- solubility
- ability of drug to traverse various types of membranes
- organ blood flow
- binding of dtrug to plasma proteins or tissues

well perfused organs recieve the most drug - liver, kidney , and brain

delivery to skin, mm, viscera,and fat is slower

Front 105

second distribution phase

Back 105

requires several min - several hours before conc of drug in tis is in eq w/blood

involves far larger fraction of body mass than initial phase which onlly accounts fir most extravascularly distributed drug

Front 106

plasma protein binding

Back 106

influences distribution of the drug

only unbound drug capable of diffusing out of the vascular system to sites of pharm activity as well as biotransformation or elimination

Doesn't limit renal excretion or hepatic metab

acidic drugs bind to albumin
basic drugs bind to alpha1-acid glycoprotien

non linear saturable process

extent - affected by disease related factors - hypoalbuinemia - severe liver dx, or nephrotic syndrome - displacement of unconj bilirubin by sulfonamides and other organic anions = increase risk ofbilirubin encephalopathy

altered by age, pregnancy and pathophysiology

Front 107

redistribution

Back 107

factor in terminating drug effect priarily when a high lipid-soluble drug that acts on brain or cardivascular system is admin IV rapidly

Front 108

drugs that cross the BBB

Back 108

must be sufficiently small and hydrophobic to cross the lipid membranes easily
use existing transport proteins in the BBB

Front 109

apparent volume distribution

Back 109

apparent volume into whcih a drug distributes in the body at equilibrium

L/kg

calculated from known Iv dose and serieral measurementso plasma conc

Vd = amt in body/ C = iv dose/ C at time 0

drug that distributes to total body water Vd = 0.6 L/kg for 70kg pt

Vd can be many times total body size due to binding of drug to tissue compartments

small Vd = uptake is limited
large Vd = indicate extensive tissue distribution

imp in peds bc kids have higher water content than adults, lower plasma conc of drugs that distribute into body water if dose is only adjusted in proportion to body weight

Front 110

drug elimination

Back 110

either unchanged or as metabolites

primarily = by renal excretion
or:
- bile
- feces
- milk
- saliva
- sweat
- tears
- lungs

eliminate polar cmpds more efficiently than substances w/high lipid solublity
- high lipid soluble drugs not readily eliminated - metabolized to more polar compounds

Front 111

clearance

Back 111

1. rate of elimination of the drug from the body relative to its concentration in plasma

2. loss of the drug across an organ of elimination - volume of blood that can be completely cleared of drug per unit time

primary organs for drug clearence = kidneys and liver

clearnace of unchanged drug in urine = renal clearance

biotransformation in liver and excreted as metabs or unchanged drug into bile

or through lungs, blood, mm

Cl=Q*E = blood flow to the organ * ability of the organ to extract the drug (extraction ratio)

high E = high clearnace by the organ 0-1

E= Cin-Cout/ Cin

Front 112

first order elimination

Back 112

elimination is not saturable and rate of drug elimination is directly proportional to its conc

drugs clearnace and extraction ratio = efficiency ofelimination process influenced by
1. total blood flow to organ Q
2. amoutn free drug abailable to organ - free fraction
3. organ's intrinsic clearince -

Front 113

flow dependent drugs

Back 113

drugs have high intrinsic clearance so that extraction ratio approaces 100%

clearance is dependent ENTIRELY on blood flow to organ

not affected by moderate changes olasma protein binding

Front 114

capacity-limited drugs

Back 114

very low intrinsic clearince

their extraction by an organ (kidneys or liver) is very inefficient
clearance becomes independent of blood flow

changes in intrinsic clearance and/or plasma protein binding become very imp in det overall organ clearance

rate of elimination = vmax*C/ (Km+C)

imp for aspirin, ethanol, and phenytoin
= in OD drugs saturate elimination process

Front 115

renal clearance

Back 115

volume of blood cleared of drug by kidneys per unit time

Cr clearance and GFR asses renal fning

Front 116

apparent volume distribution

Back 116

apparent volume into whcih a drug distributes in the body at equilibrium

L/kg

calculated from known Iv dose and serieral measurementso plasma conc

Vd = amt in body/ C = iv dose/ C at time 0

drug that distributes to total body water Vd = 0.6 L/kg for 70kg pt

Vd can be many times total body size due to binding of drug to tissue compartments

small Vd = uptake is limited
large Vd = indicate extensive tissue distribution

imp in peds bc kids have higher water content than adults, lower plasma conc of drugs that distribute into body water if dose is only adjusted in proportion to body weight

Front 117

drug elimination

Back 117

either unchanged or as metabolites

primarily = by renal excretion
or:
- bile
- feces
- milk
- saliva
- sweat
- tears
- lungs

eliminate polar cmpds more efficiently than substances w/high lipid solublity
- high lipid soluble drugs not readily eliminated - metabolized to more polar compounds

Front 118

clearance

Back 118

1. rate of elimination of the drug from the body relative to its concentration in plasma

2. loss of the drug across an organ of elimination - volume of blood that can be completely cleared of drug per unit time

primary organs for drug clearence = kidneys and liver

clearnace of unchanged drug in urine = renal clearance

biotransformation in liver and excreted as metabs or unchanged drug into bile

or through lungs, blood, mm

Cl=Q*E = blood flow to the organ * ability of the organ to extract the drug (extraction ratio)

high E = high clearnace by the organ 0-1

E= Cin-Cout/ Cin

Front 119

first order elimination

Back 119

elimination is not saturable and rate of drug elimination is directly proportional to its conc

drugs clearnace and extraction ratio = efficiency ofelimination process influenced by
1. total blood flow to organ Q
2. amoutn free drug abailable to organ - free fraction
3. organ's intrinsic clearince -

Front 120

flow dependent drugs

Back 120

drugs have high intrinsic clearance so that extraction ratio approaces 100%

clearance is dependent ENTIRELY on blood flow to organ

not affected by moderate changes olasma protein binding

Front 121

capacity-limited drugs

Back 121

very low intrinsic clearince

their extraction by an organ (kidneys or liver) is very inefficient
clearance becomes independent of blood flow

changes in intrinsic clearance and/or plasma protein binding become very imp in det overall organ clearance

rate of elimination = vmax*C/ (Km+C)

imp for aspirin, ethanol, and phenytoin
= in OD drugs saturate elimination process

Front 122

renal clearance

Back 122

volume of blood cleared of drug by kidneys per unit time

Cr clearance and GFR asses renal fning

Front 123

renal excretion

Back 123

3 distinct processes
- Glomerular Filtration
- active tubular secretion
- passive tubular reabsorption

in neonates renal fn is low compared to body mass but matures rapidly

adulthood - slow decline in renal fn 1% per year

Front 124

glomerular filtration rate

Back 124

normally 120ml/min

Front 125

renal clearance of a drug

Back 125

fn of GFR and free fraction of drug in blood
= GFR*FF

when exceeds clearance by filtration = active tubular secretion of drug must also be occuring

tubular reabs of drug must occur if the renalclearnace of a drug is less than the calculated clearance by filtration

filtration and reabs are passive

some drugs are actively transported into urine by carriers - P-glycoprotein (amphipathic anions) and MRP2 - secretion of conj metabs (glucuronides, sulfates, glutathione) ATP- binding cassette transporters - selective for organic cationic drugs - secretion of organic bases
- membrane transporters mainly in distal renal tubule = active reabs

prox/distal tubules - unionized weak acids and bases goes passive reabs - back diffusion created by the reabs of water w/Na+

Front 126

weak acid overdose

Back 126

barbiturates, aspirin, phenothiaznes

administer sodium bicarbonate

increase urine pH

Front 127

weak base overdose

Back 127

amphetamine, cocaine, PCP = phencyclidine

administer ammonium chloride

decrease urine pH

Front 128

hepatic clearance

Back 128

product of hepatic blood flow and hepatic extraction ratio

Front 129

intrinsic clearance

Back 129

max ability of liver to irreversibly remove drug by all pathways in the absence of any flow limitations

if it is very large relative to blood flow the extraction ratio approaces one and hepatic clearance depends entirely on liver blood flow- flow-dependent elimination

when intrinsic clearance is very small relative to flow extraction ratio approaches Clint/Q and hepatic clearance be approximated by Clint . = capacity limited elimination

Front 130

hepatic extraction ratio

Back 130

E=Clint / (Q+Clint)

the clearance of compounds w/ low extraction ratio
- phenytoin
- theophylline
- phenobarbital
is determined by extent of plasma protein binding and the intrinsic clearance
- sensitive to changes in plasma protein binding

Front 131

zero order elimination

Back 131

saturate drug metabolizing enzymes

ex = ethanol - constant amt of drug is metabolized each hour

Front 132

first order kinetics

Back 132

metabolic system is not saturated in which constant proportion of drug is metabolized per hour

absolute amt increasing as blood levels increase

Front 133

entrohepatic recycling

Back 133

when metabolite is secreted by liver cells into bile and paass into intestine where it is reabsorbed

can be repeated many times until biotransformation, renal excretion, or fecal excretion eliminate drug from bod

increase plasma conc of drug

Front 134

drug metab

Back 134

primary fn of liver
kidney GI lungs skin also play role

Front 135

phase I biotransformation rxns

Back 135

introduce or expose a fnal group on the parent compoud as in oxidation/reduction rxn

= loss in pharmacological activity

many drug metabolizing enzymes are located in smooth ER of hepatocytes -> microsomes

mixed fn oxidases of the cytochrome P450
- enzymes requires both reducign agent NADPH and molecular oxygen

Front 136

phase II biotransformation rxns

Back 136

biosynthetic cojugation rxn

conjugation rxn lead to formation of a covalent linkage btw a fnal group on the parent compound or phase I metabolinte and endogenously derived glucuronic acid, sulfate, glutathione, AA, or acetate

highly polar and inactive
excreted rapidly in urine and feces

phase I products may undergo subsequent phase II conjugation

co-factors = UDP=glucuronic acid (req for UDP-glucuronosyltransferases)

in cytosol

catalytic rates are faster than rates for CYPs
rate of elimiation usually dependent on Phase I rxn

Front 137

microsomal enzymes that play a role in metabolism of xenobiotics

Back 137

1.NADPH-cytochrome P450 reductase - flavoprotein containing flavin adenine dinucleotide and flavin mononucleotides

2. cytochrome P450 a heme protein serves as the terminal oxidase
- isoforms
- O-dealkylation
- N-dealkylation
- aromatic hydroxylation
- N-oxidation
- S-oxidation
- deamination
- dehalogenation

Front 138

alcohol dhydrogenase

Back 138

oxidizes alcohols to aldehyde derivitives

non-P450

Front 139

monamine oxidases

Back 139

present in the liver and nerve terminals - responsible for the oxidation of amine-containing endogenous compounds - catecholamines and tyramine

non-P450

Front 140

enzyme induction

Back 140

long term exposure to agents, either by chronic drug admin or environ exposure (pollutants, diet, smoking, industrial contact) can selectively increase thranscription of a specific P450 isoform

increase the rate of metabolism for all substrates of that isoform

reduce the duration of pharmacologic activity of the inducer and cosubstrates

facilitate production of active metabolites

Front 141

enzyme inhibition

Back 141

drugs can inhibit P450 enzyme activity

occurs selectively for particular P450 isoforms

drugs that bind tightly to P450 hemee iron will occupy enzymes active site and effectively block its ability to bind with other substrates

Front 142

suicide inhibitors

Back 142

inhibitor interacts with the microsomal enzyme to irreversably modify its activity

ex - sedatve hypnotic secobarbital

Front 143

CYP3A4

Back 143

responsible for the biotransformation of >50% of clinically prescribed drugs that undergo phase I metabolism by the liver

Front 144

genetic polymorphism

Back 144

large interindividual variability in CYP expression

diff in gene regulation too

ex - genetic defects in oxidative metab of
- debrisoquin
- phenacetin
- phenformin
- warfarin
= AR

Front 145

glucuronidation

Back 145

catalyzed by UDP-glucuronosyltransferases

transfer glucuronic acid from cofactor UDP glucuronic acid to an appropriate substrate

ex- glucuronidation of bilirubin by isoform UGT1A1 affected by genetic variation or competing drugs = hyperbilirubinemia/jaundice

Front 146

glutathione conjugation

Back 146

cytosol or ER

glutathione-S-transferases catalyze transfer of glutathione to reactive electrophiles

severe reduction in glutathione = predispose cell to oxidative damage

ex- acetaminophen metab by CYP2E1 generates toxic metabolite which depletes liver glutathione = reactive metab accumulates = tis necrosis and severe, life-threatening hepatotoxicity

acetaminophen overdose by administering N-acetylcysteine as exogenous souce of glutathione

Front 147

N-acetylation

Back 147

N-acetyltransferases responsible for metab of drugs and environ agents that contain aromatic amine or hydrazine group

addition of acetyl group from the cofactor acetyl - coenzyme A = metabolite that is less water soluble

most polymorphic of all human drug metabolizing enzymes

rapid and slow acetylators - slow = predisposed to drug toxicity bx slow acetylation can lead to high plasma levels of drug

Front 148

Sulfation

Back 148

sulfotransferases conj sulfate (derived from 3'phosphoadenosine- 5'phosphosulfate) to the hydroxyl groups of aromatic and aliphatic drugs or metabolites

lead to generation of chem reactive metabs - carcinogenic or toxic properties

Front 149

methylation

Back 149

drugs and xenobiotics undergo O-, N-, S-methylation mediated by several methytransferases using S-adenosyl methionine (SAM) as the methyl donor

most imp = S-methyltransferase - metabolizes thiopurine drugs (6-mercaptopurine)

Front 150

drug-drug interactions

Back 150

occur when 2 co-admin drugs metabolized by same enzyme - CYPs imp avoid combining drugs metab by same P450 isozyme

chronic exposure to enzyme induces or inhibitors = changing the affected drugs of their dosing regimen

Front 151

drug metab influenced by

Back 151

1. dietary components = grapefruit
2. endogenous substances = steroid hormones
3. herbal products = st. johns wart
4. acute or chronic dx that affect liver fn = alcoholic cirrhosis, hemochromatoisis, chronic active hepatitis, biliary cirrhosis, acute viral or drug induced hepatitis
5. age
6. gender

Front 152

elimination half-life

Back 152

time required to change the amount of drug in the body by 1/2 during elimination

depends on both the drug's volume of ditribution and inversely to its clearance

t1/2 = (ln2*Vd)/Cl = (0.7*Vd)/Cl

time req to atain 50% of steady state plasma levels or to decay 50% from steady state after continuous drug admin

50% steady state reached after 1 half life
75% reached after 2 half lives
97% after 5 half lives

4-5 half lives before full effects will be seen

7 half lives to reach mathematical steady staat
effective clinical steady state = plasma conc> 90% ~ 4 half lives

individual differences due to
1. differences in drugs Vd = obesity, advanced aged, changes in elimination -= hepatic/renal clearance

Front 153

target concentration

Back 153

rational dosage regimen based on acheiving this

produce the desired therapeutic effect

midway btw the minimum effective concentration for desired effect and the MEC for adverse effect - above which toxicity will result

Front 154

therapeutic window

Back 154

therapeutic goal to obtain and maintain conc. w/in this

for desired response w/min of toxicity

measure of safety for a single pt

after constant IV the Css in the body will be achieved when the rate of drug elimination = the rate of drug administration

if the desired steady state conc of drug in plasma is known, clearance of the drug in the individual pt will dictate the rate at which the drug should be given

Dose rate = Cl*Css

Front 155

drugs duration of action

Back 155

determined by time period ofver which Cp exceed the MEC for a given effect

increasing or decreasing drug dosage increases peak plasma levels as well as prolonging its duration of action

Front 156

area under the curve

Back 156

area under the blood conc - time curve used to calc drug clearance for 1st order elimination

Cl = dose/AUC

Front 157

maintenance dose

Back 157

dosiing rate that equase the rate of elimination

dose rate(ss) = rate of elimination = Cl*TC (target concentration = Cl*Cp=Css

orally administered
oral rate (ss) = dose ratess/ F = Cl*TC/F

intermittent doses
MD = dose rate(ss) * dose interval = Cl*TC* Dose interval

Front 158

minimize fluctuations

Back 158

1. slowing abs = changeing route or giving slow release form
2. deccreasing the dosing interval

Front 159

loading dose

Back 159

initial doses of drug admin in order to compensate for drug distribution into tissues
may be much higher than wouldbe req if drug were retained in the intravascular compartment

long elimination half life -the time req to reach steady state therapeutic conc could be days or weeks

to reach beneficial Cp quickly = lodading dose

entire loading dowse as a single administration

if toxicity is problem give as a slow infusion or 3 + divided doses over short period of time to avoid high Cp that could cause adverse effects

Loading dose = Vd*TC

Front 160

ionization of weak acids and bases

Back 160

pK-pH = -3
%weak acid ionized 99.9
% weak base ionized 0.1

pK-pH = -2
%weak acid ionized 99
% weak base ionized 1.0

pK-pH = -1
%weak acid ionized 90.9
% weak base ionized 9.1

pK-pH = 0
%weak acid ionized 50
% weak base ionized 50

flip with positive numbers

Front 161

peripheral nervous system

Back 161

1. afferent neurons - sensory
2. somatic motor system
3. autonomic nervous system

Front 162

somatic motor system

Back 162

- single motor neuron from spinal cord to skeletal mm
- voluntary control of mm
- cholinergic neurons activate mm through a nicotinic receptor

Front 163

autonomic nervous system

Back 163

- involuntary control of activity of the heart, smooth mm, lungs and glands
- divided into parasmp and symp

- 2 neuron systems w/pregang and post gang neurons

Front 164

parasymp nervous system

Back 164

craniosacral - through cranial nerves III, VII, IX, X, and S1-S3

preganglionics synapse with postganglionics on effector organ

ratio 1:1

pregang and postgang neurons release Ach

rest and digest
- enhance urinary tract, GI tract, pupil constriction, accomodation for near vision

nicotinic receptor at gangila
muscurinic receptor at organ - heart

Front 165

symp nervous system

Back 165

thoracolumbar spinal cord

preganglionic synapse w/postgangs in paravertebral and prevertebral ganglia

ratio 1:20

pregangs release Ach

most postgang release Norepi but some release Ach

adrenal medulla releases epi

pupil dilation, inc resp, bronchiodilation, metabolic glucose fns

nicotinic receptors in ganglia and at adrenal medula
alpha and beta receptors at target organs as well as muscurinic on glands

Front 166

cholinergic neurotransmission

Back 166

Ach nt

receptors - nicotinic and muscarininc

cholinergic neurons
- all preganglionic neurons of autonomic nervous system
- post symp receptors are nicotinic
- includes preganglionic symp fibers innervating adrenall medulla

- all post ganglion neurons of parasymp nervous system
- receptors are muscariic

atypical post ganglionic neurons of symp nervous system that innervate sweat glands, piloerector mm, symp cholinergic fibers
- receptors are muscarinic

Front 167

andrenergic neurotransmission

Back 167

receptors = alpha1,2, beta 1,2,3

norepi = nt

noradrenergic neurons - MOST post ganglionic neurons of symp nervous system

effects of adrenergic receptors
- Beta 1 = increases ALL cardiac fn
- alpha 1 = contracts smooth mm = vascular, radial mm of eye, vase deferens, prostrate
- beta 2 - relaxes smooth mm - vascular, skeletal, uterine, bronchial = due to EPI

norepi = a1, b1 (a2)
epi = a1, b1, b2, (a2)
dopamine = low = D1
moderate = D1, B1
high = a1, B1

Front 168

heart innervation

Back 168

sympathetic
Beta 1
increases heart fn

parasympathetic
M2
decrease heart fn

Front 169

vasculature innervation

Back 169

sympathetic
A1 = constriction of smooth mm
B2 = dilation in skeletal mm

parasympathetic
M3 = vestigal

Front 170

lung innervation

Back 170

sympathetic
B2
relax bronchial mm

parasymp
M3 = contract bronchial smooth mm
= stimulate glandular secretions

Front 171

GI tract innervation

Back 171

sympathetic
slight decrease in motility and secretions

parasympathetic
M3 = contract smooth mm wall - increase tone and motility
relax sphincters

Front 172

Urinary innervation

Back 172

symp
B2-3 = relax detursor mm
A1 = contract sphincter

parasymp
M3 = contract detursor, relax sphincter

Front 173

male genital tract innervation

Back 173

sympathetic
A1 = ejaculation - contraction of prostate smooth mm

parasympathetic
M3= erection

Front 174

female genital tract innervation

Back 174

symp
B2 = uterine smooth mm relaxation

Front 175

exocrine glands innervation

Back 175

sympathetic
M3 - increased sweating

parasymp
secretion = M3

Front 176

Metabolism innervation

Back 176

sympathetic
liver - gluconeogenesis/glycogenolysis = B2

fat cells = lipolysis

pancreas = decrease in insulin secretion - alpha, increase insulin secretion - beta

kidney - decrease renin relase = alpha
- increase renin release - beta

Front 177

eye innervation

Back 177

radial mm
- symp
- B1 - contraction = mydriasis

sphincter mm
- parasymp
- M3 contraction - miosis

ciliary mm
Contraction - accomodation for near vision, decrease in intraocular presure = M3

ciliary body
parasymp
- formation of aqueous humor
- beta increases
alpha 2 decreases

Front 178

synthesis of ach

Back 178

choline + acetyl CoA --> Ach
via choline acetyltransferase

rate limiting step choline uptake = b/c positive charge

Front 179

Ach release

Back 179

into synaptic cleft in synaptic vesicles

Front 180

botulinus toxin

Back 180

inhibits Ach release

local injections used to tx
- strabismus
- blepharospasm
- cosmetic use
- primary axillary hyperhidrosis

Front 181

latrotoxin

Back 181

increases Ach release

from black widow spider

Front 182

degradation of Ach

Back 182

Ach --> choline + acetic acid (acetate)

via acetylcholinesterase

Front 183

cholinesterases

Back 183

acetylcholinesterase
- found in neuromuscular junction
- at postgang parasymp synapses
- autonomic ganglia

pseudocholinesterase (Butyryl cholinesterase)
- found in plasma
- liver
- glial cells

Front 184

cholinergic receptors

Back 184

at ALL post synaptic sites on effector organs inervated by parasymp nervous system

at post synaptic sites to sweat glands innervated by symp nervous system

at all post synaptic sites on skeletal mm

at all autonomic ganglia including adrenal medulla

blood vessels - muscarininc receptors

CNS = muscarinic + nicotinic

Front 185

muscarinic cholinergic receptor location

Back 185

1. parasymp effector organ
2. sweat glands through symp=cholinergic innervation
3. BV
4. CNS

Front 186

Muscarinic cholinergic receptor response to activation

Back 186

except for ones on BV and sweat glands - same as parasymp activation

contracts smooth mm and increases tension = GI tract

hyperpolarizes cardiac mm and decreases rate of polarization

vasodilation

Front 187

muscarinic subtypes

Back 187

M1
- neuronal
- G-protein coupled = Gq
- phosphatidylinositol turnover: IP3, DAG cascade

M2
- cardiac
- g-protiencoupled - Gi
- activate K+ channels - inhibit cAMP production through adenylate cyclase

M3
- exocrine glands, smooth mm and endothelial cellls
- g-protein linked = Gq
- phosphatidylinositol turnover: IP3, DAG cascade = increase in calcium
- Nitric oxide (EDRF increases c GMP in endothelial cells
-

Front 188

nicotinic cholinergic receptors location

Back 188

striated mm - neuromuscular junction
- autonomic ganglia
adrenal medulla

Front 189

nicotinic subtypes

Back 189

neuromuscular nicotinic receptors - skeletal mm)
- ganglionic nicotinic receptors (autonomic ganglia and adrenal)

Front 190

nicotinic response to activation

Back 190

both nicotinic receptors are ligand-gated channel receptors

agonists = increase permeability to Na+ and K+ by opening membrane channels

neuromuscular nicotinic receptors
- activation causes depolarizing end plate potential which trigges mm action potential => contraction

ganglionic nicotinic receptors
- activation causes a rpapid excitatory postsynaptic potential ESPS

Front 191

depolarization block

Back 191

both nicotinic sybypes

overstimulation by agonist paralyzes channel in depolarized state

Front 192

muscarinic receptor agonists

Back 192

1. choline esters - all quaternary ammonia comounds
1. acetylcholine
2. bethanechol

natural cholinomimetic alkaloids
1. pilocarine
2. muscarine

Front 193

acetylcholine

Back 193

aka miochol

a choline ester

not very clinically useful b/c hydrolyzed too rapidly and acts too diffusely
- binds to nicotinic receptors too

abailable for intraocular application

Front 194

bethanechol

Back 194

aka urecholine

a choline ester

resistant to hydrolysis by acetylcholinesterase -= long duration

used to contract smooth mm of GI tract and bladder - not many CV effects unless really high doeses

NO nicotinic effects

derived from ach

Front 195

pilocarpine

Back 195

used primarily in glaucoma tx - treatment of xerostomia = severe dry mouth

long duration of action

tertiary amine = has CNS effects

systemic application objectionable due eto large increase in glandular and gastric secretions

Front 196

muscarine

Back 196

natural cholinomimetic alkaloid

from amantia fungi

no nicotinic effects

mushroom intoxification

Front 197

eye uses of muscarinic agonists

Back 197

induce miosis = decrease in intraocular pressure

1. surgical procedures needing miosis = contraction of ciliary mm obens trabecular membrane

2. tx of glaucoma = increase in intraocular pressure
- angle closure - or narrow angle = occular emergency
- open angle - wide angle or chronic simple = chronic permanent condition - loose peripheral vision first works w/gradual increase in intraoccular pressure
= blindness b/c axons in back of retina crushed by pressure

3.cholinergic tx for glaucoma - muscarinic agonist and acetylcholinesterase inhibitors - contract ciliary mm, free entrance to sclemm canal and increase outflow of aqueous humor

4. contract sphincter - circular mm to induce miosis
- muscarinic agonist - pilocarpine
- ach-esterase inhibitor - echothipphate, physostigmine

Front 198

Muscarinic agonist used for GI

Back 198

increases tone and motility
1. postop abdominal distension
2. gastric atony or paralysis =after bilateral vagotomy

DO NOT USE W/PERITONITIS or ?able INTEGRITY

BETHANECHOL

Front 199

Muscarinic agonist used on urinary bladder

Back 199

increases tone and motility

1. tx for urinary retention or inadequate bladder emptying - postpartum or post op

2. tx of hypotonic bladder

NOT IF OBSTRUCTION PRESENT

BETHANECHOL

Front 200

treatment of xerostomia

Back 200

muscarinic agonist used to induce slavation
- dryness of mouth due to sjogren's syndrome or radiation therapy

PILOCARPINE

Front 201

precautions/caontraindications of muscarinic agonists

Back 201

1. asthma = bronchoconstriction
2. hyperthyroid = inc symp tone more beta adrenergic receptors = heart goes into arrhythmias.
3. coronary insufficiency = dec coronary fn
4. peptic ulcer = increase gastric acid secretion
5. obstruction present - urinary tract
6. GI or urinary tract integrity questionable

Front 202

overdose of a muscarinic agonist

Back 202

indicated by excessive parasymp activation

tx - muscarinic antagonist - Atropine
epinephrine helps overcome severe cardiac effects

Front 203

acetylcholinesterase inhibitors actions

Back 203

block AchE both forms

= increase in Ach levels

parasympathomimetic + inc sweat gland activity
- increase nicotinic responses to autonomic ganglia and nueurmuscular junction = mm twitching
- CNS effects

therapeutically used for effects on eye, GI, and urinary tract, NM jnct and CNS

toxic effect = depolarization block = skeletal mm parralyzed = colapse of autonomic nervous system

Front 204

Acetylcholinesterase

Back 204

extremely effective enzyme

active center of enzyme
- negative anionic site for quaternary group of Ach - subsites
- an esteratic site for attacking acylcarbon substrate - covalent interaction
hydrolyze ester bond
- hydrolysis type phase I

Front 205

3 classes of acetylcholinesterase inhibitors

Back 205

1. reversible inhibitors: Edrophonium
2. slowly reversible inhibitors = carbamate inhibitors
3. organophosphate inhibitors 0 essentially irrevversible

Front 206

edrophonium

Back 206

reversible inhibitors of acetylchonese

binds to anionic site of active center - no interaction w/esteratic site

brief actions - rapidly eliminated = + charge directly excreted in kidneys

pulled in anionic site prevents Ach from coming in

Front 207

slowly reversible inhibitors of acetylcholinesterase

Back 207

carbamate inhibitors
- carbamylated enzyme int fairly stable

- slowly reversible b/c does interact w/ esteratic site
- as longas int can't bind ach

1. neostigmine
2. physostigmine
3. barbaryl
4. donepezil

Front 208

neostigmine

Back 208

slowly reversible inhibitor- carbamate inhibitor of acetylcholinesterase

aka prostigmin

quaternary amine

big + charge doesn't cross BBB

prototypical drug

Front 209

physostigmine

Back 209

aka eserine
slowly reversible inhibitor - carbamate inhibitor of acetylcholinesterase

tertiary amine = no + charge

can cross BBB = CNS effects

Front 210

carbaryl

Back 210

insecticide = seven dust and others

Front 211

donepezil

Back 211

aka aricept

CNS effects

tx of alzheimers plus other dementias

clowly reversible inhibitors of acetylcholine esterase - carbamate inhibitors

Front 212

organophosphate inhibitors - essentially irreversible

Back 212

produce a very stable phosphorylated enzyme intermediate of acetylcholinesterase

- echothiophate
- nerve gas
- parathion
- malathion

Front 213

echothiophate

Back 213

aka phospholine

used in treatment of glaucoma - not systematic

organophosphate inhibitors: essentially irreversible

Front 214

nerve gases

Back 214

organophosphate inhibitors: essentially irreversible
- safrin
- VX series
- tabun
- soman
= really toxic
how the organophosphate inhibitors - how they were derived

Front 215

Parathion

Back 215

organophosphate inhibitors: essentially irreversible

- insectiside

converted to active metaboline paraozone - agriculturally

Front 216

malathion

Back 216

insecticide also transformed in vivo -cyt P450

organophosphate inhibitor - essentially irreversible

degraded by carboxylesterases in plasma

degradation much more rapid in mammals and birds than in insects

safer insecticide than parathion
= head lice = topical

Front 217

cholinesterase reactivators

Back 217

pralidoxime (2-PAM) (protopam)

reactivates acetylcholinesterase after organophosphate inhibition

phosphorylated enzyme can age and make reactivation ineffective

+ charge pulled into active site = only used w/toxicity

aging -diff rates over time after PO4 => conformation changes => permenant PO4 = reactivated or no longer effective

Front 218

specific effects of acetylcholinesterase inhibitors

Back 218

1. parasympathomimetic effects
- eye - miosis, decreases intraocular pressure
- GI - increase activity
- increase glandular secretion

2. nicotinic activation
- activate receptors at autonomic ganglia - excitation followed by inhibition due to nicotinic depolarization block
- nicotinic response at skeletal mm - first inc mm cont then produce depolarization blockade

3. CNS:: activation followed by depression at higher doses = medullaryparalysis = seizures = coma

4. CV - complex effects related to activation at postsynaptic parasymp sites and activation of both sympathetic and parasymp ganglia = decrease CV

5. increase sweat gland activity

Front 219

Six main therapeutic uses of cholinesterase inhibitors

Back 219

1. eye treatment of glaucoma
2. GI/Urinary
3. Myasthenia gravis
4. reversal of neuromuscular blockade
5. treatment for intoxication with muscarinic antagonist
6. treatment for alzheimers dx

Front 220

eye tx of glaucoma w/acetylcholinesterase inhibitors

Back 220

action - increase Ach which contracts ciliary mm,
= frees entrance in canal of schlemm and increases outflow of awueous humor like muscarinic agonists

Ache inhibitors also contract sphincter (circular) mm to induce miosis

organophosphate acetylcholinesterase inhibitor - echothiophate
- longer acting
0 higher risk of developing cataracts
- use alternatives ineffective

- carbamate acetylcholiinesterase inhibitor = physostigmine

Front 221

GI/urinary treatment w/cholinesterase inhibitors

Back 221

atony of intestinal tract and urinary bladder smooth mm

tx of abd distension - several causes
- postop
- paralytic ileus
- postop dysuria
- atony oof bladder detursor mm

NOT when obstruction present, peritonitis, powel biability in questoin

Front 222

Myasthenia gravis tx w/cholinesterase inhibitors

Back 222

weakness and fatigability of skeleal mm: Autoimmune response decrease the apparent number of nicotinic receptors at the neuromuscular junction

diagnosis = edrophonium test
- an improvement in strength indicates myasthenia gravis
- a further decrease in strength = cholinergiic chrisis

tx= neostigmine = NO CNS effects

- tolerance should develop to muscarinic side effects - giving a muscarinic antagonist can block signs fo toxicity from cholinesterase inhibitor

Front 223

treatment for intoxification w/muscarinic antagonist
w/ cholinesterase inhibitor

Back 223

reverse effects of muscarinic antagonist (atropine) or other drugs w/ antimuscarinic activity = tricyclic antidepresents, phenothiazines, some H1 receptor antagonist

tx of choice = physostigmine counteracts antimuscarinic CNS - controversial tx + peripheral effects

Front 224

tx of alzheimers w/ cholinesterase inhibitor

Back 224

tacrine
realy doneprezil

mosot effective in early stages

Front 225

toxicology of cholinesterase inhibitors

Back 225

sx of intoxication = muscarinic, nicotinic and CNS signs
SLUDGE BAM = muscarinic signs

S= salivation, sweating
Lacrimation
Urination
Defecation
Gastrointestinal cramps
Emesis

Bronchoconstriction.bradycardia
Accomodation spasm - abd distress
Miosis ( mm twitches -fatigue - nicotinic

Nicotinic - twitches --<>fatigue -> weakness --> paralysis

death = resp failure w/ secondary cardiovascular problems

tx = atropine to reverse muscarinic effects
- supportive - remove exposure, maintain respirationalleviate convulsions treat shock

[ra;odpxo,e = pm;u wprgamp[jps[jate
= reactivator or long duration of supportive coma

delayed neurotoxicity = peripheral neuropathy due to organophosphate cholinesterase inhibitore=s
-- demyelination leads to paralysis, esp at low distal mm of extremities - fingers, toes, hands,, feet

Jake leg - jamaican ginger 0> lots of etoh

Front 226

muscarinic antagonist actions

Back 226

competitive antagonists at muscarinic receptors
can be over come w/sufficient Ach

Not all muscarinic response are equally sensitive
- decrease in salivary gland, sweat gland, bronchial secretions at lower doses tahn decreases in gastric secretions and GI motilit

Front 227

Belladonna alkaloids

Back 227

natural muscarinic antagonists
-blushing face dilated pupils

atropine
scopolamine

Front 228

atropine

Back 228

ebelladonna alkaloids = muscarinic antagonist

[atropine sulfate, belladona) prototypical

very specific muscarinici antagonist

CNS only in very high doses

Front 229

scopolamine

Back 229

muscarinic antagonist
belladona
more CNS effects than atropine

Front 230

synthetic muscarinic antagonists

Back 230

1. ipratropium bromide
glycopyrrolate

Front 231

ipratropium bromide

Back 231

synthetic muscarinic antagonist
atrovent

inhalent used for astmhma tx
altered so NO CNS effects

Front 232

glycopyrrolate

Back 232

aka robinul
synthetic muscarinic antagonist

quaternary ammonium compound

doesn't cross BBB

systemically used

Front 233

special effects and uses of muscarinic antagonist

Back 233

1. CNS
2.opthalmologicall
3. CV
4, respiratory
5. GI tract
6. urinary tract
7.sweat glands and temp
8. toxicological uses ts

Front 234

CNS effects and uses of muscarinic antagonists

Back 234

atropine
- high doses - impaired cognition and CNS excitation = restlessness, irritability disorientation, hallucinations, delirium

very high doses
- deporession cop medullary paralysis

scopolamine - more CNS effects than atropine
- drowsiness euphoria, amnesia, fatiugue, dreemless sleep w/decreased REM at therapeutic doses = pre-anesthtic

uses [
parkinsonism
motion sickness- vestibular effects
transderm scop = transdermal patches = straignt to site of action

pre anestehesia - sedation = dec respiratory secretions protect heart from vagal stimulation

scopolamine- more potent as a sedative

Front 235

opthalmological uses and effects of muscarinic antagonists

Back 235

pupil dilation; mydriasis
- paralyze accommodation, cycloplegia= used for eyeexam
- causes photophobia and blurred near vision n- complete paralysis
- increase intraocular pressure = ppt acute attack of angle closure glaucoma

uses = diagnostic
- refraction, intraocular exams and surgical rocedures

agents vary in duration of mydriasis and cyclopegia theyinduce

atropine sulfate max min - 30-40min
recovery 7-10 days
max time for cyclpegia -1-3 hrs
recovery 7-12 days

Front 236

cardiovascualr effects and uses of muscarinic antagonists

Back 236

effects - heart rate - uscarinic blockade at SA node increases heart rate

circulation- atropine flush - belladonnas and tachycardia due to parasymptone - always true for antagonists to parasymp is diminished

uses - clinical uses limited
- reverse cardiac effecs of muscarinic agonists
- special situations - acute myocardial infarction - halothane anesthesia

Front 237

respiratory effectas and uses of muscarinic antagonists

Back 237

effects - decresse airway resistance by relaxing bronchial mm and decrease mucous secretions

uses Ipratropium bromide
-inhalent for bronchial asthma
- intranasal for rinhorrhea

Front 238

GI tract uses and effects of muscariic antagonists

Back 238

Effects
- decrease tone, decrease the ampliude and frequency of peristaltic contractions
- decrease gastric and salivary secretions

uses
- antispasmodics for treating spastic or irritable bowel
-decrease excessive salivation
- gi effects require high doses which are assoc w/many side effects not related to GI tracts

GLYCOPYRROLATE

Front 239

urinary tract uses and effects of muscarinic antagonists

Back 239

effects = decreases tone and contractipon of bladder, ureters
usees - to inc urinary retention or capacity
- enuresis in kids = bed wetting
- can induce urinary retention in elderly men w/prostatic hyperplasia = precuation

Front 240

sweat glands and temperature effects of muscarinic antagonists

Back 240

small doses decrease sweat glandactivity - symp chol very pronounced in kids
- large doses increase body temp
= atropine fever

Front 241

toxicological uses of muscarinic antagonists

Back 241

atropine used to treat poisoning from achesterase inhibitors muscharinc agonists and some mushroom species

Front 242

toxicology of muscarinic antagonist symptoms

Back 242

1. paralysis of parasymp innervated organs
2. dry mouth
3. mydriasis//cycloplegia
4. hot, dry skin w/flushing
5. constipation
6. urinary retention
7. tachy
8. CNS impaired cognition, excitement, hallucinations, restlessness

Front 243

drugs that have antimuscariic side effects

Back 243

tricyclic antidepressants
phenothiazines (antipsychotics)
H1-receptor antagonist(antihistamines)

Front 244

therapy for toxicity of muscarinic antagonists

Back 244

children and elderly esp susceptible to toxic effects

many cold remedies have drugs w/antimuscarinic effects

Front 245

therapy for muscarinic antagonists

Back 245

achesterase inhibitor = physostigmine - controversial therapy that also revereses CNS effects

diazepam for convulsions

supportive - maintain respiration, decrease fever

Front 246

nicotinicotinic agonists actions

Back 246

receptor agonists = nicotine

actions
1 . at autonomic ganglia - nicotine causes stimulation followed by depression due to depolarization block

2. specific effects depend on which branch of autonomic system takes precedence at each organ
- stimulates CNS - tremors, convulsions, vomiting

= CV = increase heart rate, increase BP
--> due to stimulation of symp ganglia (vasoconstriction and release of catecholamines from adrenal medulla

GI tract - increase tone and activity: nausea, vomiting diarrhea

exocrine glands - stimulates then depresses salivary and bronchial glands

Front 247

uses of nicotine agonists

Back 247

nicotine patches and nicotine gum as aids for cessation of smoking

Front 248

nicotinic antagonists - selective ganglionic blockers

Back 248

completitively antagonize nicotinic receptors at autonomic ganglia

- nicotinic receptors at autonomic ganglia and neuromuscular junction are different

differentiated using series of compounds w/basic structure N- 3 methyls - carbon chain to N - 3 methyls

ganglionic nicotinic receptors antagonized best by compound where n= 6 = carbon chain between N's consist of 6 C = hexamethonium

neuromuscular nicotinic receptors antagonized best by cmpd where n=10 =decamethonium

specific ganglionic blockers (mecamylamine) not very useful therapeutically

Front 249

effects of ganglionic blockade by nicotinic antagonists selective ganglionic blockers

Back 249

1. block adrenergic control of arterioles
= vasodilation = decreased BP
= postural hypertension

2. block parasympathetic control of GI/urinary tracts, eyes and glands
- decrease tone of GI bladder - constipation - urinary retention
- cycloplegia - mydriasis
- decrease glandular secretion

block sympathetic control of sweat gland activity

Front 250

therapuetic uses of nicotinic antagonists-selective ganglionic blockers

Back 250

once used in prod of controlled hypotension in surgical/emergency situations
==therapeutic use is limited and compounds have been replaced by better drugs

tourette's syndrome (mecamylamine)

Front 251

nicotinic antagonists - neuromuscular blockers actions

Back 251

1. 2 main types
a. competitive or nondepolarizing blockers
b. depolarizing blockers

2. both types block neurotransmission at the neuromuscular jnct via binding to nicotinic cholinergic receptors
= side effects result from binding to nicotinic ganglionic receptors and/or muscarinic receptors (esp cardiac)

competitive and depolarizing compounds inhibit neuromuscular activity in different mechanisms

Front 252

nicotinic antagonists neuromuscular blockers

competitive or nondepolarizing neuromuscular blockers

Back 252

d-Tubocurarine (curare) = prototype
atracurium
vecuronium

competitively antagonize the actions of Ach at neuromuscular nicotinic receptors

induce flaccid paralysis w/o prior mm fasciculations

paralysis progresses from small rapidly moving mm (eyes,fingers,) => limbs, neck trunk --> intercostals and diaphragm --> resp paralysis

Front 253

d-tubocurarine

Back 253

nondepolarizing drug - nicotinic antagonists neuromuscular blockers

long acting non-depolarizing blocker

onset 5 min
duration 60-120 min
prolonged duration results from renal impairment
quaternary ammonium cmpds

- limited lipid solubility
no CNS effects
oral admin = not effective

side effects = block ganglionic nicotinic receptors and histamine release
- decrease BP

newer generation nondepolarizing blockers differ in side effects

Front 254

general characteristics neuromuscular blockers - nicotinic antagonists w/intermediate duration of action

Back 254

onset 5 min or less

duration 30 min

not as sensitive to renal imp as long-acting drugs

reduced CV effects

Front 255

atracurium

Back 255

[tacrium]

nicotinic antagonist - neuromuscular blocker

undergoes spontaneous in vivo degradation = Hofmann elimination

safer in pt w/renal impairments

degradation to laudanosine = build up of this product can increase seizure susceptibility

Front 256

vecuronium

Back 256

[norcuron]

intermediate duration of action

second generation of steroid derivative

Front 257

reversal of neuromuscular blocade w/non-depolarizing blockers

Back 257

reversal decreases postop period

Ach-esterase inhibitors reverse nondepolarizing neuromuscular blockade (neostigmine, edrophonium)

muscarinic antagonist glycopyrrolate prevents muscarinic effects of cholinesterase inhibitor

Front 258

Succinylcholine

Back 258

depolarizing neuromuscular blocker
nicotinic antagonist

bind to neuromuscular nicotinic receptors opens a receptor gated channel in membrane

resulting membrane depolarization is sustained = channel remains open
depolarized membrane can no longer respond to Ach

=> depolarizing blockade called phase I blockade which cannot be reversed by inc Ach levels w/cholinesterase inhibitor

rapid onset - 60 sec
brief duration 5 min
hydrolyzed by pseudocholinesterase (butyryl cholinesterase)
- prolonged response results from pseudocholinesterase
- inhibition or presence of atypical pseudocholinesterase causes increased potassium levels - hyperkalemia - increased intraocular pressure, increased intragastric pressure

mimics Ach at cardiac muscarinic receptors to cause cardiac dysrhythmias
- useful in facilitating tracheal intubation

Front 259

side effects of neuromuscular blocker - nicotinic antagonist

Back 259

1. effects at autonomic ganglia
effects on cardiac vagus histamine release
increased potassium release (hyperkalemia - succinylcholine
CV effects of neuromuscular blockers result from a combination of effects at autonomic ganglia at cardiac muscarinic receptors and due to histamine relase

Front 260

sympathomimetic amines

Back 260

mimic the actions of epi and norepi

catecholamines - cotain a catechol group
1. norepi
2. epi
3. dopamine

direct acting - activate adrenergic receptors

indirect acting - increase release or block reuptake of norepi = requires presence of endogenous neurotransmision

Front 261

synthesis of norep and epi

Back 261

1. tyrosine --> DOPA via tyrosine hydroxylase (rate limiting enzyme

2. dopa-->dopamine via aromatic amino acid decarboxylase (AAAD or doap decarboxylase

3. dopamine is transported into synaptic vesicles by an active carrier

4. dopamine --> norepi in synaptic vessicles by dopamine beta hydroxylase

5. in adrenal medulla norepi is converted to epi

Front 262

compounds that block syn of norepi

Back 262

1. metryrosine = inhibits tyrosine hydroxylase

2. reserpine blocks carrier for catechols into vesicles

Front 263

metyrosine

Back 263

alpha methyltyrosine

inhibits tyrosine hydroxylase blocking the synthesis of catecholamines

decrease in sympathetic tone

Front 264

reserpine

Back 264

blocks carrier for catechols into vesicles and depletes neurotransmitter stores

- the depletion of NE stores and destruction of storage granules = decrease in symp fn
1. CNS reserpine depletes NE, erotonin 5HT and dopamine == side effect severe sedation or major depression - monamine hypothesis for depression

side effects:
= increase tone and motility of gut causes gastric acid secretion = unapposed parasymp
= severe sedation and major depression

USE = antihypsertensive

Front 265

drugs that increase release of NE

Back 265

release by calcium dependent exyocytosis

amphetamine
tyramine in foods

uptakein into presynaptic terminal via reuptake site => stimulate the release of NE

tyramine in foods = fermented foods like cheese, wine, sausages, first pass effect = monamine oxidase A in liver => not in circulation

amphetamine cross BBB serotonin and dopamine = indirect acting sympothemetic

Front 266

drugs that decrease release of NE

Back 266

guanethidine

Front 267

guanethidine

Back 267

decrease release of NE taken up by reuptake system
1. block release of NE from neurons
2. deplete NE stores
= decrease in sympathetic fn

USe = antihypertensive

contraindication
= HTN from pheochromocytoma = exacerbates BP due to competition w/ epi/NE at reuptake

Front 268

drugs that inactivation of andrenergic effects

Back 268

1. reuptake = major route of inactivation
- blocked by ticyclic antidepressants and cocaine

2. metabolism via MAO and COMT
- MAO-A in mito in presynaptic terminals
- inactivates NE, EPi, herotonin, tyramine
- MAO-B -= in CNS and inactivates dopamine

COMT inhibitors = Tolcapone =- increase nt NE and DA levels

Front 269

MAO inhibitors

Back 269

phenelzine and tranylcypromine
= inc nt levels in presynaptic terminal available for release
= cheese effect = consuming tyramine containing foods w/MAO-A inhibitors = hypertensive chrisis = whole bunch of NE released

Front 270

adrenergic receptor agonists

Back 270

sypathomimetics

pharmacological effects of adrenergic receptor agonists predicable from physiologic effects of adrenergic receptor stimulation

B1 activation increases all cardiac fn
= inc HR, SV, AV- conduction, and automaticity

A1 = contracts smooth mm
- Vascular
- radial mm eye
- vas deferns

B2 - relaxes smooth mm
- vascular
- uterine
- bronchial

Front 271

direct acting alpha receptor agonist

Back 271

phenylephrine = a1

A2
- clonidine
- methyldopa = prodrug (alpha methylnorepinephrine
- brimonidine

Front 272

phenylephrine

Back 272

alpha 1 sepelctive agonist
aka Neosynephrine

effects:
- CV = vasoconstriction = inc TPR = inc diastolic BP and reflex dec HR
- Occular = inc outflow of aqueous humor from eye and decrease intraocular production
- contract radial mm of eye = mdriasis

uses
- decongestant
- hypotension
- ocular xams reqmydriasis and glaucoma tx

side effects
- mydriasis w/p cycloplegia
- hypertension

Front 273

clonidine

Back 273

catapress
CNS
alpha 2 selective agonist

decrease release of NE from presynaptic terminals

Front 274

Methyldopa

Back 274

prodrug for A2 agonist
active metabolite = alpha-methylnorepiniephrine

effects - CNS actions of alpha 2 agonists cause withdrawl of symp tone, decreased TPR and decreased diastolic BP

USE - antihypertensives

Front 275

brimonidine

Back 275

a2 agonist
iophthalmic for glaucoma
activation of Gi decreases in cAMp - dec prod of aqueous humor from ciliary body = inc outflow as well

Front 276

direct acting beta receptor agonists

Back 276

non-selective B1/B2 - isoproterenol

B1 selective = dobuamine

B2 selective
- albuterol
- salmeterol
- ritodrine

Front 277

Isoproterenol

Back 277

aka isuprel
non-selective b1/b2 agonist

B1 stimulation = inc HR and SV = inc CO = inc systolic BP

B2 stimulation = vasodilation of skeletal mm beds = decrease TPR and dec diastolic BP
- bronchodilation
- relax uterine mm

Front 278

dobutamine

Back 278

dobutrex

B1 agonist

B1 = inc HR and SV = inc CO = inc systolic BP

used for tx of acute CHF

Front 279

albuterol

Back 279

b2 agonist
proventil

bronchodilation

asthma

side effect - tremors at rest = B2 acting at spindles

Front 280

salmeterol

Back 280

serevent w/fluticasone = advair

long acting B2 agonist

bronchodilation
vasodilation of skeletal mm bds decrease TPR and reduces diastolic BP

for asthma
not used alone but in combo with other drugs
b/c doesnt treat inflammation if used along = worse long term

side effects - resting tremors - B2 acting at mm spindles

Front 281

ritodrine

Back 281

yutopar
B2 agonist

vasodilation of skeletal mm bed = dec TPr = dec diastolic BP
relax uterine smooth mm

use = tocolyitic
= termination of preterm labor
systtemic prep
-practice not very effective
maternal/fetal outcomes not great

side effects = resting b2 tremor acting at mm spindles

Front 282

mixed acting adrenergic receptor agonists

Back 282

act at alpha 1 and beta receptors

beta receptors are more sensitive to them than alpha

low doses = beta = vasodilation = dec TPR = dec diastolic BP

higher doses = alpha = inc TPR = inc BP = reflex dec in HR

norepi
epi
dopamine

Front 283

norepi

Back 283

levophed
A1, A2, B1 agonist
no effects at B2

A1 = vasoconstriction = inc TPR = inc BP = relfex dec HR

B1 = inc HR and SV = Inc CO = inc systolic BP

ocular A1 = mydriasis w/o cycloplegia
= decreased intraocular pressure because increased outflow of humor

USE = hypotension - cardiogenic shock

side effects = severe local ischemia and necrosis w/subcutaneous application

Front 284

epi effects

Back 284

adrenaline chloride etc

A1, A2, B1, B2 agonist
dose dependent CV effects

low dose = looks like isoproterenol =
B1 = inc HR and SV = inc CO = inc systolic BP
B2 = relaxation of vasculature = dec TPR = decrease diastolic BP

higher dose
B1 = inc HR and SV = inc CO = inc systolic BP
A1 = vasoconstriction = inc TPR = inc diastolic BP = reflex dec HR

occular effects A1 = mydriasis w/o cycloplegia and dec intraoccular pressure = inc outflow of humor

resp = b2 stimulation = bronchodilation

Front 285

epi uses

Back 285

1. hemostasis for surgery = constriction of smooth m vasculature

2. reduce diffusion of local anesthettics = local application

3. heart block/cardiac arrest = helps redistribute blood flow

4. bronchial spasms

5. anaphylaxis = bronchospasm, mucous congestion, angioedema, CV collapse B1 activation of heart and A1 to maintain BP

6. mydriasis = ocular exams and open angle glaucoma = dipiven prodrug for epi

Front 286

epi side effects

Back 286

CV
- hypertension
- angina
- cardiac arrhythmias

CNS
- fear
- anxiety
- resltessnes
= local effects mimic fight or flight does not cross BBB well

Intraocular
- mydriasis
- stinging
- hyperemia

Front 287

dopamine

Back 287

D1, B1 in moderate doses and a1 in high doses agonist

low dose
- D1 stimulation - vasodilation in renal and mesenteric vascular beds = inc urine flow

moderate doses = D1 + B1
- D1 = vasodilation in renal and mesenteric beds
- B1 = inc HR and SV= inc CO and inc systolic BP

High doses = A1 and B1
= looks like NE

USE = moderate doses in cardiogenic shock

Front 288

epinephrine reversal

Back 288

differentiating high dose epi from NE

in presence of A1 antagonist effects of Epi go from hypertensive (pressor to hypotensive (depressor response due to unmasking of the B2 effect

Not case in NE

Front 289

beta 1 agonists and heart

Back 289

increase HR and SV = inc CO = inc systolic BP

= increase BP = triger baroreceptor reflex = dec HR
= blocked b nicotinic ganglionic blocker

Front 290

what is the driving force behind epi's increase in BP

Back 290

alpha 1 = inc TPR

Front 291

amphetamine

Back 291

taken up into presynaptic terminals via reuptake system and release the presynaptic stores of NE

increase catecholamine release NE, serotonin, dopamine in CNS

CNS stimulant
- increased attention
- increased mood
- insomnia
- euphoria
- anorexia

used to tx
- ADHD
- narcoplepsy
- appetite suppressant

Front 292

Tyramine

Back 292

increase NE release - taken up into presynaptic terminals via reuptake system

found in fermented foods - cheese, red wine, bear

- metabolized by first pass biotransformation by MAO=A in liver

- inc release of catecholamines and produces NE- llike effects

- effects magnified by MAO inhibitors cheesy effect =htn crisis

Front 293

cocaine

Back 293

blocks catecholamine reuptake

CNS stimulant
- inc NE, serotonin and DA in CNS

uses - local anesthetic

Front 294

tricyclic antidepressants

Back 294

block catecholamine reuptake

Front 295

Tranylcypromine/phenelzine

Back 295

parnate/nardil

inhibit both MAO-A (NE, serotonin, tyramine metab) and MAO-B (dopamine metab)

use -= anti-depressant

precaution = Avoid foods containing tyramine = hypertensive crisis

Front 296

Selegiline

Back 296

eldepryl

inhibits MAO-B only increases dopamine in CNS

tx of parkinson's dx

Front 297

Tolcapone

Back 297

tasmar

blocks COMT
inc dopamine in CNS

adjunct tx in parkinsons

Front 298

general side effects of adrenergic agonists

Back 298

1. Inc BP
- headache
- palpitations
- cerebral hemorrhage
- pulmonary edema

2. inc cardiac workload
- angina
- MI

3. cardiac arrhythmias

4. CNS stimulation

5. NE = marked ischemia nad necrosis w/subcu application
occur during IV admin
- reversed w/alpha antagonist

Front 299

warnings/precautions of adrenergic agonists

Back 299

1. hyperthyroidism = inc in efficacy of betaq receptors = more stimulated esp at heart = rapid heart rate

2. severee HTN

3. heart dx = angina, CHF - inc HR but makes heart less effective

4. halogenated hydrocarbons halothane - sensitize heart to sympathomimetics = cardiac arrhythmias

Front 300

alpha adrenergic antagonists

Back 300

blocks:
contract smooth mm
- vascular
- radial mm
- vas deferens
- prostrate

CV = dec TPR = dec BP = reflex inc in HR
postural HTN

block at presynaptic alpha 2 = inc NE release from terminals = more tachycardia

uses = block NE/epi effects on smooth mm of vascular system and prostate

- miosis
- nasal congestion
- decrease resistance to blood
- inhibits ejaculation

Front 301

nonselective alpha adrenergic antagonists

Back 301

1. phentolamine = competitive alpha 1 and A2 antagonists
2. phenoxybenzamine = noncopetative = lond duration - irreversible block

used to tx pheochromocytoma = preop management of catecholamine secreting tumor

Front 302

prazosin

Back 302

selective alpha 1 receptor antagonist

prototypical drug

A1 block decreases TPR decrease BP = rflux inc in HR
= bock of symp effects on smooth mm of prostate

use
= antihypertensivie
= BPH
= reverse vasoconstriction induced by NE

side effects
- miosis
- nasal congestion
- inhibit ejaculation

Front 303

beta adrenergic antagonists

Back 303

block B1 = activation of CV = dec HR, dedc SV, AV-cond and automaticity

block B2= relaxation of smooth mm -= vascular, uterine, bronchial

blocks symp metabolic/endocrine effects
blocks beta mediated renin release
inhibits stimulation of glycogenolysis B2
blocks production aqueous humor = decrease intraoccular pressure

Front 304

competitive B1 and B2 receptor antagonist uses

Back 304

propranol - protatypical
timolol = mostly used to tx glaucoma

uses
1. antihpertensive
2. ischemic heart dx
- reduce episodes of angina
- decrease O2 demand
- improve survival after MI 25-30%
3. cardiac arrhthmias
- decrease SA node activity and slow AV conduction

4. hyperthyroidism
- block effects of symp stimulation of heart
- inhibits deiodiase activity blocking conversion of T4 (thyroxine) to triiodothyronine (T3)

5. essential familial tremor = block B2 activation of mm spindle afferents

6. prevent performance anxiety (social phobias)
- block somatic sx of sympathetic activation

7. prevent migranes - CNS effect

8, tx of open angle glaucoma - intraocular timolol

Front 305

competitive B1 and B2 receptor antagonist effects

Back 305

effects =
1. antagonize symp stimulation of heart
2. block renin release
3. dec BP
4. block prod of aqueous humor = dec intraocular pressure

Front 306

competitive B1 and B2 receptor antagonist side effects

Back 306

1. bronchoconstriction
2. block symp responses assoc w/hypoglycemia
3. CNS - sedation, sleep disturbances (night mares), depression
4. chronic admin may shift plasma levels = inc VLDL and dec HDL
5. rapid discontinuation after chronic use not recommended due to receeptor up regulation

Front 307

pindolol

Back 307

partial agonist at Beta adrenergic receptors

- sim effects as beta adrenergic antagonists
- less effects on plasma lipids

- less receptor -up regulation

- increased exercise reserve

Front 308

carvedilol

Back 308

blocks B1, B2, and A1 receptors

effects sim to beta adreneric antagonist + decrease in BP due to A1 block
- inc efficiency of heart

use = antihypertensive
- CHF

Front 309

beta1 seective antagoinsist

Back 309

cardio-selective
metoprolol
atenolol = less CNS effects, renal excretion - so safe for liver prob pt

effects - competitive antagonist at B1 receptor
- block slymp stimulation of heart
- less bronchoconstriction than non selective blockers
- less influence on glycogenolysis and insulin release

use - antihypertenisvie
- ischemic heart dx
- cardiac arrythmias

Front 310

general side effects of beta adrenergic antagonist

Back 310

1. bronchoconstriction - less w/metoporolol than with atenolol
2. CNS sx
= sedation
- sleep disturbances
- depression
- less w/atenolol
3. chronic admin -= plasma lipids shift - inc in VLDL and dec in HDL

Front 311

precautions w/beta adrenergic antagonists

Back 311

1. asthma or obstructive airway dx
2. CHF = although some used to tx
3. depress myocardial contractility and excitability - remove symp drive
4. diabetes mellitus
- block compensatory symp responses induced by hypoglycemia - symp stimulation of glucose release
-blocks ability of pt to recognize hypoglycemia

rapid discotinuation after chronic use dangerous b/c receptor upregulation
- severe inc in HR and change in BP

Front 312

glaucoma tx

Back 312

Agents that increase the outflow of aqueous humor

1. muscarinic agonists = pilocarpine
- cholinesterase inhibitos - echothiophate and phsostigmine

= act by contracting cilliary mm and inc outflow
side effects - spasm of accomodation

2. sypathomimetic = dipivefrin, epi
- inc outflow
side effect = mydriasis, but vision unaltered
- adenochrome
-stinigng and hyperemia

3. prostaglandin = latanoprost
-inc outflow
side effect = brown pigmentation of iris
- blurred vision
- stinging and hyperemia
- keratopathy
- foreign body sensation

AGENTS THAT DEDREASE PROD/SECRETION OF HUMOR

1. beta adrenergic antagonists = Timolol
dec prod and secretion
side effect = bronchospasm/bradycardia

2. A2 agonist = brimonidine
- decrease prod and increase outflow
side effect = dry mouth, ocular hyperemia and stinging
- headache
- foreign body sensation

3. carbonic anhydrase inhibitor = dorzolamide
- decreased prod
- side effects - occular stinging
= mild keratitis
= biter taste
4. hyperosmotics = systemic mannitol
- systemic tx
-for emergency - attack of angle closure glaucoma

Front 313

uses of nicotinic antagonist of neuromuscular blockers

Back 313

1. provide optimal surgical working condition s b/c - cannot subs for anesthetics
- reduces amt of general anesthetic required
- relaxes mm of abd wall 2. f

2. facilitate intubation of trachea
- succinylcholine due to brief duration
3. mm relaxant for orthopedic procedures
4. decrease muscular component of electroshock therapy

Front 314

other drugs that can enhance neuromuscular blocade from nondepolarizing blockers

Back 314

1. inhalant anesthetics
2. local anesthetics
3. abx
- aminoglycosides
- tetracycline enhance actions of nondepolarizing blockers

Front 315

toxicology of neuromuscular blockers

Back 315

overdose sx
- prolonged apnea
- CV collapse
- histamine release

tx
- maintain respiration
cholinesterase inhibitor + atropine for nondepolarizing blockers (revrese neuromuscular blockade

precautions/contraindication
-asthmatics
trauma (burn) pts ( succinylcholine)

malignant hyperthermia
- cuccinylcholine _ inhalant anesthetics
Datrolene = to control hyperemia
-sarcoplasmic reticulum Ryanodine blocks camplcium release

Front 316

comparison of depolarizing and nondepolarizing neuromuscular blockers

Back 316

onset and duraition
- nondepolarizing - slower onset / longer duration
depolarizing - fast onset brief duration

2 response to tetanic stimulation
nondepolarizing - TE reverses block
depolarizing - TE cannnotreverse block