Download Pharmacokinetics and Pharmacodynamics

Pharmacokinetics and Pharmacodynamics
Quantitative , time-dependent changes
of plasma and total drug concentration
Quantitative description of the
effects of a drug on the body
Pharmacokinetics and
Pharmacodynamics
• Pharmacodynamics is the study of how drugs
interact with a molecular target, i.e; effect of the
drug on the body.
• Pharmacokinetics is the study of how a drug
reaches its target in the body and how it is affected
on that journey, i.e; effect of the body on the drug.
• Pharmacokinetics is the study of how is the
drug absorbed, distributed, metabolized and
excreted in the body
2
Response proportional Number of receptors
Efficacy is the maximal response a drug can produce
Potency is a measure of the dose needed to produce a response and is
expressed as the dose required to achieve 50% of the desired therapeutic
effect.
TI= TD50
ED50
e.g. Heparin TI < 2 measure PTT
Aspirin TI 1000
4.Therapeutic Effect and Adverse Action
Clinical effects of drug action have the dualism, The aim of drug therapy is
to cure or suppress disease, called therapeutic action, but also bring about
some harmful effects, named untoward or adverse reaction.
Therapeutic Effect
It implied the effects that conform the goal of therapy, including
etiological treatment and symptomatic treatment.
•
•
1．etiological treatment implies primary therapy (e.g. in bacterial and
parasitic infections), when the disease is eliminated and the drug is
withdrawn; or auxiliary therapy, also called supplement therapy or
replacement therapy.
2．symptomatic treatment means suppression of diseases or symptoms is
used continuously or intermittently to maintain health without attaining
cure (as in hypertension, diabetes, epilepsy, asthma) or to control
symptoms (such as pain and cough) whilst awaiting recovery from the
causative disease.
Generally, etiological treatment is more important than symptomatic
treatment. However, symptomatic treatment is not necessarily trivial in
emergency rescue, such as heart failure, shock, epilepsy, asthma, etc.
Adverse Reaction (Untoward)
1.
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•
•
•
•
The term adverse reaction is defined as unwanted, seriously
unpleasant, or even harmful effects.
Side effects is to be the undesired effects unrelated to therapeutic
aim and occurring at doses intended for therapeutic effect.
①It is often slight, recoverable functional alteration of the body.
②Some of side effects may make a quick recovery without
withdrawal of the drug, but others dose not disappear until
withdrawal of the drug.
③The pharmacological basis of side effect is lower selectivity
④Side effects vary with different therapeutic goals. For example,
atropine is used as an antisecretory agent to block secretions in the
upper and lower respiratory tracts prior to surgery .
⑤Usually drug in combination is the best way to prevent from side
effects.
2. Toxic reaction is the adverse reactions that occur frequently due to
overdose or longterm use.
①Any drug in overdose could induce toxicity, which implied a direct
action.The toxic reactions vary with different drugs, but much of the
serious drug toxicity in clinical practice represents a direct
pharmacological extension of the therapeutic action of the drug, thus they
are predictable.
②The severity of a toxicity is deteriorated with dose increase, so we cannot
rise the therapeutic effect by increasing doses of drug, which is very
dangerous.
③Toxicity can not automatically disappear because it often damages the
function or the morphology of organs, even inducing teratogenicity,
carcinogenicity and mutagenicity.
Toxicities include the acute toxicity, subacute toxicity and chronic toxicity
3. Residual effect implies the biological responses induced by residual drug
below effective concentration after cessation of administration, including a
short period, long term and permanent.
4. Withdrawal reaction implies a worsening of original diseases occurred after
suddenly cessation of administration, also called the rebound reaction.
Agonists and antagonists
Two states: closed or open
An antagonist is a molecule that inhibits the action of an agonist but
has no effect in the absence of an agonist
e.g. protamine binds heparin
e.g. Pravastatin inhibits HMG CoA
Reductase, which is the rate limiting
enzyme in cholesterol synthesis
e.g. aspirin is a noncompetitive
antagonist.
It acetylates cyclooxygenase
-reduced efficacy
-same potency
Raloxifene = SERM (selective estrogen receptor antagonist
Bone is a Partial agonist
Breast is an antagonist
Inverse agonist decrease inherent activity of receptor
e.g BCR-Abl
Spare receptors : a maximal response is achieved with < 100%
occupancy e.g. GPCRs where one G protein can stimulate
second messenger formation.
Thiopental and diazepam in fat
Heparin to plasma proteins
First-Pass
Metabolism can
occur with orally
administered
drugs
Bioavailability = Quantity of drug reaching the circulation
Quantity of drug administered
1. First-Pass hepatic metabolism e.g P450 enzymes in liver transform drug
2. Solubility: extremely hydrophilic and hydrophobic drugs are poorly absorbed
3. Instability: penicillin G is unstable at low pH, insulin is digested
Route
Enteral
e.g. aspirin
Parenteral
e.g. morphine
Routes of Drug Administration
Advantages
Disadvantages
Simple, inexpensive
Drug exposed to GI and
painless
first-pass metabolism,
slow delivery
Rapid delivery
no first-pass metabolism
high bioavailability
Irreversible, infection
pain, skilled personnel
Mucous
Rapid delivery, simple
Beclomethasone No first-pass metabolism
(Sublingual,nasal, rectal)
Direct delivery (lungs)
Few drugs
Transdermal
Nicotine
lipophilic drug
slow delivery
Simple, prolonged admin.
No First-pass
Parenteral Drug Administration
Advantages
Disadvantages
Subcutaneous
Xylocaine
slow onset, oil based
slow onset, small vol.
Intramuscular
Haloperidol
Intermediate onset, oil-based
hemorrhage, pain
Intravenous
morphine
Rapid onset, controlled
delivery
peak-related toxicity
Intrathecal
methotrexate
Bypasses BBB
Infection, skilled
personnel
pKa= pH + log [HA]
[A-]
3=log [HA]
[A-]
1,000= [HA]
[A-]
Most drugs are rapidly distributed from the systemic circulation to
other compartments e.g. interstitium and adipose tissue See Table 33 e.g. diazepam (valium)
Half-life: time for drug conc to
decrease to half its original value
First-order kinetics: the amount of
drug metabolized or excreted is
proportional to the conc in the
systemic circulation i.e the fraction
eliminated remains the same.
e.g. Warfarin
And fluoxetine (Prozac)
METABOLISM
45% whites and Blacks are slow
acetylators; 90% Asians "Fast acetylators"
Prodrugs: Tamoxifen, codeine
See table 4-3
Fluoxetine; CCB, grapefruit
Anti-HIV
Question: Which of the following statements is correct?
1. The greater the number of receptors occupied by a drug, the greater
the potency.
2. Drugs with high potency have a high EC50.
3. Drugs with high potency have a drug DR curve that lies to the right
of a less potent drug
4. The presence of a competitive antagonist shifts the agonist DR
curve to the right and decreases the potency
5. The greater the drugs potency, the higher its drug receptor
dissociation constant, Kd.
Ans. D The potency is the conc at which the drug elicits 50% max response. Very potent
drugs have a low EC50. In 4, the binding of a competitive antagonist alters the equilbrium
binding of the agonist. The greater a drugs potency the lower its Kd.
Question: What properties of certain drugs, such as aspirin, allow
them to be taken without monitoring plasma drug levels, whereas
heparin requires monitoring.
1. Whereas aspirin is taken orally, heparin is administered parenterally
2. Aspirin is available without prescription and can be taken safely
3. Whereas aspirin events are irreversible, which does not need
monitoring, the reversible effect of heparin must be monitored.
4. Whereas aspirin causes a graded DR relationship, heparin causes a
Quantal DR relationship that must be monitored.
5. Whereas aspirin has a larger therapeutic index, heparin has a small
TI.
Ans. E. Heparin has a TI <2 I.e it can cause toxicity and bleeding at
less than twice the therapeutic dose.
Your patient, Mr. S, is a 65-year old man that you are monitoring for elevated BP. His BP is
145/105 mm Hg this morning. You decide to to give a diuretic, thiazide and a betareceptor blocker as an anti-hypertensive therapy. As you decide between atenolol and
propranolol you remember that thiazide is 95% bound to albumin plasma protein.
Plasma protein binding
Urinary excretion
Atenolol
5%
85%
Propranolol
95%
1%
HOW DOES THE DIFFERENTIAL BINDING DETERMINE WHICH DRUG TO USE?
A. Atenolol is less bound and so has less ability to reach the receptor
B. Atenolol is less bound and so is less likely to interfere with plasma binding of thiazide
C. Propranolol is highly bound, so it is less likely to displace thiazide
D. Propranolol is highly bound, so it is more likely to compete with thiazide
E. Propranolol is highly bound, so it will require a lower dose to achieve effect similar to
atenolol
Ans. B. Atenolol is less likely to displace thiazide. Propranolol is
expected to displace thiazide. Drugs that are bound to plasma proteins
may require a higher dose to achieve a therapeutic effect.
Ms. B is a 32-year old woman who complains of a sore throat. Physical exam reveals creamy
white lesions on the tongue that is identified as oral thrush, a fungal infection. Her history
includes sexual activity with multiple partners, inconsistent use of condoms. She is
diagnosed wth an HIV-1 infection, confirmed by PCR. She is started on an anti-HIV regimen
that includes the protease inhibitor sequinavir. Despite this treatment she presents several
months later with a persistent cough that turns out to be TB.
Q.
What factors should the physician consider when deciding a course of treatment with the
anti-TB drug, Rifampin.
A.
B.
C.
D.
E.
If oral thrush is present it will prevent GI absorption of oral contraceptives
The MDR1 transporter will block GI absorption of anti-TB agents in HIV patients
The metabolism of sequinavir will be enhanced by anti-TB drugs
The metabolism will be enhanced by drinking grapefruit juice
Renal excretion of anti-TB drugs is prevented by sequinivir
Ans C. Rifampin induces P450 3A4 and so will enhance metabolism of
sequiniavir. The MDR1 actively transports drugs back into the
intestine. Grapefruit juice contains psoralen that inhibit P450 and so
may reduce metabolism.
CASE: Mr W is a 66 year old technology consultant. His only medical
Problem is chronic atrial fibrillation, and his only medication is
WARFARIN. He flies to Turkey where he eats shish kebabs. The next
day he develops foul smelling diarrhea and his physician precribes a 7
day course of trimethoprim-sulfamethoxazole.
He feels well for 2 days and goes on another dinner where much alcohol
was consumed. Upon leaving the restaurant he falls and the next day he
has a swollen knee. Upon examination and lab studies show a elevated
International Normalized Ratio, which is a standardized measure of
Prothrombin time- a surrogate marker of for warfarin levels.
The physician advises Mr W that his warfarin level is in the supraTherapeutic (toxic) range and is likely the result of an adverse drugDrug interaction between warfarin and the antibiotics (and the recent
Alcohol!).
Q. What was the cause of Mr. W's supratherapeutic Warfarin level?
A. Trimethoprim inhibited the hepatic metabolism and clearance
B. Trimethoprim enhanced growth of GI bacteria that normally
Degrade warfarin
C. Trimethoprim has an anticoagulant adverse effect
D. Trimethoprim competed with warfarin for binding to its receptor
E. Trimethoprim prevented the renal secretion of warfarin
Ans. A. Trimethoprim inhibited the hepatic metabolism of warfarin.
In addition the ethanol also inhibited metabolism.