Pharmacodynamics

11/28/2014 1:50:00 PM

Dose-Response Relationship:
The relationship between the size of administered dose (Milliliters,
Milligrams, Grams) and the intensity to the response to the drug.
What determines the dose response? The minimum amount of drug
to use.
o So drugs are not equivalent (Equal). Some may use 0.25mg
of digoxin and 500mg of metformin. It depends on the nature
of the drug.
o It is determined by the maximum response elicited, and how
much increase is needed to produce the desired increase in
response.
o The dose of the drug and in relationship to how the body
responds to the dose of that drug.
Phases of Dose-Relationship Response:
Phase 1: Doses are too low to elicit a clinical response
o Not to say even a therapeutic response, but a response at all.
o If you took 81 mg of aspirin today, I really wouldnt do much
for you. Prolong a few platelet clots for you but not much of a

response.
Phase 2: The response is graded on a graphTherapeutic level
Phase 3: Higher doses do NOT cause much response but can cause
toxicity.
o More is not always better.
o Higher doses do not always cause much response but they
can cause toxicity.
o Some higher doses do not cause an effect at all.
For example: Hydrochlorothiazide, we use to give 50 mg

Efficacy:

of that but after studies, we found that 25 mg its

maxed out. So giving 50mg didnt make a use at all.
So in this case, more doesnt do anything besides
putting more drugs inside someones body for not good
reason.

How effective a drug at a given dose is at eliciting the desired

response.
Maximum efficacy-largest effect a drug can produce.
o Does it mean that it is the highest dose of the drug? NO.
Whats the trick? We want desired effect with least adverse effect.
o I want to achieve my therapeutic effects with the tiniest dose
I can.
Do you always want highest efficacy? YES. ALWAYS.
o Because it means that drug is really doing its job.
o So the more efficient and accurate drug is at producing its
desired effect Thats the drug you want.
o So if we can achieve high efficacy with a small dose, with no
great side affects of adverse events, thats the drug you want
for that problem.

Potency:
Amount of drug (mg, g, units etc.) needed to elicit a response.
Drug A is more potent than Drug-B, which drug has a higher dose?
A or B? Drug B. Less potent, takes more of it. The more potent, the

lesser dose.
A more potent drug is not always more therapeutically effective
o Whats another term for therapeutically effective that we just
learned? Efficacy.
Whats more important-potency or efficacy? Efficacy.
We want the drug to be most efficient, we arent worried about how
much. Now in most cases, the drugs on the market will not be in a
form that takes it to be in a toxic level for it to work, then we
wouldnt be able to use it, but there are a few drugs that use that.
Potency: A highly potent drug for instance (morphine, alprazolam,
chlorpromazine, Ativan, Xanax) gives a large response at low
concentrations, compared to a drug of lower potency, for ex.
Ibuprofen, acetylsalicylic acid) evokes a small response at low
concentration. It is proportional to affinity and efficacy.
o What makes for a potent drug? Affinity

o Efficacy relates to the nature of the drug and the attraction

for the receptors, how attracted, how specific is it for those
receptors. How well does the drug work at dose X.
Drug Receptors:
Control normal body processes
Normally controlled by endogenous substances (coenzymes,
hormones, histamines) that attach to our receptors
Drugs either:
o Mimic endogenous substances (Agonist)

Mimic something me make, we would name that type of

drug an agonist where it acts like something we make.
Now if Im agonist, and still sit on a B1 receptor, and if
they made me look like the endogenous substance that
would stimulate the B1then I would stimulate the B1.

Block action of endogenous substances (Antagonist)

o Can block the action of something we make that would be an
antagonist.
o It keeps them from binding to something we make.
o If I am drug is a Beta-blocker, and there is a beta 1 receptor
near me, and Im a B1 blocker, I am going to sit on that B1
receptor and now it cant come. So the B1 effect is not
achieved because Im sitting there on its receptor
ANTAGONIST.
Is drug binding to receptors reversible? Yes.
Drugs do not cure: drugs treat symptoms, kill organisms, and hope
the person gets better, but that is not a cure.
Drugs have molecular structures that are similar to endogenous
substance.
o Many drugs have similar chemical properties that look like
things we make
Drugs and their endogenous counterparts exert their action by
binding to a function macromolecule on a cell (receptor)
o They can either be taken inside the cell, like insulin, takes
things inside the cell and pops out, or on the outside of a

receptor, like sitting on an outside of the cell. Whether it be

on the inside or the outside of the cell, I can either occupy the
position and act like what that receptor is suppose to doing, I
can either stimulate it or block it.
When competing with endogenous molecule, drugs may bind to
several different receptors besides intended site (Especially if it not
very selective)
o This is a problem but very common.
o Carvedilol: Beta-blocker: Non-selective. It will get on B1 and
B2. It will get on receptors its not suppose to be.
o There are a lot of drugs like this. Some are very specific for
specific receptors and they dont make side effects of getting
on other receptors.
o When drugs are not selective, and get on other receptors, this
is what causes side effects (unwanted effects)
Antihistamines: make use sleepy because they jump on
other receptors that affect our sleep

Simple Occupancy Theory:

Intensity of a drug response is proportional to the number of

receptors occupied by the drug.
Max response is when all receptors are occupied.
o If I sit on a bunch of receptors, I can produce a big effect.
This is for both stimulation (agonist) or blocking (antagonist)
o Intensity depends on how many receptors a drug can occupy.
o THIS IS NOT POSSIBLE, in theory it is, but its not in reality.
o Plavix: (antiplatelet aggregation) Irreversible, the effect of
Plavix on a cell, is irreversible; this is scary because its
anticoagulant. Where is their receptor? On the platelets. Why
is okay for this to be irreversible? How quickly do you replace
your platelets? Every seven days because every day the
platelets are dying off because our cells turn over.
Assumes all drugs binding to a receptor to have same abilities to
bind and elicit response.
o This isnt true either, not all drugs bind the same, not all
drugs accept the drugs exactly the same.

Modified Occupancy Theory

Consider 2 characteristics of drug-receptor interactions
o Affinity
Strength of attractive between drugs and receptors
How strongly is my relationship to this receptor, if its
weak, then it may not sit on the receptor, but if the
attraction is strong, it will sit on every one of the
receptors it can. Weather its an antagonist or an
agonist.
Do you want high affinity? Yes
o Intrinsic activity What drug does on the receptor
Ability of drug to activate receptor after binding
I could sit here and be really strongly attracted to this
receptor but I could not really elicit an effect or I could
have A LOT of effect, it just depends.
Huge aspect of efficacy.
o Simple theory + explanation of how 2 drugs on same receptor
have different abilities.

Because one may have high affinity with little intrinsic,

or vice versa
Heparin: Antidote for HeparinProtamine sulfate
Vitamin K is antidote for: Coumadin

Affinity:
High affinity: Strong attraction
o If my drug molecule is that effective and that every receptor
it sees, it gets on, I can use a low dose drug. Why? Because

every receptor it sees its on there. HIGH AFFINITY.

Low affinity: Weak attraction
o Maybe it will sit there, maybe it wont, so you have to give
more molecules of the drug to occupy more receptors.
High Intrinsic Activity: Intense receptor activity. High MAXIMAL
efficacy.
o This is a good drug.

o High affinity and high intrinsic activity: Great drug,

small dose.
Low intrinsic activity: Weaker receptor activity-Lower efficacy
o Drug with low intrinsic activity, low affinity: BIG DOSE,
because it takes a lot of molecules of the drug to reach
your therapeutic effect because its kind of interested
in the receptor and if it does get on the receptor it will
do a little big of work but this means you have to
give a higher dose.

Post-Receptor Response:
Agonist:
o Activate receptors
o Mimic endogenous substance
o May bind to different receptors at different doses
Metoprolol: Selective: Its trait is to bind to beta 1
receptors and leave beta 2 receptors alone but in a
higher dose, it will spill over and go to the beta 2.
The higher the dose, the more receptors it will effect, if
its not really strongly affinity type of drug.
THIS IS WHAT SIDE EFFECTS ARE CAUSED FROM
because its affecting other receptors.
o Has both affinity and high intrinsic activity.

Antagonist:
o Block actions of endogenous substances of other drugs
Beta antagonist: What are be blocking when it says its
blocking a B1 receptor? Hypertension, increased heart
rate, vasoconstriction, vagal stimulationbut if Im
taking Metoprolol is blocking the normal function of that
receptor.
o Have affinity but dont have intrinsic activity
Pharmacological effects result from blocking post receptor
responses
No agonist: no pharmacological effect

Partial

Agonist:
Has moderate intrinsic activity
Maximal effect is lower than that of full agonist
Act as both agonist & antagonist
o May do a little bit of intrinsic activity, other main function is to
block more stimulation. Main job is blocking.
Elicit small response and also block other agonists
Administer alone= small response
Administer in large doses with another drug:
occupies receptors- blocks full agonist from
binding to receptor=lower response

Receptor Sensitivity
Receptor sensitivity is not constant
Number of receptors on cell is not constant
o This is why we get some affinity, some intrinsic activity, we
get some connecting between receptors and sometimes not, it
just depends.
Drugs may be selective to a receptor but produce nonselective

effects
o For example: Metoprolol: if I give it a big enough dose, it will
spill over and effect other receptors even though it is
selective.
That receptor may be responsible for several process drugs not
selective for process, only for receptor.
o Book lists some examples of these.
Continuous exposure to agonist can cause:
o Cell to be less responsive (Desensitize or refectory)

Overloaded, starts to shut off and doesnt respond

anymore until you give a bigger dose or add more drug.
What drug do you know that does this? Opioids.
AKA down regulation
Becomes tolerant
Nasal sprays: OTC with stimulants.
Patient is tolerant to drug
May need higher & higher doses

o Liver to produce more metabolizing enzymes to that drug

Therefore breaks it down quicker.
o Can happen quickly or slowly

Continuous exposure to antagonist can cause:

o The intrinsic property gets more active. More receptors are
even produced.
Receptor to become more responsive
Aka hypersensitive or super sensitive
More receptors are synthesized

ED50: Standard therapeutic response, 50% of the population

Receptorless Drug Response:
Some drugs do not act on receptors
Act through physical/chemical interactions
o Antacids
o Antiseptics-topical
o Laxatives

o Chelating agents Kayexalate

o Charcoal
Drugs that prevent absorption of fat in the gut
Prevent absorption of carbohydrates

Drug Interactions:
When more than one drug is taken by a patient, there is a risk that
the drug will conflict with each other by altering ADME.
o The more drugs, the more risk.

Risk increases with the number of drugs a person takes, including

OTC agents such as pain relievers, herbal supplements, and alcohol.
o People sometimes think that over the counter medications
dont do so much and do a lot of them and a lot of time the
OTC are in purer forms.

Drug-Drug Interactions

There is a linear relationship between the drugs taken and the risk
for a serious interaction.
o The average 65-year-old takes seven medications and has
about 70% risks for one or more drug-drug interactions.
Whats your job as a nurse? Is to look for those
interactions and knowing the nature of the drugs, you
have to pick out which drugs can really do them harm
and to prevent that, watch closely, vitals, lab work
(HUGE)imperative, check labs before give drugs.

Possible Interactions:
Intensifications of effects (Potentiation)We can mix two drugs that
enhance the effect of another drug, for example: when people come
in with high potassium, we can give them insulin in an IV with a D5
and move the potassium from the serum, and back into the cell.
o Increased therapeutic effects- AUGMNTIs Penicillin that
the organisms made some enzymes that would destroy the
penicillin. So the pharmaceutical company made
clavulanate, which would deactivate the organisms enzyme
and the penicillin, can do its job. So it prevent the organism
from making this destructor-compound so that the penicillin
could destroy cell wall and kill the organism.
o So Penicillin and Clavulanate is an example of two
drugs that can increase a therapeutic effect.
o There are many piggy backs that are combo drugs like this
because in the organism realm, they are constantly changing,
so the drugs change to fight them.
o Increased adverse effects- ASA/WARFARIN

Aspirin and Coumadin/Warfarin

What happens when we have somebody on these
two drugs? Why is it not good? They bleed,
interferes with the cascade of clotting factors.
Its not always bad, we do this all the time but
you have to watch it because we put them in a
tough situationso watch they can bleed out in
the gut, urine, stomach because its too much.

Reduction of effects (Inhibition)

o Reduced therapeutic effects-beta agonist/antagonist
For example: People who have asthma, and the are on
a beta-agonist (inhalers), it stimulates beta 2s in the
lungs, and it opens them up. If they are cardiac, and we
give them something to reduce their heart rate, for
example, or their blood pressure and we give them
Metoprolol or Carvedilol, then we got these two things
going on. So what do you think would be a warning on
the Carvedilol? You cant use a beta antagonist on
someone that has a reactive airway disease because we
fill them with this drug and they have a reaction, and
they have an asthma attack and they go to puff their
agonist(inhaler) who is sitting on that receptor?
Carvedilol. So theyre inhaling but someone is already
sitting on that BETA 2 receptor. So what happens to
their pulmonary tree? Stays constricted.
o Reduced adverse effects-naloxone/morphine
We give to much morphine and too much Talwin, we
put a lady one time in a hypoxemic state just because
we gave her too much pain medication every 2 hours,
checked her pulse ox at 85 without pulmonary disease,
and they overdosed the lady on some Talwin. So what
did we have to give her? A reverser drug, NALOXONE.
NALOXONE reverses MORPHINE
Suppressed her respiratory system.
What is the antidote for heparin:
Protamine sulfate

Antidote for Coumadin: Vitamin K

The drug combination may elicit a response not seen, either drug
alone- etoh/flagyl/antabuse
o Flagyl(metronidazole)- You take it for vaginosis & C diff.
o But if we have somebody taking this, and they drink it acts as
anabuse (makes them sick as a dog). Do not take alcohol
when taking Flagyl because it will make them sick.

Is this always bad? No, it is not. Potentiation is a good thing. If I

gave morphine for pain, I could potentiate it for some Phenergan. If
I gave Demerol for pain, I could potentiate the effect of that drug
by also giving Phenergan. They work synergistically.

4 basic Mechanisms of drug-drug interactions are:

o 1. Direct interaction by way of physical contact or chemical
reaction- MUST USE DRUG REFERENCE/PHARMACIST
How do we know what drugs react? Where do you go
look? Your drug book, your Lenhe book, who do you

call? Pharmacist, you can call a 24 hour pharmacy.

Incompatibility issues
Could happen in a syringe, in tubing (Feeding,
IV), solution, or in blood vessel
You could have an incompatibility issue in the
syringe, you pulled one drug in there, and youre
putting something else in there (mixing), could be
in tube feeding, definitely in IV bad, IV tubing, or
even in blood vessel.

Never assume that drugs go together.

This is especially true of IV.
Double check compatibility charts before mixing
two drugs or giving one after the other.
Never try to dissolve a drug in hot water before
administering it through GI feeding tube.

What we typically do when we give multiple drugs

IV push or given in an IV, we FLUSH. So we clear
the tube and clear the blood at that site from that
compound and that chemical, so we wait a few
minutes and we start the next thing so that we
dont build up two incompatible drugs in the same
spot.
Always assume is that two drugs are not
compatible until proven otherwise.

If a drug precipitates after mixing with another,

drug, dispose of the solution, WHEN IN DOUBT
THROW IT OUT.

2. Pharmacokinetic interactions (affecting ADME)-pH effected

o We alter the pH, it can effect where the drug is suppose to be
staying, on a receptor or in a cell, if I change that outside pH,
it will push that drug outside of that cell, it will be useless.
o Absorption What can affect the efficacy of a drug, its
intrinsic activity, or its affinity.
Changes in gastric or intestinal pH
How well is it absorbed
Changes in peristalsis
Vomiting
Drugs that absorb or bind other drugs
Anti-invectives that kill intestinal bacteria
We give someone an antibiotic because they have
pneumonia, what did we just do to their
intestines? We killed their normal bacterial flora.
What if ^ is on Coumadin? What is the
relationship? It prevent from making vitamin K so
were going to see possible toxic effect from the
Coumadin because we knocked out the control
mechanisms.
Drugs that reduce regional blood flow
o Distribution
Competition for protein binding sites

Remember: Only free drug can elicit

response
What is an important lab that you want to
check protein binding? Albumin. If I have a
low albumin? More free drug. You can easily
double their drug level with the same dose
you would normally give because there isnt
enough protein for it to bind to, easily toxic.

o Alterations of extracellular pH-if a drug increases pH, ionize

acidic drugs, drawing acidic drug from within cell to ECF.

Metabolism
o Some drugs have the potential to compete with other drugs
for enzymes ( Primarily isonez. CYP)
CYPs (1A2, 2C9, 2C19, 2D6, 3A4)
Some agents increase the synthesis of certain CYP
enzymes (enzyme inducers)

Metabolism increased
Some people naturally have enzymes that
are more active than the person sitting next
to you. Someone might have to give
someone Dilantin 900 mg and give you 600
mg a day because everyone is different.
Other decrease the activity of CYP enzymes (
Enzyme inhibitors)
Metabolism is decreased

What would you do with a dose with

someone who is an increase metabolism?
You will have to increase that dose, but if
you have someone that has inhibitors so
you have to drop it. This is how we prevent
toxicity. This is why we always start at a
small dose, especially older people.
It is important to consider how every drug a
patient takes is metabolized (including alcohol,
tobacco, and herbal supplements) so that drug
interactions of this sort can be avoided.

Enzyme Induction:
Some drugs and toxins increase the levels of, or
induce, certain CYPs.

This increases the rate of biotransformation of

inducing drug & other drugs using the enzyme as
much as 3 times normal rate.
It may take 4-10 days of exposer before the full effect
of enzyme induction appear.
It takes as long as 7-10 days after withdrawal of the
inducer for the CYPs to return to previous levels of
activity.
Takes 7 to 10 days to see what the effects are
going to be and return to previous.

Examples of enzymes inducers:

Cigarettes/marijuana smoke and chewing tobacco
Induction of enzymes from 1 joint equals
that from 7 cigarettes.
Passive smoke can induce enzyme in some
people.
Alcohol (Chronic use, consumption of 1-3
drinks/day)
Alcohol-induced cirrhosis and binge drinking

shut down hepatic enzymes.

Compounds in charcoal-broiled food
St. Johns wart
Phenobarbital
Phenytoin (Dilantin)
Rafampin

3. Pharmacodynamics interactions- receptors-separateagonist/antagonist or same-two narcotics

o Occupying similar receptors and we get this huge response.

4. Combined toxicity-inh/rifampin and liver

o There are tons drugs that can cause to the liver to go up, tons
of combinations. We can easily push people into toxicity.
o Whats another thing that people at home can do to push
themselves into toxicity? OTC, Tylenol, herbals, and people

that become dehydrated. Older people that dont drink get

toxic in a heartbeat. We have all these drugs piled up in their
body and theyre not getting distributed. So they are
concentrated, and they get toxic. They get confused/coo-coo
and everyone things that grandma had a stroke. You hydrate
her and shes fine and with hold the drugs.
May experience more than 1 at a time.

11/28/2014 1:50:00 PM
Chapter 6
*Know what drugs are contraindicated for people.
*Should I give this?
*Always assess patients labs before giving any medication.
*Know the nutritional status of patient.
Drug-Food Interactions- PO medications
Some drugs require an empty stomach for best absorptioncan
cause an upset stomach.

Some medications are required with food because it helps with

bioavailability.
Muscle mass, liver function, kidney function all effects process of
drugs.
Food generally decreases rate of absorption- some medications
suggest to be taken with high fat to increase absorption.
More fat in meals= longer gastric emptying time.
Milk can effect absorption of tetracycline and iron.
Drugs absorbed in the stomach or with slow rate of intestinal will
not have enough time for absorption.
Drugs that can be inactivated by stomach will have increased
bioavailability because it was not in stomach long enough to be
inactivated.
Some nutrients are transported by plasma protein (albumin)

Effect of food on CYP enzymes

Inducer (speeds up enzymes in liver to metabolizer drugs faster)
o BBQ, Cabbage, Broccoli= burn up drugs quickly/ give drugs
more often.

Inhibitors: Make drugs stay around.

o Grapefruit
Can cause toxicity ( Do not give especially with beta
blockers)

Drug action and food

Vitamin K and Coumadin/anticoagulants

Protamine Sulfate and Heparin
MAOI and tyramine foods
Milk and tetracycline

Food and Drug Toxicity

Tyramine is bad
o Hypersensitive crisis can result from ingestion of the tyramine
rich foods with MAOI ( Psych drug)
o Tyramine comes from aged cheeses, meats, overripe figs,
bananas, soy sauce, wines, yeast
Potassium-sparing drugs: help us keep our potassium.
Supplements(Avoid salt substitute)
o CNS stimulants: Avoid caffeine
o Lithium: maintain consistent sodium intake
o Aluminum antacids + citrus= excessive aluminum absorption
Drugs & Appetite

Many drugs can decrease appetite

ACE inhibitors & antibiotic can alter taste
Chemo causes mouth sores & decreased saliva.

ADR & MED ERRORS

ADRs can occur at normal doses.
o Extent can range from annoying to life threatening.
ADRs are most common in are extremes, severe illness, multiple
drug therapy.
Side Effects:
Nearly unavoidable secondary drug effect predictable
Intensity is dose dependent
Can develop immediately or after long use
Toxicity
Can be severe regardless of dose

Caused be severe regardless of dose

Allergic Reaction
Immune response
Steven-Johnson syndrome (caused by allergic reactions
usually caused by a sulfa drug.)
Must have sensitive prior to administration
Largely independent of dosage.
Idiosyncratic effect:

Uncommon response resulting from genetic predisposition.

Iatrogenic disease:
Produced by physician or drugs nearly identical to idiopathic
diseases.
Physical Dependence:
Develops after long use
Body has adapted to drug; abstinence syndrome develops if drug is
stopped.
o DO NOT ABRUPTLY STOP(BP, BETA BLOCKERS, SSRI)
Carcinogenic:
Medications that cause cancer.

Teratogenic effect:
Drug induced birth defect
Organ Specific Toxicity:
Kidneys: Gent
Lungs: amiodarone
Heart: Chemoextensive heart monitoring.
Inner ear: gent
Hepatotoxic Drugs:

Leading cause of acute liver failure in US

Acetaminophen: ETOH
Statins
Liver function tests must be monitored if on these drugs.
Instruct on s/s of liver injury
o Jaundice, dark urine, light stools, n/v, malaise, abdominal
pain, anorexia.

QT Interval: Antifungals, SSRI, Inhalers, genetic (women longer

QT)

Time required for ventricles to repolarize after contraction.

Prolongation, low pilassium,

11/28/2014 1:50:00 PM