basic principles (2-8)

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pharmacokinetics

deals with absorption, distribution, biotransformation and excretion of drugs

pharmacodynamics

is the study of biochemical and physiological effects of drugs and their mechanisms of action

graded dose response

shows the effect of various doses of a drug on an individual

quantal dose response

shows the effect of various doses of a drug on a population of individuals

graded dose response equation?

E= [ Emax x C] / [ C + EC50]
E: is the effect observed at concentration C
Emax: is the maximal response that can be produced by the drug
EC50: is the concentration of the drug that produces 50% of maximal effect
curve= hyperbolic

KD?

equilibrium dissociation constant= represents the concentration of free drug at which half maximal binding is observed. This constant characterizes the receptors affinity for the drug.
If KD is low, binding affinity is high, vice versa.

maximal efficacy?

is the maximal effect (Emax) an agonist can produce. Efficacy is determined mainly by the nature of the receptor and its associated effector system.

Potency

refers to the concentration (EC50) of a drug required to produce 50% of that drug's maximal effect. The potency depends in part on the affinity (Kd) of receptors for binding the drug and in part on the efficiency with which drug-receptor interaction is coupled to response.

noncompetitive antagonists bind to ?
uncompetitive antagonists bind to?

non= allosteric site, decreased Emax b/c its insurmountable
uncomp= bind only to the agonist-receptor complex.

Non-receptor antagonism- functional-indirect

Binds to an intermediate macromolecules in the pathway that links the receptor to the physiological effect. For example, a drug that inhibits protein kinase A blocks the effects of a B-adrenoceptor agonist.

Non-receptor antagonism-functional-physiological

One agonist opposes another agonist, but through different receptors. Ex. A muscarinic agonist inhibits B-adrenoceptor-stimulated adenylyl cyclase activity in the heart

Non-receptor antagonism- chemical

A drug that reacts chemically with an agonist to form a product that cannot activate a receptor. Ex. protamine (positive charge)- binds to heparin (negative).

When can a partial agonist act like a competitive antagonist?

in the presence of a full agonist

inverse agonist?

reverse the constitutive (basal) activity of a receptor. In systems that are not constitutively active, inverse agonists behave like competitive antagonists.

The slope of the quantal dose-effect curve is?

an expression of the pharmacodynamic variability in the population, rather than an expression of the concentration range from a threshold to a maximal effect in an individual patient.

measures variability?

quantal dose curve

measures maximal efficacy?

graded- dose response

the effect of most drugs result from their interaction with? bind to? exception?

macromolecular components of the organism.
bind to= 1st= protein molecule
exception= DNA

graph shift
1. reversible competitive antagonist
2. irreversible competitive antagonist
3. non-competitive antagonist

1. shift to the right
2. shift downwards
3. shift downwards

two types of ion channels?

1. Voltage gated-regulated by changes in membrane potential
2. Ligand gated- via ligand binding to the channel. Ligand can be an extracellular mediator (NT: GABA) or an intracellular mediator (Ca)

Examples of ion channels?

1. Local anesthetics- voltage gated Na
2. Benzodiazepines- GABAa receptor in the CNS

components of a G protein receptor?

1. Cell surface receptor
2. G protein on the cytoplasmic face of the plasma membrane
3. An effectors: enzyme or ion channel whose activity is affected by the activated G protein

G protein components? which units interact with targets? which unit has GTPase?

alpha, beta and gamma
beta and gamma form a complex
unstimulated form: alpha subunit has bound GDP

All 3 can interact with targets located in the plasma membrane

alpha has GTPase

How do G protein receptor ion channels work?

Directly with the channel (no 2nd messenger)

G protein enzyme receptors

Gs= stimulate adenylyl cyclase (causes formation of cAMP)
Gi= inhibit adenylyl cyclase and open K channel
Gq= stimulate phospholipase C (causes formation of IP3 and DAG)

cAMP acts on ? is turned off by?

acts usually on Protein Kinase A
turned off by phosphatases (phsophodiesterases PDE)

PLC?

causes formation of
1. DAG- membrane bound where it (and Ca) activate PKC which cause phosphorylation of a variety of intracellular proteins
2. IP3- causes Ca release from the ER and Ca promotes binding of Ca to calmodulin, which regulates activities of other enzymes, including Ca dependent protein kinase

Ligand gated transmembrane enzymes- signals and receptors

1. Signals= insulin, EGF, PDGF and ANF and others
2. Receptors= tyrosine kinase, serine/threonine kinase, tyrosine phosphatase and guanylyl cyclase

intracellular receptors are generally?

Enzymes, gene regulatory proteins or structural proteins

4 ways of drug permeation?

aqueous diffusion (paracellular), lipid diffusion (transcellular), special carriers and endo/exo-cytosis

absorption?

is the transfer of a drug from its site of administration to the bloodstream

Enteral routes that avoid first pass effect?

complete= sublingual
partial= rectal
oral=NO

when are parenteral routes used?

When the drug is poorly absorbed in the GI tract or too unstable for it, if the person is unconscious or if rapid onset is required. Provides the most control over actual dose of drug delivered to the body.

example of subcutaneous and intradermal drug injection?

subcut= insulin
intradermal= PPD test

Factors that influence drug absorption

1. pH= non-ionized drugs are liposoluble (uncharged/protonated form HA and uncharged/nonprotonated form of B)
2. Surface area for absorption
3. Blood flow to absorption site
4. contact time at the absorption surface
5. P-glycoprotein
6. bioavailability (F)- fraction of administered dose that teaches systemic circulation

HH equation

pH= pK + log {unprotonated form/ protonated form}

= the relationship between the ratio of protonated to unprotonated forms of a molecule, the pK of the molecule and the pH of the solution is given by the above equation.

ionization

affects not only the rate at which drugs permeate membranes but also the steady-state distribution of drug molecules between aqueous compartments that differ in pH.

the lower the pH relative to the pKa, the greater will be the fraction of drug in the protonated form

ex. because the uncharged form of a weak acid is more liposoluble, more of a weak acid will be in the lipsolulbe form at acidic pH, while more of a basic drug will be in the liposoluble form at alkaline pH.

Ion trapping in urine

Weak acids are usually excreted faster in alkaline urine while weak bases are usually excreted faster in acidic urine

3 things about HH

1. When pH = pH, then unprotonated = protonated
2. For each unit pH above the pK, the unprotonated will be ten times the protonated.
3. For each unit of pH below pK, protonated will be ten times the unprotonated.

P-glycoprotein

Usually reduces drug absorption and is associated with multidrug resistance via
1. liver- drugs into bile
2. kidney- drugs into urine
3. intestines- drugs into intestinal lumen
4. brain capillaries- drugs back into blood, limiting access to brain

Determination of bioavailability?

is determined by comparing AUC (of drug vs. time) after a particular route of administration with the AUC after IV injection

(F) equation?

F= {[AUCoral]/[AUCiv]} x 100

factors affecting F?

1. drug formulation
2. chemical stability
3. food and drug interactions
4. First-pass hepatic metabolism
5. Drug solubility (drugs that are largely hydrophobic are most readily absorbed)
6. P-glycoprotein

Bioequivalence

Is the equivalence of blood concentration of two preparations of the same drug measured over time. If the two concentration-time plots are nearly superimposable, they are said to be bioequivalent: one can safely be replaced by the other

Drug distribution

is the process by which a drug leaves the blood stream and enter the extracellular fluid and or the cells of the tissues

Rate of drug delivery and the amount of drug distributed into tissues is determined by?

CO, regional blood flow, capillary permeability, tissue volume, degree of binding of the drug to plasma and tissue proteins and the hydrophobicity of the drug

The most important determinant of blood-tissue partitioning is?

The relative binding of drug to plasma proteins and tissue macromolecules that limits the concentration of free drug

Plasma protein drug binders/

acidic= albumin
basic= alpha-1-acid glycoprotein

What drug is unable to enter the CNS from circulation?

Strongly ionized agents such as quaternary ammonium compounds

Placental transfer of drugs?

Primarily via simple diffusion. Liposoluble, non-ionized drugs readily enter the fetal blood from maternal circulation

Drug elimination?

2 major routes are metabolism in the liver and excretion as unchanged drug by the kidney

lipophilicity of drug problem?

A drug needs to be lipophilic to easily cross plasma membranes but lipophilic drugs are largely reabsorbed through glomerular tubular membranes.

It is essential that a drug is turned into a hydrophilic metabolites for elimination from the body

Biotransformation reactions generally...?

Generate more polar, inactive metabolites that are readily excreted from the body.

Drug metabolism 1?

Phase 1= oxidation, reduction, decarboxylation, deamination and hydrolytic reactions. Usually convert parent drug into a more polar metabolite by adding or unmasking a functional group (-oh, NH2, -SH). This functional group then may serve as the point of attack of the conjugating system in Phase 2 to attach a substituent such as glucuronide.

generally phase 1 reactants results in inactive metabolites

Drug metabolism 2?

2=conjugation reactions that lead to formation of a covalent linkage between a functional group on the drug molecule and glucuronate, acetate, glutathione, amino acid or sulfate. These highly polar conjugates are generally inactive and excreted rapidly into urine or feces (exception: morphine-6-glucuronide)

Prodrugs?

Are inactive and designed to maximize the amoutn of active species that reaches the site of action. Usually are activated by hydrolysis of an ester or amide linkage.
ex. cyclophosphamide

drug metabolism principle ?

Not all drugs undergo sequential biotransformation and phase 2 reactions can precede phase 1 reactions

Sites of drug metabolism in organs and cells?

primarily= liver
also= skin, lungs, GI tract and kidneys.

cells= mostly in the ER (phase 1) and cytosol (phase 2) but also in the mitochondria, nuclear envelope and plasma membrane.

ER phase 1 reactions?

Typically oxidases- majority are heme protein mono-oxygenases of the cytochrome P450 class. Also known as microsomal mixed function oxidases and are involved in 75% of all drugs used today.

Cytochrome P450 reaction?

NADPH + H(+) + 02 + SH -> NADP(+) + H20 +SOH
s= enzyme substrate (can be steroid, FA or drug) and the reaction is a monooxygenation and the E=monooxygenase

- in mammals- the C P450 serve as terminal electron acceptors
In order for the reaction to occur- the heme iron must be reduced from ferric to the ferrous state so that the oxygen may bind the heme iron.

most important cytochrome ?

CYP3A4 metabolized approx. 50% of all therapeutic drugs.

family of CYP 1-3 are mostly active in the metabolism of xenobiotics, whereas other families have important endogenous functions

P450 enzyme induction typically occurs through?

via increased transcription but can occur via translation and decreased degradation

acetaminophen is made toxic in large doses by?

CYP2E1 -> NAPQ1 which is highly toxic to liver tissues.

antidote= N-acetylcysteine

What does grapefruit juice inhibit?

CYP3A4 and P-glycoprotein in the SI.

Age and drug metabolism?

Are slowed in both young children and elderly

Things that can effect liver architecture and affect hepatic metabolism of drugs?

Fat accumulation, alcoholic hepatitis, active/inactive alcoholic cirrhosis, hemochromatosis, chronic active hepatitis, biliary cirrhosis, acute viral or drug induced hepatitis

Drug excretion?

1. primarily= liver
2. small amount= bile
3. oral= incompletely absorbed from upper GI tract and residual is eliminated via fecal excretion
4. breast= important during nursing infants
5. lung= anesthetic gases
6. quantitatively unimportant= sweat, saliva and tears
7. detection= hair and skin (forensic)

glomerular capillaries allow?

drug molecules MW < 20,000 to diffuse into the glomerular filtrate (unbound). Heparin cannot freely cross.

*liposolubility and pH dont influence the passage of drugs into the glomerular filtrate.

Tubular secretion?

Drugs are transfered to the tubular lumen by 2 independent and relatively non-selective active transport systems: one for organic anions and one for organic cations

drugs with high liposolubility are excreted slowly

Clinical pharmacokinetics aim?

Design dose regimens that
1. optimize therapeutic response of a drug
2 minimize change of adverse reactions

Fundamental tenet of pharmacokinetics?

A relationship exists between the effects of a drug and the concentration of the drug in the blood

The plasma concentration of a drug is?

A function of the rate of input of the drug into the plasma, the rate of distribution to the tissues and the rate of elimination.

3 most important pharmacokinetic parameters are?

clearance (CL), volume of distribution (Vd) and bioavailability (F)

Clearance?

Is a measure of the body's ability to eliminate drug

definition= the volume of blood cleared of drug per unit time. Clearance predicts the rate of elimination of the drug in relation to the drug concentration.

CL equation?

CL = rate of elimination of drug (amount/time) / plasma drug concentration (amount/volume)

unit= volume per unit time

The clearance of a given drug is?

usually constant over the range of drug concentrations encountered clinically. This occurs because the physiological mechanisms of elimination are NOT saturated and thus the rate of elimination of a drug is directly proportional to its concentration in plasma

Rate of elimination?

= CL x C

This is called "first order" elimination. For a drug eliminated with 1st-order kinetics, CL is a CONSTANT (ie. the ratio of rate of elimination to plasma concentration is the same regardless of plasma concentration).

aka: linear kinetics b/c there is a linear relationship between the rate of elimination and the plasma concentration of the drug.

when a drug follows 1st order kinetics, a constant fraction of the drug is eliminated per unit time

What happens when the mechanism for a drug elimination is saturated?

= zero order kinetics
ie= a constant amount of drug is eliminated per unit time. Under such circumstances, clearance will vary with the [drug]

First order clearance calculation ?

CL= dose/ AUC

which describes the concentration of drug in the systemic circulation as a function of time.

Volume distribution?

Is a measure of the apparent space in the body available to contain the drug.

Vd= amount of drug in the body / plasma drug concentration

units= volume
vD= doesn't necessarily refer to an identifiable physiological volume

Minimum possible vD?

Drugs are are completely retrained within the vascular compartment have a minimum possible vD equal to the blood component in which they are distributed.

very high vD?

have a much higher concentration in the extravascular tissues than in the vascular compartment (ie. they are not homogeneously distributed)

compartment: examples
1. total body water (.6 L/kg)
2. extracellular water (.2 L/kg)
3. Blood/ plasma
4. fat
5. bone

1. relatively liposoluble molecules
2. hydrophilic molecules
3. strongly plasma protein-bound molecules and very large molecules
4. Highly liposoluble molecules
5. certain ions (lead, fluoride)

Vd plot?

2 phases
1. Rapid initial fall in drug plasma concentration = distribution phase ( alpha)
2. Slower phase = elimination phase ( Beta)
each phase has a characteristic 1/2 life.

kinetics of drug elimination: initial and later time t?

initial = dose/ Vd
later at time Ct will depend on the rate of elimination of the drug.

most drugs exhibit 1st order kinetics of elimination ( elimination is directly proportional to drug concentration C) Drug concentration decays exponentially.

Ct?

Ct= C0 e ^ (-ke x t)
ke= rate constant for elimination of the drug
-plotting the logarithm of Ct vs t yields a straight line with slope ke.

ke?

ke= CL / Vd

CL?

ke x Vd

The elimination rate constant is inversely related to the 1/2 life of the drug (t1/2)

ke= 0.693 / t (1/2)

1/2 life is ( blank) for drugs eliminated by 1st order kinetics (great majority of drugs)

blank= constant
zero order= not constant

1/2 life can be derived from?

A graph, Vd and Cl or

t 1/2= 0.693 x Vd / CL
unit=time

Constant infusion steady state and elimination based on 1/2 life?

50% steady state after 1 half life
75% on 2 half lives
87.5% on 3 half lives
93.75% on 4 half lives

In most clinical situations, it can be assumed that steady state is attained after ?

4 half lives (same with elimination)
note= increasing rate of infusion does not influence the time required to each Css
note= 1/2 life does not depend on dose

Non-linear kinetics (saturation) equation?

rate of elimination = Vmax x C / Km + C

km= plasma [] at which 1/2 of the maximal rate of elimination is reached
Vmax= the maximal rate of elimination

equation is entirely analogous to the MM equation for enzyme kinetics

when drug [ ] is significantly higher than Km, equation reduces to?

rate of elimination= Vmax x C / C = Vmax

Drugs with zero order elimination have clearance that is?

not constant and will vary with [ ] of drug.

therefore

Cl= rate of elimination / C = Vmax / Km + C
so clearance increases as the drug concentration decreases

Dosing plan?

Is based on knowledge of both the min. therapeutic and min. toxic [ ] for a given drug as well as its clearance, Vd and bioavailability.

TI?

is the window between the minimum therapeutic [ ] and the min. toxic [ ] of a drug. It is used to determine the range of plasma levels acceptable when designing a dosing regimen.

The minimum effective [ ] will determine the trough levels, while the min. toxic [ ] determines the peak plasma concentration.

Dosing rate ss=?

rate of elimination = CL x target [ ] / F

intermittent doses are given, then maintenance dose is calculated as?

maintenance dose= dosing rate x dosing interval

loading dose?

ld= Vd x target [ ] / F

Km?

Represents the plasma concentration at which half of the maximal rate of elimination i reached (in units of mass/time)

Vmax?

is equal to the maximal rate of elimination (in units of mass/time)

Dosing plan is based on what ?

1. Min. therapeutic []
2. Min. toxic []
3. Cl
4. Vd
5. F (bioavailability)

What is the most important parameter in defining a rational steady state drug dosage regimen?

Clearance

Dosing Rate ss?

=rate of elimination =
Cl x target Concentration / F

Intermittent doses- maintenance dose=?

dosing rate x dosing interval

At different dosing intervals, what will be the same and what will be different?

different= min and max values
same= the average level

If the therapeutic concentration must be achieved rapidly, and the Vd is large then ?

A large loading dose may be needed at the onset of therapy.

Ld= Vd x Target Concentration / F

When is steady state achieved?

WHen the rate of drug elimination is equal to rate of administration

Css?

rate of elimination = infusion rate = Cl x Css

Css= infusion rate / CL

In first order kinetics, the ss plasma [] is directly proportional to?

the infusion rate
-if infusion rate is doubled, the ss plasma [] is doubled.

Fixed doses result in?

time dependent fluctuations in the plasma level of the drug

Accumulation i s a function of?

half life of a drug and of the dosing interval

AF predicts?

the ratio of the peak concentration at ss to the peak concentration after the first dose

AF?

= 1/ fraction lost in one dosing interval = 1/ 1-fraction remaining

for a drug given once every half -life: AF=?

1/0.5= 2

PCss?

PC1 x AF
= the peak concentration after intermittent doses at ss will be equal to the peak concentration after the first dose multiplied by the AF

Maintenance dose=?

(dosing rate / F) x Dosing interval

adverse drug reaction?

noxious and unintended effect of a drug, occuring at doses used for prophylaxis, diagnosis or therapy

Type A?

explainable, 80% of ADRs
-an exaggerated, but otherwise expected pharmacological effect of a drug
-predictable and dose dependent

Type B?

unexplainable
-idiosyncratic effects- not expected from the known pharmacological action of a drug
-dose independent and unpredictable

Type C?

chronic effects
-ass. with long term therapy (benzo dependence)
-well known and can be anticipated

type D?

delayed effects
-carcinogenic and teratogenic effects
-delayed in onset and rare

mechanisms of drug toxicity?

1. on target- binds to intended receptor but at inappropriate concentration
2. off target- drugs binds to unintended receptor or right receptor but in wrong tissue, enantiomers, different receptor subtypes
3. toxic metabolites
4. harmful immune response
5. idiosyncratic response- rare adverse effects for which no obvious mechanism is apparent (d/t to unique individual genetic difference in the response to the drug molecule)

Ginkgo biloba?

inhibits platelet aggregation and used with NSAIDS may increase risk of bleeding

St. Johns Wort?

in combo with SSRI's, may cause a mild serotonergic syndrome

Long term treatment of schizo?

with dopamine receptor antagonists can lead to tardrive dyskinesia due to increase in # of receptors

when is teratogenesis likely to happen?

during organogenesis (weeks 3-8 of gestation) is when teratogens have most profound effect

FDA classification of drugs for use in pregnancy?
A,B,C,D,X

A. no shown increase in risk of fetal problems
B. Animal studies show no risks or well controlled study not done or animal study shows risk but well controlled human studies fail to show a risk to fetus
C. animal studies so adverse effects and no well controlled studies in women or no animal or well controlled studies have been done
D. Well controlled studies show risk to fetus but benefit may outweigh harm
X. All studies show positive evidence of fetal issues and drug use is contraindicated in women who are or may become pregnant

drug discovery?

1. Discovery- ID or screen compounds to find potentially active therapeutic agents
2. Hit- a compound that passes a screen
3. Lead- leading candidate for a successful new drug

Drug discovery should be?

-cost effective
-produce hits with high likelihood of conversion to leads

2 basic strategies used to identify hits?

1. Compound centered approach
2. Target centered approach

shot gun approach?

use of combinatorial chemistry and high throughput

lead optimization?

takes "lead" molecules and refines physical, chemical and biological and pharmacological properties.
Goal is selection of a single molecule to enter clinical testing and formal drug development

Phases of drug development?

Discovery (chemistry, biology)
ADME- absorption, distribution, metabolism and excretion
toxicology
development chemistry
formulation

no effect dose?

maximum dose at which specified toxic effect is not seen

preclinical safety and toxicity testing limitation?

1. time consuming and expensive.
2. large #'s of animals needed
3. extrapolations of data from animal to humans are not always correct
4. rare adverse effects unlikely to be detected

goal of testing acute toxicity? subacute/subchronic?

acute= no effect dose and max. tolerated dose
sub= biochemical and physiologic effects

before moving onto phase studies, you must have?

INDA

phase 1?

20-100 subjects
-intention is to establish safety, toxicity, kinetics and major adverse effects
outcome= max tolerated dose, absorption, distribution and metabolism and excretion
-may involve non blinded trials

phase 2?

several 100's subjects with medical condition of interest
-objectives include acquisition of preliminary data regarding the efficacy of the drug for treatment of a particular condition
-single or double blind studies

phase 3?

end of phase 2 must happen first. Must establish safety or FDA can mandate more studies.
-100-1000's of patients
-done at multiple sites, randomized, controlled, double blind trials with multiple study arms.
-usually performed in settings similar to those anticipated for drug's ultimate use
-based on specific end points (better for FDA approval) or surrogate endpoints

what is needed before market approval given?

NDA.
-requires full reports of all preclinical and clinical data
-can take months-> years for approval/denial

phase 4?

can happen once market approval given.
-monitoring is continued
-important in observing adverse effects that are rare or due to chronic dosing
-no fixed duration

inducers of P450 enzyme?

Phenobarbital, Rifampin, and Carbamazepine

Inhibitors of C. P450?

Amiodarone
Cimetidine
Azole anti fungals (ketoconazole)
Macrolide antibiotics (erythromycin)
Chloramphenicol
Ritonavir
Grapefruit juice

P-glycoprotein can be inhibited by? what can this effect? what is the transporter regulated by?

Macrolide antiobiotics

P-glycoproteins limit the oral F of drugs like digoxin and HIV-1 protease inhibitors thus inhibition of the P glycoprotein can cause increased serum levels of digoxin

Is transcriptionally regulated by PXR (hence if drugs can target PXR -> effect)

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