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Pharmacokinetics VS. Pharmacodynamics
Transcript of Pharmacokinetics VS. Pharmacodynamics
- Definition : effect of body on drugs
- Proprieties that determine ( determine the speed of onset of drug action, the intensity of the drug’s effect, and the duration of drug action ) :
• Elimination: the drug and its metabolites are eliminated from the body in urine, bile, or feces.
ROUTES OF DRUG ADMINISTRATION
- determined primarily by the
(for example, water or lipid solubility, ionization) and by the
: Oral / sublingual / Reactal (considerd this by the Dr. cause fraction of drug will not bypass first-pass effect)
: IV / IM / SC
: Inhalation / Intranasal / Intrathecal , intraventricular / Topical / Transdermal
• Absorption: mover drug from the site of administration into plasma.
* The delivery of a drug from the plasma to the interstitium primarily depends on :
A ) blood flow
( unequal distribution of cardiac output )
B ) capillary permeability
: determined by
1 )capillary structure
( no slit in brain )
2 ) the chemical nature of the drug.
* major factor influencing the hydrophobic drug's (no net charge )distribution is the blood flow to the area/ across most biologic membranes.
* hydrophilic (have a net charge ): must go through slit junctions
C ) the degree of binding of the drug to plasma proteins and tissue
1. Binding to plasma proteins
* Reversible / albumin / drug reservoir / duo to elimination drug can dissociate
2. Binding to tissue proteins :
* accumulate , duo to binding to lipids , proteins , NA
* Reservoir , or toxicity
: chemical nature of a drug !
• Metabolism: drug may be biotransformed by the liver, or other tissues.
- rate and efficiency depend on :
* drug’s chemical characteristics
* route of administration
A ) Mechanism of absorption of drugs from the GI tract
B ) Factors influencing absorption
: Most drugs are weak acid or weak base
** Role : uncharged pass more rapidly
- Acid : protonated ( HA )
- Base : unprotonated ( B )
just study it from the laws summary
2. Blood flow to the absorption site
(blood to intestine more than stomach )
3. Total surface area available for absorption
(brushborder in the inestine )
4. Contact time at the absorption surface:
* Parasympathetic : decrease the time , cause it increase the rate of gastric emptying
* Sympathetic : increase the time
* Drug with meal absorbed slowley
5. Expression of P-glycoprotein : (smt for transport)
* reduces drug absorption
* liver > bile
* Kidney > urine
* Placenta (( good )) ! > to the maternal blood
* intestine > lumen ( decrease )
* brain > to the blood , limit access to brain
: fraction of administered drug that reaches the systemic circulation
* important for calculating drug dosages for non-intravenous routes of administration.
1. Determination of bioavailability :
* comparing !
2. Factors that influence bioavailability
a. First-pass hepatic metabolism :
portal circulation ! ( liver is stupid -_- )
b. Solubility of the drug
* Very hydrophilic drugs are poorly absorbed because of their inability to cross the lipid-rich cell
*extremely hydrophobic are also poorly absorbed, because they are totally insoluble in aqueous body fluids
* Drug should be : largely hydrophobic, with some solubility in aqueous solutions
c. Chemical instability
: depend on structure
* pencilin G : not stable in stomach
* insulin : destroyed in GI
d. Nature of the drug formulation
* things added to the drug , can influence the ease of dissolution
- bioequivalent Drugs : if they show comparable bioavailability and similar times to achieve peak blood concentrations.
- bioinequivalent Drugs : Two related drugs with a significant difference in bioavailability .
** Two similar drugs are therapeutically equivalent if they have comparable efficacy and safety
** two drugs that are bioequivalent may not be
therapeutically equivalent. ? because Clinical
effectiveness often depends on both the maximum serum drug concentrations and on the time required (after administration) to reach peak concentration
D. Volume of distribution
- The apparent volume of distribution, Vd, can be thought of as the fluid volume that is required to contain the entire drug in the body at the same
concentration measured in the plasma.
1. Distribution into the water compartments in the body :
once drug enter the body it will distribute to one of three sites :
** Plasma compartment
: very large molecular
weight or binds extensively to plasma proteins
- drug distributes in a volume (the plasma) that is about 6 percent of the body weight ( = 4 L in 70kg )
** Extracellular fluid
: low molecular weight but is
hydrophilic (( cannot move across the lipid membranes of cells to enter the water phase inside the cell. ))
- volume = plasma water + interstitial fluid
interstitial fluid, which together constitute the extracellular fluid (( about 20 percent of the body weight, or about 14 L ))
** Total body water
: low molecular weight and is
- drug distributes into a volume of about 60 percent of body weight, or about 42 L
2. Apparent volume of distribution
* vast majority of drugs distribute into several compartments
Vd is a useful pharmacokinetic
parameter for calculating a drug’s loading dose
3. determination of Vd
: just see the laws summary
4. Effect of Vd on drug half-life:
* If the Vd for a drug is large : most of the drug is in the extraplasmic space and is unavailable to the excretory organs. Therefore, any factor that increases the volume of distribution can lead to an
increase in the half-life
and extend the duration of action of the drug.
E . Binding of Drugs to Plasma Proteins :
* Bound drugs are pharmacologically inactive
1 . Binding capacity of albumin
* reversible / low or high /
* Albumin has the strongest affinities for anionic drugs (weak acids) and hydrophobic drugs.
2. Competition for binding between drugs
* The drugs with high affinity for albumin can be divided into two classes, depending on whether the dose of drug is greater than, or less than, the binding capacity of albumin into 2 classes :
Class 1 : dose less than binding capacity > binding sites are more ! > (dose/capacity) is low
Class 2 : dose is more than albumin sites ! > (dose/capacity ) is high
what is the importance if given togather ?!
class 2 displace class 1 .. lead to increase of therapeutic effect or toxic !
3. Relationship of drug displacement to Vd :
- impact of drug displacement from albumin depends on both the Vd and the therapeutic index
* high Vd : drug displaced from the albumin distributes to the periphery , and the change in
free-drug concentration in the plasma is not significant.
* Low Vd : the newly displaced drug does not move
into the tissues as much, and the increase in free drug in the plasma is more profound. If the therapeutic index of the drug is small, this increase in drug concentration may have significant clinical consequences
- Drugs are most often eliminated by
biotransformation and/or excretion into the urine or bile.
- Metabolism transforms
readily excretable products.
- The liver is the major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues, such as the kidney and the
** (pro-drugs) : agents are initially administered as inactive compounds and must be metabolized to their active forms
A. Kinetics of metabolism
1- First-order kinetics:
The metabolic transformation
of drugs is catalyzed by enzymes, and most of the reactions obey Michaelis-Menten kinetics
of drug metabolism is directly proportional to the
of free drug, and first-order
kinetics are observed .... This means that a constant fraction of drug is metabolized per unit of time ( V = Vmax [c] / Km )
2. Zero-order kinetics
: With a few drugs,
such as aspirin, ethanol , and phenytoin, the
doses are very large
. Therefore [C] is much greater than Km, and the velocity equation becomes
( V = Vmax )
- The enzyme is saturated by a high free-drug concentration, and the rate of metabolism remains constant over time
** independent of drug dose
B. Reactions of drug metabolism
** Why do we have Phase 1 and phase 2 ?
- The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell membranes and are
in the distal convoluted
tubules. Therefore, lipid-soluble agents must first be metabolized into more polar (hydrophilic) substances in the liver .
1. Phase I: convert lipophilic molecules into
molecules by introducing or unmasking a
group, such as –OH or –NH2.
** Phase I metabolism may increase,
decrease, or leave unaltered the drug’s pharmacologic activity.
a. Phase I reactions utilizing the P450 system
Certain drugs (for example, phenobarbital, rifampin, and carbamazepine) are capable of increasing the synthesis of one or more CYP isozymes. This results in
and can lead to significant decreases in plasma concentrations of drugs metabolized by these CYP isozymes, as measured by AUC (a measure of drug exposure), with concurrent
loss of pharmacologic effect.
Consequences of increased drug metabolism include:
1) decreased plasma drug concentrations,
2) decreased drug activity if the metabolite is inactive.
3) increased drug activity if the metabolite is active
4) decreased therapeutic drug effect.
Inhibition of CYP isozyme activity is an important
source of drug interactions that lead to serious adverse events. The most common form of inhibition is through
for the same isozyme. Some drugs, however, are capable
of inhibiting reactions for which they are not substrates (for example, ketoconazole), leading to drug interactions.
b. Phase I reactions not involving the P450 system:
* amine oxidation * alcohol dehydrogenation
* esterases * hydrolysis
2. Phase II: This phase consists of conjugation reactions.
** If the metabolite from Phase I metabolism is sufficiently polar, it can be excreted by the kidneys. ** BUT many Phase I metabolites are too lipophilic , A subsequent conjugation reaction with an
, such as
sulfuric acid, acetic acid, or an amino acid
, results in polar, usually more water-soluble compounds that are most often therapeutically inactive.
is the most common
and the most important conjugation reaction
Drugs already possessing an –OH, –NH2, or –COOH
group may enter Phase II directly and become conjugated without
prior Phase I metabolism.]
3. Reversal of order of the phases: Not all drugs undergo Phase I and
II reactions in that order. For example, isoniazid is first acetylated (a
Phase II reaction) and then hydrolyzed to isonicotinic acid (a Phase I
** Role : Elimination of drugs from the body
requires the agents to be sufficiently
polar for efficient excretion.
A. Renal elimination of a drug
1. Glomerular filtration:
* Free drug (not bound to albumin) flows through the capillary slits into Bowman’s space as part of the glomerular filtrate .
* The glomerular filtration rate (125 mL/min)
* Lipid solubility and pH do not influence
the passage of drugs into the glomerular filtrate. >> (( rate and plasma binding )) !
2. Proximal tubular secretion
* Secretion primarily occurs in the proximal tubules by two energy-requiring active transport (carrier requiring) systems:
- one for anions (for example, deprotonated forms of weak acids)
- and one for cations (for example, protonated forms of weak bases).
3. Distal tubular reabsorption
* The drug, if uncharged, may diffuse out of
the nephric lumen, back into the systemic circulation
* As a general rule, weak acids can be eliminated by alkalinization of the urine , to keep the drug ionized ! ... whereas elimination of weak bases may be increased by acidification of the urine. This process is called “ion trapping.”
* Drug concentration increases more than the perivascular space.
4. Role of drug metabolism:
** Role : charged molecules cannot back-diffuse out of the kidney lumen
* By metabolism we can make changes in the drug to be more polar by :
- Phase 1 : addition of hydroxyl groups or the removal of blocking groups from hydroxyl, carboxyl, or amino groups
- Phase 2 : use conjugation with sulfate, glycine,
or glucuronic acid to increase drug polarity
CLEARANCE BY OTHER ROUTES
* Includes : feces , intestines, the bile, the
lungs, and milk in nursing mothers,
* Total body clearance, and drug half-life
are important measures of drug clearance calculated to prevent drug
toxicity. (( THE LAWS SUMMARY ))
* The half life of a drug is increased by :
1) diminished renal plasma flow or hepatic
2) decreased ability to extract drug from plasma (renal failure)
3) decreased metabolism (when another drug inhibits its biotransformation or in hepatic insufficiency, as with cirrhosis)
** The half-life of a drug may decrease by :
1) increased hepatic blood flow
2) decreased protein binding
3) increased metabolism.
DESIGN AND OPTIMIZATION OF DOSAGE REGIMEN
A. Continuous-infusion regimens
* results in accumulation of the drug until a steady state occurs. Steady state is the point
at which the amount of drug being administered equals the amount being eliminated,
1. Plasma concentration of a drug following IV infusion
- rate of drug entry into the body is constant.
- elimination of a drug is first order, that is, a constant fraction of the agent is cleared per unit of time.
- plasma concentration of drug rises until the rate of
drug eliminated from the body precisely balances the input rate >> steady state !
2- Influence of the rate of drug infusion on the steady state :
- steady-state plasma concentration is directly proportional to the
- steady-state concentration is inversely proportional to the
clearance of the drug
( any factor decrease clearance from kidney will increase the steady state )
3- Time required to reach the steady-state drug concentration:
- (3.3) half life is 90% of steady state
- (95% ) is ( 4 to 5 ) half life's
The sole determinant of the rate that a drug approaches steady state is
t1/2 or ke
, and this rate is influenced only by the factors that affect the half-life. The rate of approach
to steady state is not affected by the rate of drug infusion. ( rate of infusion increase , elimination will increase also to compensate the effect )
4) Rate of drug decline when the infusion is stopped: When the infusion is stopped, the plasma concentration of a drug declines (washes out) to zero with the same time course observed in approaching the steady state
B. Fixed-dose/fixed-time regimens
result in time-dependent fluctuations in the circulating level of
1. Multiple IV injections
plasma concentration increases until a steady state
drug accumulates until, rate of drug loss exactly balances the rate of drug administration
## . Effect of dosing frequency :
of the drug, and the
at which the steady state is approached, are not affected by
the frequency of dosing.
2. Multiple oral administrations
drugs may be absorbed slowly, and the plasma concentration of the drug is influenced
by both the rate of absorption and the rate of drug elimination
C. Optimization of dose
** drug must be within therapeutic window
1. Maintenance of dose
Drugs are generally administered to maintain
a steady-state concentration within the therapeutic window.
- rate of administration and the rate
of elimination are important
2. Loading dose:
single dose to achieve the desired plasma level
rapidly, followed by an infusion to maintain the steady state
3. Dose adjustment:
Vd is useful because it can be used to calculate the amount of drug
needed to achieve a desired plasma concentration.
E. Therapeutic equivalence :
• Distribution: drug may reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids.
Figure 1.5 !
- Definition : Pharmaco
ynamics describes the actions of a
on the body and the
influence of drug concentrations on the magnitude of the response.
- Drug to make an effects .. need receptor = target molecule !
- Reaction produce >> drug–receptor complex , which initiate alterations
- Drug = signal
- Receptor = signal detector
- Ligand = small molecule that binds to a site on
a receptor protein , could be the drug
- Second messenger = effector molecules = part of
the cascade of events that translates ligand binding into a cellular response.
A. The drug–receptor complex
- Receptors are specific
- Exact function : transduce the binding into a response by causing a conformational
change or a biochemical effect.
B. Receptor states
- Old ( required ) = binding of a ligand was thought to cause receptors to
change from an inactive state (R) to an activated state (R*). The activated
receptor then interacts with intermediary effector molecules to produce
a biologic effect
- New ( just to know ) = receptors exist in at least two states, inactive (R)
and active R* states that are in reversible equilibrium with one another.
In the absence of an agonist, R* typically represents a small fraction of
the total receptor population (that is, the equilibrium favors the inactive
C. Major receptor families
- receptors are proteins that are responsible
for transducing extracellular signals into intracellular responses
Transmembrane signaling mechanisms.
- for regulation of the flow of ions across cell membranes
- activity of these channels is regulated by the binding of a ligand to the channel
- Response to these receptors is very rapid (milliseconds )
- Function : neurotransmission, cardiac conduction,
and muscle contraction.
- Examples : nicotinic ( ACH ) / (GABA) receptor
** not ligand-gated, ion channels, such as the voltagegated sodium channel ( anesthetics )
- The extracellular domain of this receptor usually
contains the ligand-binding area
- Intracellularly, these receptors
are linked to a G protein , having three subunits
- α subunit that binds guanosine triphosphate (GTP) and a βγ subunit
- Binding of the ligand to the extracellular
region of the receptor activates the G protein so that GTP replaces (GDP) on the α subunit
- Dissociation of the G protein occurs, and both the α-GTP subunit and the βγ subunit subsequently interact with other cellular effectors ( as enzymes , proteins , ion channels )
- These effectors then activate
- G protein–coupled receptors are the
most abundant type of receptors,
- Mechanism :
- Structure :
- Examples :
- neurotransmission, olfaction, and vision.
- Second messengers: These are essential in conducting and amplifying signals coming from G protein–coupled receptors
- Gs Pathwasy : activation of adenylyl cyclase by α-GTP
subunits, which results in the production of cyclic adenosine
monophosphate (cAMP)—a second messenger that regulates
- G proteins also activate phospholipase
C, which is responsible for the generation of two other second messengers, (IP3) >> regulate Ca << and (DAG) >> activates kinase C <<
- consists of a protein that spans the membrane once and may form dimers or multisubunit complexes.
- Binding of a ligand to an extracellular domain activates
or inhibits this cytosolic enzyme activity
- Duration of responses to stimulation of these receptors is on the order of minutes to hours
Duration : sec - minutes
- Functions : Metabolism, growth, and differentiation
- Examples : epidermal growth factor, platelet-derived
growth factor, atrial natriuretic peptide, insulin,
- Most important : have a tyrosine kinase activity as part of their structure
- Mechanism :
- binding of the ligand to receptor subunits, the receptor undergoes conformational changes, converting kinases from their inactive
forms to active forms.
- activated receptor autophosphorylates
and then phosphorylates tyrosine residues on specific proteins , modify the three-dimensional structure of the target protein, thereby acting as a molecular switch
- Structure :
- receptor is entirely intracellular, and, therefore, the ligand must diff use into the cell to interact
with the receptor ( lipid solubility ! )
- Function : complex > go to the nucleus > bind with DNA , transcription factors > The activation or inactivation of these factors causes the transcription of DNA into RNA and translation of RNA into an array of proteins
- Mechanism :
- Binding of the ligand with its receptor > becomes activated
- The activated ligand–receptor complex migrates or translocates to the nucleus, where it binds to specific DNA sequences, resulting in the regulation of gene expression
- Duration : hours - days
D. Some characteristics of signal transduction
1. Signal amplification :
- happen in receptors which respond to hormones, neurotransmitters, and peptides,
- Example : G-protein
- Because of this amplification, only a fraction of the total receptors for a specific ligand may need to be occupied to elicit a maximal response from a cell
- Systems that exhibit this behavior are said to have spare receptors ( Ex : insulin , 99% are spare ! / heart 5-10% are spare ! )
2. Desensitization and down-regulation of receptors
- Desensitization : By time , The receptor becomes desensitized to the action of the drug , the receptors are still present on the cell surface but are unresponsive to the ligand .
- Down regulation : Receptors can also be down-regulated in the presence of continual stimulation
( receptor undergoes endocytosis and is sequestered within the cell )
- To prevent potential damage to the cell , several mechanisms have evolved to protect a cell from excessive stimulation.
- Agonist = agent that can bind to a receptor and elicit a biologic response , mimics the action of the original endogenous ligand
- magnitude of the drug effect depends on the drug concentration at the receptor site, which, in turn, is determined by both the dose of drug administered and by the drug’s pharmacokinetic profile
A. Graded dose–response relations
- concentration of a drug increases, the magnitude of its pharmacologic effect also increases
- properties that can be determined from graded dose–response plots
1. Potency : [ ] need to produce 50% effect
- measure of the amount of drug necessary to produce an effect of a given magnitude
- EC50 : The concentration of drug producing an effect that is 50 percent of the maximum
Reversible relation ! >> Drug A is more potent than Drug B, because a lesser amount of Drug A is needed when compared to Drug B to obtain 50-percent eff ect
2. Efficacy: max . effect
- the ability of a drug to elicit a response when it interacts with a receptor
- dependent on the number of drug–receptor complexes formed and the efficiency of the coupling of receptor activation to cellular responses
- efficacy, is more important than drug potency
- A drug with greater efficacy is more therapeutically beneficial than one that is more potent
- Maximal efficacy of a drug assumes that all receptors are occupied by the drug, and no increase in response will be observed if more drugs are added
efficacy : just look at max . [ ]
potency : just look at EC50
A is more efficacy than B
B. Effect of drug concentration on receptor binding
C. Relationship of drug binding to pharmacologic effect
- agonist binds to a receptor and produces a biologic response. An agonist may mimic the response of the endogenous ligand on the receptor
- another definition of an agonist is a drug that bindsto a receptor, stabilizing the receptor in its active conformational state
- A. Full agonists :
- drug binds to a receptor and produces a maximal biologic response
- B. Partial agonists :
- Partial agonists have effiacies greater than zero but less than that of a full agonist
- Partial with full ?!
partial act as antagonist to the full !
- C. Inverse agonists
- Inverse agonists, unlike full agonists, stabilize the inactive R form.
- inverse agonists reverse the constitutive activity of receptors and exert the opposite pharmacological
effect of receptor agonists
- drugs that decrease or oppose the actions of another drug or endogenous ligand and has no effect if an agonist is not present.
- no intrinsic activity and, therefore, produce no effect by themselves
A. Competitive antagonists :
- both the antagonist and the agonist bind to the same site
- The competitive antagonist will prevent an agonist from binding to its receptor and maintain the
receptor in its inactive conformational state.
- competitive antagonists can be overcome by
adding more agonist.
- increase the ED50 ( An effective dose (ED) is the dose that produces a therapeutic response or desired effect )
. Irreversible antagonists
- irreversible antagonists do not increase the ED50 (unless spare receptors are present)
- An irreversible antagonist causes a downward shift of the maximum,
with no shift of the curve on the dose axis
- binds permanently to a receptor
- can't be overcome by adding more agonist.
- mechanisms :
1 ) bind covalently to the active site of the receptor
2 ) binds to a site ("allosteric site") other than the agonistbinding
B- noncompetitive antagonist
- In the presence of the noncompetitive antagonist : ** a maximal response is not observed even
with increasing dose of the agonist.
(( noncompetitive antagonists reduce agonist efficacy ))
QUANTAL DOSE–RESPONSE RELATIONSHIPS
- the influence of the magnitude of the dose on the proportion of a population that responds
- quantal responses : effect either occurs or it does not.
- Quantal dose–response curves are useful for determining doses to which most of the population responds.
A. Therapeutic index : (TI)= TD50/ED50
- ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals
** TD50 = the drug dose that produces a toxic effect in half the population ( low : dengrous ! small dose kill many how about high does !! )
** ED50 = the drug dose that produces a therapeutic or desired response in half the population
B. Determination of therapeutic index :
- measuring the frequency of desired response, and toxic response,
- In the presence of a competitive antagonist :
** the maximal response of the agonist can be obtained by increasing the amount of agonist administered.
** This results in an increase in the EC50 value
** maintenance of agonist efficacy. >> the same number of receptors are available
((((( competitive antagonists reduce agonist potency )))))
Best wishes .. Omar Sawas ^_^