IVMS BASIC PHARMACOLOGY-General Principles, Pharmacokinetics and Pharmacodynamics Notes

Marc Imhotep Cray, M.D.

BASIC PHARMACOLOGY:

Pharmacokinetics and Pharmacodynamics

PHARMACOKINETICS: what the body does to the drug

PHARMACODYNAMICS: Study of what a drug does to the body

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HENDERSON-HESSELBACH EQUATION:

 Weak Acid
 pKa:

If its pKa < pH of the environment, then
the conjugate base (anion) form of the
species will predominate. Example =
CH3COO-
 If its pKa > pH of the environment, then
the environment is more acidic, so its
acidic (neutral) form will predominate.
Example = CH3COOH
 Weak acids tend to be absorbed in acidic
environments, like the stomach.
 Weak Base
 pKa
 If its pKa < pH of the environment, then
the environment is more basic, so the
species will remain in the neutral form.
Example = NH3
 If its pKa > pH of the environment, then
the environment is more acidic, so it will
give up its extra H+ to the base, and the
base will exist in its cation form. Example
= NH4+
 Weak bases tend to be absorbed in basic
environments, like the duodenum.

Pharmacokinetics and Pharmacodynamics Page 1


( pKa : negative log of the ionization constant and is
equal to the pH at which a drug is 50 % ionized.)

 Weak acids become highly ionized as pH increases,weak
bases become highly ionized as pH decreases



DRUG PERMEATION:

 Partition Coefficient: The ratio of lipid solubility to aqueous
solubility. The higher the partition coefficient, the more
membrane soluble is the substance.
 Kidney Glomeruli have the largest pores through which drugs
can pass ------> drug filtration.
 Blood Brain Barrier (BBB): Only lipid-soluble compounds get
through the BBB.
 Four components to the blood-brain barrier:
1. Tight Junctions in brain capillaries
2. Glial cell foot processes wrap around the
capillaries
3. Low CSF protein concentration --> no
oncotic pressure for reabsorbing protein
out of the plasma.
4. Endothelial cells in the brain contain
enzymes that metabolize, neutralize, many
drugs before they access the CSF.
 MAO and COMT are found in
brain endothelial cells. They
metabolize Dopamine before it
reaches the CSF, thus we must
give L-DOPA in order to get
dopamine to the CSF.
 Exceptions to the BBB. Certain parts of the brain are
not protected by the BBB:
 Pituitary, Median Eminence
 Supraventricular areas
 Parts of hypothalamus
Meningitis: It opens up the blood brain barrier, due to edema.
Thus Penicillin-G can be used to treat meningitis, despite the
fact that it doesn't normally cross the BBB.
Penicillin-G is also actively pumped back out of the
brain once it has crossed the BBB.



Routes of Administration:

 ORAL

FIRST-PASS EFFECT: Alteration of drugs in liver via
portal circulation. Some drugs have a high first-pass
effect and thus a lower bioavailability. Know these:
 Morphine
 Imipramine
 Propanolol
 Gastric Emptying: Generally, anything that slows
gastric emptying will slow the absorption of drugs.
 Things that slow gastric emptying: Fats,
acidic pH, bulk, anticholinergics,
hypothyroidism, Al(OH)3
 Faster gastric emptying is beneficial for
the absorption of most drugs
 Tetracycline chelates calcium and should
therefore not be given with milk.
 TOPICAL: Lipophilic drugs absorbed through skin.
 Examples: Nicotine patch, nitroglycerine,
scopolamine = for motion-sickness.

VOLUME OF DISTRIBUTION: The apparent amount of volume that a
drug seems to distribute to.





 Sites of Concentration: They can affect the Volume of
Distribution
 FAT: Drug concentrates in fat --> lower concentration
of drug in the plasma --> high Vd
 BONE: Drug concentrates in bone --> lower
concentration of drug in the plasma --> high Vd
 TISSUE: Drug concentrates in tissue--> lower
concentration of drug in the plasma--> high Vd
 PLASMA PROTEINS: Drug binds to plasma protein --
> higher concentration of drug in the plasma ---> low
Vd.
 The Vd is based on the total amount of drug
in the plasma (not just the amount of free
drug)
 TRANSCELLULAR: Drug concentrates in non-
plasma locations --> lower concentration of drug in
the plasma --> high Vd




Apparent Apparent #Liters % Total Example,
Vd Vd in 70kg Body Explanation
man Weight
(L / kg)
Plasma 0.045 3L 4.5% Plasma-Protein-bound
Water L/kg drugs, and large drugs
that stay in plasma.
Concentrates in blood
and thus has a small Vd.

Example = Heparin
Extracellular 0.2 14 L 20% Large water soluble
Water L/kg drugs.

Example = Mannitol
Total Body 0.6 42 L 60% Small water soluble
Water L/kg drugs; rapid equilibration
between body
compartments.

Example = Ethanol
Tissue >0.7 L/kg >42 L ----- Drugs that bind to tissue

Concentration Example = chloroquine,
which intercalates with
DNA intracellularly.

Vd may be greater than
TBW volume, hence
some drug must be
bound to plasma.

This is very common and
occurs with many drugs.



 Enterohepatic Circulation: Drugs that are recycled through the
enterohepatic circulation will have a lower concentration of drug
in the plasma, and therefore a higher V d.



PLASMA PROTEIN BINDING: Two main plasma proteins carry drugs
in the blood.

alpha1-Acid Glycoprotein

ALBUMIN OROSOMUCOID
Negatively Charged, hence it Positively Charged, hence it
binds primarily to weak binds primarily to weak
acids. bases.
Negative acute-phase Positive acute-phase
protein: its synthesis protein: its synthesis
decreases during time of increases during times of
body insult. body insult.
Examples: Phenytoin, Examples: Quinidine,
Salicylates Propanolol

BIOTRANSFORMATION: Alteration of drugs by the liver. Drugs can
be metabolized from active to inactive, or from inactive to active.
Generally drugs are made more hydrophilic by the process.

 PHASE I: Mixed-Function Oxidases, formed by microsomes
made out of SER folded over on itself.
 Cytochrome-P450 Enzyme Complex: Has four
required components in order to work.
 Cytochrome-P450 Enzyme
 Cytochrome-P450 Reductase
 O2
 NADPH: NADPH is the only energy
source. No ATP is required!
 Phase I enzymes perform multiple types of reactions:
 OXIDATIVE REACTIONS: on drugs, such
as Aromatic hydroxylation, aliphatic
hydroxylation, N-dealkylation, O-
dealkylation, S-dealkylation, N-Oxidation,
S-Oxidation, Desulfuration.



 REDUCTIVE REACTIONS: Azo, Nitrile,
Carbamyl
 HYDROLYTIC REACTIONS: Ester
hydrolysis, Amide hydrolysis.

 PHASE II: Drug Conjugation. usually to glucuronides, making
the drug more soluble.

CYTOCHROME-P450 COMPLEX:

 There are multiple isotypes.
 CYT-P450-2 and CYT-P450-3A are responsible for
the metabolism of most drugs.
 CYT-P450-3A4 metabolizes many drugs in the GI-
Tract, where it decreases the bioavailability of many
orally absorbed drugs.
 INDUCERS of CYT-P450 COMPLEX: Drugs that increase the
production of Cyt-P450 enzymes.
 ANTICONVULSANTS:Phenobarbitol,Phenytoin,Ca
rbamazepine induce CYT-P450-3A4
 Phenobarbitol, Phenytoin also induce CYT-P450-
2B1
 Polycyclic Aromatics (PAH): Induce CYT-P450-
1A1




Glucocorticoids induce CYT-P450-3A4
 Chronic Alcohol, Isoniazid induce CYT-P450-2E1.
This is important as this drug activates some
carcinogens such as Nitrosamines.
 Chronic alcoholics have up-regulated
many of their CYT-P450 enzymes.
 INHIBITORS of CYT-P450 COMPLEX: Drugs that inhibit the
production of Cyt-P450 enzymes.
 Acute Alcohol suppresses many of the CYT-P450
enzymes, explaining some of the drug-interactions of
acute alcohol use.
 Erythromycin, Ketanazole inhibit CYT-P450-3A4.
 Terfenadine (Seldane) is metabolized by
CYT-P450-3A4, so the toxic
unmetabolized form builds up in the
presence of Erythromycin. The
unmetabolized form is toxic and causes
lethal arrhythmias. This is why Seldane
was taken off the market.
 Chloramphenicol, Cimetidine, Disulfiram also
inhibit CYT-P450's.

EXCRETION:

 KIDNEY
 GLOMERULAR FILTRATION: Clearance of the
apparent volume of distribution by passive filtration.
 Drug with MW < 5000 ------> it is
completely filtered.
 Inulin is completely filtered, and its
clearance can be measured to estimate
Glomerular Filtration Rate (GFR).
 TUBULAR SECRETION: Active secretion.
 Specific Compounds that are secreted:
 para-Amino Hippurate (PAH)
is completely secreted, so its
clearance can be measured to
estimate Renal Blood Flow
(RBF).



 Penicillin-G is excreted by
active secretion. Probenecid
can be given to block this
secretion.
 Anionic System: The anionic secretory
system generally secretes weak ACIDS:
 Penicillins, Cephalosporins
 Salicylates
 Thiazide Diuretics
 Glucuronide conjugates
 Cationic System: The cationic secretory
system generally secretes BASES, or
things that are positively charged.
 Ion-Trapping: Drugs can be "trapped" in
the urine, and their rate of elimination can
be increased, by adjusting the pH of the
urine to accommodate the drug. This is
useful to make the body get rid of poisons
more quickly.
 To increase excretion of acidic
drugs, make the urine more
basic (give HCO3-)
 To increase excretion of basic
drugs, make the urine more
acidic.
 BILIARY EXCRETION: Some drugs are actively secreted in the
biliary tract and excreted in the feces. Some of the drug may be
reabsorbed via the enterohepatic circulation.
 Transporters: The liver actively transporters generally
large compounds (MW > 300), or positive, negative,
or neutral charge.
 Anionic Transporter: Transports some
acids, such as Bile Acids, Bilirubin
Glucuronides, Glucuronide conjugates,
Sulfobromophthalein, Penicillins
 Neutral Transporter: Transports lipophilic
agents, such as:
 Steroids
 Ouabain



 Cationic Transporter: Transports
positively charged agents, such as n-
Methylnicotinamide, tubocurarine.
 Charcoal can be given to increase the fecal
excretion of these drugs and prevent enterohepatic
reabsorption.
 Cholestyramine can be given to increase the rate of
biliary excretion of some drugs.

PHARMACOKINETICS: what the body does to the drug

 ORDERS of EXCRETION:
 ZERO-ORDER EXCRETION: The rate of excretion of
a drug is independent of its concentration.
 General properties:
 dC/dt = -K
 A plot of the drug-concentration
-vs- time is linear.
 The half-life of the drug
becomes continually shorter as
the drug is excreted.
 Examples:
 Ethanol is zero-order in
moderate quantities, because
the metabolism system is
saturated. The rate of
metabolism remains the same
no matter what the
concentration.
 Phenytoin and Salicylates
follow zero-order kinetic at high
concentration.
 FIRST-ORDER EXCRETION: The rate of excretion of
a drug is directly proportional to its concentration.
 General properties:
 dC/dt = -K[C]



 A plot of the log[conc] -vs- time
is linear. slope of the line = -Kel
/ 2.303
 The half-life of the drug remains
constant throughout its
excretion

Equation:
 HALF-LIFE: The half-life is inversely proportional to the Kel,
constant of elimination. The higher the elimination constant, the
shorter the half-life.



 COMPARTMENTS:
 One-Compartment Kinetics: Kinetics are calculated
based on the assumption that the drug is distributed
to one uniform compartment.
 One compartment kinetics implies that the
drug has a rapid equilibrium between
tissues and the blood, and that the release
of the drug from any tissues is not rate-
limiting in its excretion.
 One-compartment kinetics also assumes
that the drug is distributed instantaneously
throughout the body. This is only true for
IV infusion.
 Multi-Compartment Kinetics: Most drugs follow
multi-compartment kinetics to an extent.
 Biphasic Elimination Curve: Many drugs
follow a biphasic elimination curve -- first a
steep slope then a shallow slope.
 STEEP (initial) part of curve ---
> initial distribution of the drug
in the body.
 SHALLOW part of curve --->
ultimate renal excretion of drug,



which is dependent on the
release of the drug from tissue
compartments into the blood.

 CLEARANCE: The apparent volume of blood from which a drug
is cleared per unit of time.
 CLEARANCE OF DRUG = (Vd)x(Kel)
 The higher the volume of distribution of the
drug, the more rapid is its clearance.
 The higher the elimination constant, the
more rapid is its clearance.


 This is based on the Dilution Principle:
 (Conc)(Volume)=(Conc)(Volum
e)
 Total Amount=Total Amount
 MEANING: In first-order kinetics, drug is cleared at a
constant rate. A constant fraction of the V d is cleared
per unit time. The higher the K el, the higher is that
fraction of volume.
 Drug Clearance of 120 ml/min --> drug is
cleared at the same rate as GFR and is
not reabsorbed. Example = inulin




Drug clearance of 660 ml/min --> drug is
cleared at the same rate as RPF and is
actively secreted, and not reabsorbed.
Example = PAH
 BIOAVAILABILITY: The proportion of orally-administered drug
that reaches the target tissue and has activity.




 AUCORAL = Area under the curve. The total
amount of drug, through time, that has any
activity when administered orally.
 AUCIV = Area under curve. The total
amount of drug, through time, that has any
activity when administered IV. This is the
maximum amount of drug that will have
activity.
 100% Bioavailability = A drug administered by IV
infusion.
 BIOEQUIVALENCE: In order for two drugs to be
bioequivalent, they must have both the same
bioavailability and the same plasma profile, i.e. the
curve must have the same shape. That means they
must have the same Cmax and Tmax.
 Cmax: The maximum plasma concentration attained
by a drug-administration.
 Tmax: The time at which maximum concentration is
reached.

 REPETITIVE DOSES:
 FLUCTUATIONS: Drug levels fluctuate as you give
each dose. Several factors determine the degree to
which drug levels fluctuate.



 There are no fluctuations with continuous
IV infusion.
 Slow (more gradual) absorption also
reduces fluctuations, making it seem more
like it were continuous infusion.
 The more frequent the dosing interval, the
less the fluctuations. Theoretically, if you
give the drug, say, once every 30
seconds, then it is almost like continuous
IV infusion and there are no fluctuations.

 Steady-State Concentration (CSS): The plasma
concentration of the drug once it has reached steady
state.
 It takes 4 to 5 half-lives for a drug to reach
the steady state, regardless of dosage.
 After one half-life, you have
attained 50% of CSS. After two
half-lives, you have attained
75%, etc. Thus, after 4 or 5
half-lives, you have attained
~98% of CSS, which is close
enough for practical purposes.
 If a drug is dosed at the same interval as
its half-life, then the CSS will be twice the
C0 of the drug.
 If you have a drug of dose 50
mg and a half-life of 12 hrs, and
you dose it every 12 hrs, then
the steady-state concentration
you will achieve with that drug
will be 100 mg/L.


 D: Dose-amount. The higher
the dose amount, the higher the
Css.



: Dosage interval. The shorter the dosage
interval, the higher the Css

 F: Availability Fraction. The higher the
availability fraction, the higher the Css
 Kel: Elimination Constant. The higher the
elimination constant, the lower is the Css
 Vd: Volume of Distribution. A high volume of
distribution means we're putting the drug into a
large vessel, which means we should expect a
low Css.
 Cl: Clearance. The higher the drug-clearance,
the lower the Css.


 If you know the desired steady-state
concentration and the availability fraction,
then you can calculate the dosing rate.

 LOADING DOSE: When a drug has a long half-life, this is a way
to get to CSS much faster.
 Loading Dose = twice the regular dose, as long as
we are giving the drug at the same interval as the
half-life.


 INTRAVENOUS INFUSION: The CSS is equal to the input
(infusion rate x volume of distribution) divided by the output (Kel)



R0 = the rate of infusion.
 Vd = the volume of distribution, which
should be equal to plasma volume, or
3.15L, or 4.5% of TBW.
 Kel = Elimination Constant
 Loading Dose in this case is just equal to Volume of

distribution time the Css :




 RENAL DISEASE: Renal disease means the drug is not cleared
as quickly ---> the drug will have a higher CSS---> we should
adjust the dose downward to accommodate for the slower
clearance.
 If the fraction of renal clearance is 100% (i.e. the drug
is cleared only by the kidneys), then you decrease
the dosage by the same amount the clearance is
decreased.
 For example: If you have only 60% of
renal function remaining, then you give
only 60% of the original dose.
 If the fraction of renal clearance is less then 100%,
then multiply that fraction by the percent of renal
function remaining.
 For example: If you have only 60% of
renal function remaining, and 30% of the
drug is cleared by the kidney, then the
dose adjustment = (60%)(30%) = 20%.
The dose should be adjusted 20%, or you
should give 80% of the original dose.

 G =The percentage of the original dose
that we should give the patient.

If G = 60%, then we should give the patient 60% of the original dose.

 f =The fraction of the drug that is cleared by the
kidney.

If f is 100%, then the drug is cleared only by the kidney.




ClCr =Creatinine clearance of patient, and normal
clearance. The ratio is the percent of normal kidney
function remaining.
 Renal disease increases the time to reach steady-state
concentration. Renal Disease ---> longer half-life --->
longer time to reach steady-state.

PHARMACODYNAMICS: Study of what a drug does to the body

METABOTROPIC RECEPTOR-COUPLING MECHANISMS:

 SPECIFIC G-RECEPTORS

Gs Stimulates adenylate
cyclase (cAMP)
Gi Inhibits adenylate cyclase alpha2-Receptors have Gi --->
inhibit post-synaptic adrenergic
neurons
Gq Stimulates Phospholipase- alpha1-Receptors have Gq --> Ca+2
C (IP3/DAG) in smooth muscle
Go Inhibits Ca+2 channels
Gi Opens K+ channels

 (A) cAMP PATHWAY (beta-Adrenergic)
 HORMONE RECEPTORS: beta-Adrenergic, GH,
most hypothalamic and pituitary hormones.
 Signal Transduction Pathway:
 Adenylyl Cyclase ---> cAMP ---> PKA --->
phosphorylate target protein.
 Phosphodiesterase then cleaves cAMP -
--> 3',5'-AMP
 The GTP on the G-Protein spontaneously
cleaves back to GDP, to inactive the G-
Protein.
 Xanthines: Caffeine inhibits phosphodiesterase --->
cAMP.
 Desensitization:




beta-Arrestin Kinase (betaARK) is
activated by tonically high cAMP levels.
cAMP phosphorylates betaARK to activate
it.
 betaARK phosphorylates the regulatory
domain of the target receptors ---> prevent
cAMP activation.
 (B) PHOSPHO-INOSITOL PATHWAY (alpha-Adrenergic)
 HORMONE-RECEPTORS: alpha-Adrenergic
 Signal Transduction Pathway:
 Phospholipase-A2 cuts apart PIP2 ---> IP3
+ DAG
 IP3 goes to Rough-ER where it opens
calcium channels ---> Ca+2
 DAG phosphorylates PKC, a calmodulin-
kinase, which then phosphorylates the
target protein, whenever Ca+2 (from IP3) is
available.
+2
 Ca is then sequestered back into the
Rough-ER by active transport.
 (C) STEROID RECEPTORS:
 HORMONES: Cortisol, sex steroids, Thyroid
Hormone, Aldosterone
 Signal Transduction:
 Heat-shock proteins normally bind to the
nuclear receptor to hold it inactive.
 The hormone (Cortisol, Sex Steroids,
Tyrosine) bind to the nuclear receptor,
releasing the heat shock protein.
 The hormone-receptor complex then binds
to DNA to effect transcription.
 Cortisol stimulates Lipocortin ---> inhibit
Phospholipase-A2 ---> inhibit synthesis of
prostaglandins ---> anti-inflammatory properties.
 (D) TYROSINE-KINASE RECEPTORS
 Hormones: Insulin, IGF, EGF
 Pathway: auto-phosphorylation of tyrosine --->
phosphorylate target protein.



 (E) NITRIC OXIDE:
 NO-Synthases:
 Constitutive NO-Synthase: Present in
most cells, and is responsible for ACh-
activated smooth muscle relaxation.
 Inducible NO-Synthase: Induced by
cytokines to cause acute vasodilation.
 NO Functions:
 Forms free radical intermediates in PMN's
and macrophages.

IONOTROPIC RECEPTOR-COUPLING MECHANISMS:

 (A) GABA RECEPTOR:
-
 RECEPTOR MECHANISM: In the CNS, it is a Cl
channel. GABA binds ---> Cl- comes into neuron --->
hyperpolarization ---> Inhibitory effects in CNS.
 Barbiturates (Phenobarbitol): It binds at an
allosteric site to increase the effectiveness of GABA.
It is GABAergic, but it is not a GABA agonist,
because it does not bind to the same site as GABA.
 Benzodiazepines (Diazepam, Valium): It binds at a
separate site than the barbiturates, but it is still
GABAergic and binds at an allosteric site.
 Picrotoxin: GABA Antagonist, it antagonizes GABA,
causing excitability in the CNS. Thus it is a
convulsive agent.
 (B) NMDA RECEPTOR: N-Methyl-D-Aspartate
 MECH: It binds excitatory neurotransmitters,
glutamate and aspartate. It lets in Ca +2 (primarily) and
also Na+.
 Alzheimer's Disease: The NMDA receptor may play
a role in the pathogenesis of Alzheimer's Disease.
+
 Leaky NMDA Channels ---> Na comes in
the neuron ---> water follows Na+ --->
reversible cell damage to neurons
(hydropic swelling).
+2
 Leaky NMDA Channels ---> Ca builds up
in neuron ---> irreversible, oxidative



damage (free radicals) to neuron --->
permanent damage and cell death.
 MK-801 is an NMDA Receptor Blocker that has
been tried as experimental treatment for Alzheimer's.
But it doesn't work because it has a stimulatory effect
on the hippocampus, causing hallucinations, similar
to taking phencyclidine (PCP).
 (C) ACETYLCHOLINE NICOTINIC RECEPTOR:
+ +
 MECH: It is a Na channel. When 2 ACh's bind, Na
comes in, depolarizing the membrane.
 Desensitization: If you let ACh hang around long
enough (such in the presence of cholinesterase
inhibitors), then some of the ACh-receptors will
convert to a high-affinity state, and the ACh will stay
locked onto the receptors.
 RESULT: Fewer receptors are available ---
> ACh's effect is therefore antagonized ---
> depolarization blockade.
 This explains the way in which
cholinesterase inhibitors cause paralysis.
 Succinylcholine binds to the ACh with a higher
affinity than ACh.
 Early on, you will see fasciculations, as it
has its stimulatory effect on ACh.
 After that you see paralysis.
Succinylcholine becomes an ACh
antagonist, as all the receptors convert to
the high-affinity state, and the molecule
locks on.



DOSE-RESPONSE CURVES:

 Definitions:
 Affinity: A measure of the propensity of the drug to
bind with a given receptor.
 Potency: A potent drug induces the same response
at a lower concentration. A potent drug has a lower
EC50 value.
 Efficacy: The biologic response resulting from the
binding of a drug to its receptor. An efficacious drug
has a higher Emax value.
 Partial Agonist: A compound whose maximal
response (Emax) is somewhat less than the full
agonist.
 GRADED-RESPONSE CURVE: A plot of efficacy (some
measured value, such as blood pressure) -vs- drug
concentration.
 EC50 = The drug concentration at which 50%
efficacy is attained. The lower the EC50, the more
potent the drug.
 Emax = the maximum attained biological response out
of the drug.




 QUANTAL DOSE-RESPONSE CURVE: A graph of discrete
(yes-or-no) values, plotting the number of subjects attaining the
condition (such as death, or cure from disease) -vs- drug
concentration.
 ED50: The drug-dosage at which 50% of the
population attains the desired characteristic.
 LD50: Lethal-Dose-50. The drug-dose at which 50%
of the population is killed from a drug.



 THERAPEUTIC INDEX = LD50 / ED50
 The ratio of median lethal dose to median effective
dose.
 The higher the therapeutic index, the better. That
means that a higher dose is required for lethality,
compared to the dose required to be effective.
 MARGIN OF SAFETY = LD1 / ED99
 The ratio of the dosage required to kill 1% of
population, compared to the dosage that is effective
in 99% of population.
 The higher the margin of safety, the better.

 COMPETITIVE INHIBITORS: They bind to the same site as the
endogenous molecule, preventing the endogenous molecule
from binding.
 The DOSE-RESPONSE CURVE SHIFTS TO THE
RIGHT in the presence of a competitive inhibitor.
 The EC50 is increased: more of a drug
would be required to achieve same effect.



 The Emax does not change: maximum
efficacy is the same, as long as you have
enough of the endogenous molecules
around.
 The effect of a competitive inhibitor is REVERSIBLE
and can be overcome by a higher dose of the
endogenous substance.
 The intrinsic activity of a competitive inhibitor is 0. It
has no activity in itself, but only prevents the
endogenous substance from having activity.
 Partial Agonist: A substance that binds to a receptor
and shows less activity than the full agonist.
 At low concentrations, it increases the
overall biological response from the
receptor.
 At high concentrations, as all receptors are
occupied, it acts as a competitive
inhibitor and decreases the overall
biological response from the receptor.
 NON-COMPETITIVE INHIBITORS: They either (1) bind to a
different (allosteric) site, or (2) they bind irreversibly to the
primary site.
 The DOSE RESPONSE CURVE SHIFTS DOWN in
the presence of a non-competitive inhibitor.
 The EC50 is increased: more of a drug
would be required for same effect.
 The Emax decreases: The non-competitive
inhibitor permanently occupies some of
the receptors. The maximal attainable
response is therefore less.
 The intrinsic activity of the non-competitive inhibitor is
actually a negative number, as the number of
functional receptors, and therefore the maximum
attainable biological response, is decreased.




ADVERSE EFFECTS:

 Drug Toxicity: Dose-dependent adverse response to a drug.
 Organ-Directed Toxicity:
 Aspirin induced GI toxicity (due to
prostaglandin blockade)
 Epinephrine induced arrhythmias (due to
beta-agonist)
 Propanolol induced heart-block (due to
beta-antagonist)
 Aminoglycoside-induced renal toxicity
 Chloramphenicol-induced aplastic
anemia.
 Neonatal Toxicity: Drugs that are toxic to the fetus
or newborn.
 Sulfonamide-induced kernicterus.
 Chloramphenicol-induced Grey-Baby
Syndrome
 Tetracycline-induced teeth discoloration
and retardation of bone growth.
 TERATOGENS: Drugs that adversely affect the
development of the fetus
 Thalidomide:
 Antifolates such as Methotrexate.
 Phenytoin: Malformation of fingers, cleft
palate.
 Warfarin: Hypoplastic nasal structures.
 Diethylstilbestrol: Oral contraceptive is
no longer used because it causes



reproductive cancers in daughters born to
mothers taking the drug.
 Aminoglycosides, Chloroquine:
Deafness
 Drug Allergy: An exaggerated, immune-mediated response to a
drug.
 TYPE-I: Immediate IgE-mediated anaphylaxis.
 Example: Penicillin anaphylaxis.
 TYPE-II: Antibody-Dependent Cellular Cytotoxicity
(ADCC). IgG or IgM mediated attack against a
specific cell type, usually blood cells (anemia,
thrombocytopenia, leukopenia).
 Hemolytic anemia: induced by Penicillin
or Methyldopa
 Thrombocytopenia: induced by Quinidine
 SLE: Drug-induced SLE caused by
Hydralazine or Procainamide.
 TYPE-III: Immune-complex drug reaction
 Serum Sickness: Urticaria, arthralgia,
lymphadenopathy, fever.
 Steven-Johnson Syndrome: Form of
immune vasculitis induced by
sulfonamides. May be fatal.
 Symptoms: Erythema
multiforme,arthritis,nephritis,CN
S abnormalities,myocarditis.
 TYPE-IV: Contact dermatitis caused by topically-
applied drugs or by poison ivy.
 Drug Idiosyncrasies: An unusual response to a drug due to
genetic polymorphisms, or for unexplained reasons.
 Isoniazid: N-Acetylation affects the metabolism of
isoniazid
 Slow N-Acetylation: Isoniazid is more
likely to cause peripheral neuritis.
 Fast N-Acetylation: Some evidence says
that Isoniazid is more likely to cause
hepatotoxicity in this group. However,
other evidence says that age (above 35
yrs old) is the most important determinant
of hepatotoxicity.



 Alcohol can lead to facial flushing, or Tolbutamide
can lead to cardiotoxicity, in people with an oxidation
polymorphism.
 Succinylcholine can produce apnea in people with
abnormal serum cholinesterase. Their cholinesterase
is incapable of degrading the succinylcholine, thus it
builds up and depolarization blockade results.
 Primaquine, Sulfonamides induce acute hemolytic
anemia in patients with Glucose-6-Phosphate
Dehydrogenase deficiency.
 They have an inability to regenerate
NADPH in RBC's --> all reductive
processes that require NADPH are
impaired.
 Note that this is Acute Hemolytic Anemia,
yet it is not classified as an allergic
reaction -- it is an idiosyncrasy when
caused by sulfonamides or primaquine.
Other anemias are Type-II hypersensitivity
reactions.
 G6PD deficiency is most prevalent in
blacks & semitics. It is rare in caucasians
& asians.
 Barbiturates induce porphyria (urine turns dark red
on standing) in people with abnormal heme
biosynthesis.
 Psychosis, peripheral neuritis, and
abdominal pain may be found.

TOLERANCE

 Pharmacokinetic Tolerance: Increase in the enzymes
responsible for metabolizing the drug.
 Warfarin doses must be increased in patients taking
barbiturates or phenytoin, because these drugs
induce the enzymes responsible for metabolizing
warfarin.



 Pharmacodynamic Tolerance: Cellular tolerance, due to down-
regulation of receptors, or down-regulation of the intracellular
response to a drug.
 Tachyphylaxis: When using indirect agonists, which stimulate
the endogenous substance, this occurs when you run out of the
endogenous substance and therefore see the opposite effect, or
no effect at all.
 Tyramine can cause depletion of all NE stores if you
use it long enough, resulting in tachyphylaxis.
 Physiologic Tolerance: Two agents yield opposite physiology
effects.
 Competitixve Tolerance: Occurs when an agonist is
administered with an antagonist.
 Ex.: Naloxone and Morphine are chemical
antagonists, and one induces tolerance to the other

Further Study of Basic Medical Pharmacology:

PHAR - CH02 Pharmacokinetic Basis of Therapeutics and
Pharmacodynamic Principles-ANDREW M. PETERSON


IVMS BASIC PHARMACOLOGY-General Principles, Pharmacokinetics and Pharmacodynamics Notes

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IVMS BASIC PHARMACOLOGY-General Principles, Pharmacokinetics and Pharmacodynamics Notes