1General Concepts Flashcards
Pharmacokinetics
What body does to a drug
Pharmacokinetics -4processes
1.Absorption
2.Distribution
3. Metabolism (Biotransformation)
4. Excretion
Li
Nk between pk and pd
Concentration
Absorption
Drug uptake from site of ADMINISTRATION to BLOOD stream
Factors related to drug absorption
- DRUG characteristics
2.Route of administration
3.Blood flow
4.CELL MEMBRANE characteristics
 Drug characteristicsg
Drug formulation
Concentration of the drug
Lipophilic, lipophobic
non-ionized drugs , ionized
Acidic drugs,alkali drug
Blood flow
Increase blood flow causes increased absorption
Decrease blood flow causes decreased absorption
Cell membrane characteristics
Drugs cross the membrane via passive diffusion or active transport
Routes of drug administration
5
Enteral
Parenteral
Inhalation
Topical
Transdermal
Enteral route
- buccal or sublingual.
- Oral -most common
Most unpredictable
Least effective
30 minutes
Absorption in the DUODENUM - Rectal -anima or suppository 
Parenteral route
Intramuscular
Intravenous
Subcutaneous 
- Inhalation.
5 minutes
Can be titrated
IV. Can also be treated.
- Topical
Placed on skin for local effects
- Transdermal.
 Patch placed on the skin(fentanyl patch)
15 minutes
Intravenous
100% bioavailability
Immediate action, very rapid
Titration can be done
Disadvantage -can cause overdose due to rapid onset
Intramuscular
Acts in 5 minutes
Site buttocks, gluteal, muscle,upper lateral quadrant
Deltoid
Anterior thigh
Injected at 90°
Depth -adults 1 inch
Kids 1/4 inch
Never beyond 2/3 of the needle
length
Absorption : QUICKLY from AQUEOUS solutions and SLOW from OILYsolutions
- subcutaneous.
Action is in 15 minutes
The angle is 45°
Important points for onset of drug effects
Oral route 30 minutes
Subcutaneous injection and patch—- 15 minutes
INtramuscular and INhalation—- 5 minutes
IV-immediate
Bioavailability
How much a Drug reaches the circulator system is AVAILABLE AT THE SITE OF ACTION .
It is an INDEX
Factors affecting bioavailability
8
1 drug chemical formulation
2 Route of administration
3. Degradation of the drug prior to absorption
4. G.I. perfusion and the pH
5. Presence of other substances, like binders, or dispersing agents in G.I. tract
6. GI absorption mechanism that is active transport versus passive diffusion
7. Solubility to be well absorbed, the drug must be likely hydrophobic
8. Hepatic first pass mechanism
Normal drug metabolism
Normally, swallow drugs—— G.I. system—-blood—-site of action—-go to the liver—-gets metabolized——-excreted by the kidneys
Hepatic first pass metabolism
Swallowed drug——-a portion of the drug goes to the digestive system, and it gets metabolized——-another potion goes to the hepatic portal system—— then to the liver—— then to the rest of the body
So efficacy decreases, and by availability decreases, it’s only for some medications
The biological membran
It’s a bilayer of phospholipid, 100 Angstrom thick and adsorbed protein molecules
Transfer mechanisms across the biological membranes
1 passive transfer
2. Active transport
Passive transfer
1. Simple passive diffusion QQQ
does not require energy
Only lipid soluble drugh
- Simple passive diffusion.—-for LIPID SOLUBLEdrugs
Penetrate the bi membrane through membrane phospholipids
2.requirements:
1. Drug should be lipid soluble
- Have a high concentration on the outside and low on the inside that is concentration gradient.
Passive transfer
2. Filtration.
Only water molecules pass.
Water soluble molecules,small enough to pass through the membrane channels are carried by the bulk flow of WATER
Passive transfer
3 . Facilitated diffusion.
CARRIER BASED transfer
the driving force of the CONCENTRATION DIFFERENCE of the drug across the membrane
Active transport
For lipids, insoluble substances like GLUCOSE
Require energy as the carrier transfers the molecules across the concentration gradient
Osmosis
A pure, solvent like water moves to a semi permeable membrane.
The membrane is IMPRRMEABLE to the SOLUTE , but PERMEABLE to the SOLVENT .
This is against a concentration gradient.
Properties of drug for osmosis
- Lipid solubility.
- Degree of ionization.
- Molecular size and shape.
Normal drug
Activates in the body
Gets metabolized
Becomes inactive
Prodrug
Inactive
Becomes metabolized
Becomes active
Some drugs have active metabolites, even in Secondary
Example -1diazepam to DESMETHYL DIAZEPAM
2 codeine it gets metabolized to morphine, which is way more potent than codeine
- Digitoxin to digoxin.
 Only lipid soluble compounds go through the blood brain barrier
Example : THIOPENTAl is highly LIPID SOLUBLE and NON IONIZED it easily penetrate the blood brain barrier and gain access to the cerebral spinal fluid (CSF)induces sleep within seconds after IV administration
Drug distribution definition
Transport of a drug from bloodstream to various tissues in the body
Factors affecting drug distribution
4
rate of blood flow
Protein binding
Permeability
Gastric emptying time
Rate of blood flow
Increase blood flow increase perfusion
Decrease blood flow decrease perfusion
Protein binding
Most of the drugs have some CARRIERS in blood. Most important is ALBUMIN
these carriers DELAY delivery to the site of action.
Inc lipophilic—- inc BBB
Permeability
Ability to cross the capillary barriers like the blood brain barrier
Drug should be very LIPOPHILIC, and NON- IONIZED
Gastric emptying time
Indirect effect,
If drug in the stomach is for a longer time it takes more time for the drug to get distributed to the tissues
So longer gastric entering time has a negative effect
Solid meals 20 to 30 minutes
Liquid nails shorter
Sit ups, have a shorter gastric and entering time
Bi transformation/metabolism, definition
What is the chemical alternation of a NON POLAR… LIPID SOLUBLE DRUG, or compounds TO a more POLAR.. LIPID INSOlUBLE or water soluble compounds, so that they do not get reabsorbed in the renal tubule, and that easily excreted out through the body
Difference between active drug and drug for excretion
Active drug —nonpolar and lipophilic
For excretion drug has to be -ionized and hydrophilic
Biotransformation leads to
- Normal drug.— active drug to inactive, drug or it’s metabolites example morphine
- Prodrug.— an inactive drug becomes active.
Example levodopa, (inactive) to dopamine (active )
Prednisone, (inactive)to prednisolone (active)
- Active drug forms, active metabolites
Example diazepam to desmethyl diazepam
Digitoxin to digoxin
Phase 1 reaction
CYP 450 is responsible for drug metabolism IN BOTH PHASES
This phase occurs in liver microsomal enzyme systems
Liver has HEPATOCYTES which helping metabolism
Common drug reaction in phase 1
Oxidation
reactions in phase 1
Hydroxylation
Reduction
Hydrolysis
Oxidation
CYP 2D6
Related to codeine metabolism
Also causes genetic polymorphism
Patterns in phase 1 reaction
- Active drug to inactive metabolite
- Inactive, drug, active metabolite ( prodrug)
- Active drug do a second active compound, which converts to an inactive metabolite
The enzyme families involved in microsomal drug metabolism
Cytochromes
The cellular site of cytochrome P4 50 system
Hepatocytes
P4 50 inducers
They metabolize faster
so the therapeutic affect of other drugs is seen for a shorter time
Therefore efficacy is decreased
P4 50 inhibitors
The metabolize slower
so the therapeutic effect of other drugs can be seen for a longer time
Therefore efficacy is increased
Phase 1 reaction
Oxidation reduction, hydrolysis, and hydroxylation
All others like conjugation, glue colonization, etc. are in phase 2
Phase 1 to phase 2
Lipophilic drug gets converted to a hydrophilic drug
Phase 2 reactions
Occur mainly in the liver and kidneys
Most common reaction is conjugation, which comprises of
acetylation
methylation
Sulphation
Glucoronidation
Function of phase 2 reaction
Makes the drug HYDROPHILIC so that it can leave the body through KIDNEYS
Makes a non-ionized substance ionized
Conjugation mainly occurs in
Liver and kidneys
In Phase 2
Factors affecting hepatic drug metabolism
5
1.Microsomal enzyme, inhibitors
2.Microsomal enzyme, inducers
3.Plasma, protein binding
4.Genetic factors
5.Liver diseases
Microsomal enzyme, inhibitors examples
Grapefruit juice
Antifungals ketoconazole
Cimetidine
mechanism of action of microsomal enzyme, inhibitors
De inhibit or slow, the metabolism of other drugs.……so there are higher than expected blood levels of a drug.
so the therapeutic effects of a drug can be seen for a longer time
The efficacy of the drug is increased
for inhibitors, the enzymes are less functional
saw Drug levels are higher, because enzymes are less
therefore the efficacy is greater
Grapefruit juice / ketoconazole and warfarin
they will inhibit the metabolism of warfarin
so concentration and therapeutic effects of warfarin are increased
Efficacy is increased
So INR is increased
Microsomal enzyme, inducer example
Rifampicin
mechanism of action of microsomal enzyme induction
The inducer causes more rapid metabolism of other drugs,
so lower than expected blood levels of a drug,
the therapeutic affect of drug is seen for a short amount of time
So the efficacy of the drug is decreased
for inducer, there is more enzyme
So drug levels are low,
because the enzyme is more
so more drug is metabolized
the efficacy is less
rifampin and warfarin
rifampin is an inducer,
so the drug warfarin will metabolize faster,
so warfarin concentration decreases quickly,
and therefore INR decrease
Plasma, protein binding
So… the drug will not enter the liver to be metabolized
Results in longer plasma, half life of the drug
example of a plasma, protein binder
Albumin
genetic factors
CYP two D6
Liver diseases
because IMPAIRMENT of the microsomal drug metabolizing system,
so there are elevated levels of UNMETABOLIZED DRUG
stages of the liver disease
Fatty liver,
hepatitis,
cirrhosis
In liver disease
Most of the drug should be given in LOWER doses
acute alcohol
Microsomal enzyme, inhibitor
Chronic alcohol
Microsomal enzyme, inducer
One shot of alcohol, and acetaminophen or amitriptyline
this is microsomal enzyme, inhibitor
this prevents the metabolism of acetaminophen or amitriptyline,
so there are toxic levels of acetaminophen or amitriptyline
chronic alcoholic and acetaminophen or amitriptyline used
alcohol at as microsomal enzyme, inducer
so acetaminophen gets metabolized very quickly
so the analgesic effect of acetaminophen is decreased
in liver cirrhosis due to alcohol if we give acetaminophen
same reaction as acute alcohol
liver does not work anymore
so the drug is not being metabolized
it acts as P4 50 inhibitor so the dosage can go up, and the patient has toxicity of acetaminophen 

cimetidine and propanolol
Cimetidine is CYP 450 inhibitor therefore order the propanol bioavailability is doubled
Genetic factors like CYP two D6, (genetic polymorphism)
They rapidly metabolize the Drug
Example codeine
So efficacy is decreased
Also, The morphine toxicity goes up so there is respiratory depression
In In drugs with 450 inducer
The drug gets metabolized faster,
The therapeutic is seen for a shorter period of time
so efficacy is decreased
in having P450 inhibitor
The drug gets metabolized slower.
The therapeutic effect can be seen for a longer period of time,
and the efficacy is increased.
codeine is contraindicated in kids less than 12 years of age
this is because if a kid has CYP 2D6 GENETIC POLYMORPHISM it would result in
decreased efficacy of codeine and also morphine toxicity, and hence respiratory depression and death,
as we do not know who has, which child has this genetic polymorphism 
This genetic condition is very rare, but still
Molecules which cannot cross the membrane
Glucose, which is a large molecule
Charged molecules example sodium chloride
These are all HYDROPHILIC
After prodrugs get activated
They go to systemic circulation so that we can see the effect. They do not go to kidneys for excretion
Codeine is not a prodrug. why?
As codeine is active, but when it gets active, it forms morphine, which is active to
If a Drug does not get metabolized
It stays active for a longer period of time
Amphetamine
It is an indirectly acting sympathomimetic(breaking bad)
Use in narcolepsy that is, if anybody sleeps a lot
Drug for insomnia
Hypnotics like benzodiazepines
Or GABA Benz agonist like
zolpidem and
zopiclone.…they do not have any side effects
Microsomal enzyme, inhibitors
They in higher level cause toxicity
Liver, disease, example, severe hepatitis, or any liver problem
There is a decrease number of P4 50 cells or hepatocytes, so decrease the metabolism of the drug, and therefore toxicity
Inhibitors
They cause increased efficacy of drug in the beginning, but eventually cause toxicity due to overdose
Alcohol
Acute alcohol—-(alcohol plus drug simultaneously)—-it is an inhibitor
so the longer time the drug is available the drug does not get metabolized example acetaminophen itself is hepatotoxic. Alcohol is also hepatotoxic, therefore increased hepatotoxicity, and this can cause liver problem damage.
Chronic alcohol —-inducer
Severe alcohol —— drug does not get metabolized at all, as there is no P450 available so drug toxicity
Less than 12 years of age codeine is contraindicated
CYP two D6 is rapid metabolizer
Codeine levels decrease and morphine levels increase
elimination of the drug or excretion of the drug
It is a process by which the drug and their metabolites are removed from the body
drugs are excreted from the body either UNCHANGED or as METABOLITES
most important sites for drug elimination
Kidneys
biliary,
lungs
renal excretion
Occurs mainly by:
glomerular filtration,
tubular secretion, and
partial reabsorption,
mostly done for IONIZED WATER SOLUBLE compounds as compared to lipid soluble compounds
Factors affecting renal excretion
7
glomerular filtration rate
kidney tubular reabsorption
active secretion
changes in
plasma protein concentration, and
plasma protein binding
blood flow
number of functional nephrons and renal disease
volume of distribution
Metronidazole and warfarin
Metronidazole decreases the clearance of warfarin by 40%
Biliary excretion
Numerous CATIONIC,
ANIONiC and
STEROID like molecules are
selectively removed from the blood for excretion into the bile, and eventually the
FAECES
Lungs
excrete VOLATILE compounds that were originally inhaled into the system
example of compounds excreted by the lungs
Nitrous oxide
volatile general anesthetics, example, halothane ether, chloroform
Saliva
Most drugs can be detected in saliva after administration, but it is not considered a route of drug excretion
Zero order elimination of drug
Occurs in a LINEAR constant fashion regardless of the concentration.
Concentration will decrease linearly.
Examples of zero order elimination
alcohol,
phenytoin
aspirin, at high or toxic doses
first order elimination
Elimination of the drug in a proportional fashion to drug concentration.
Concentration of the drug will decrease EXPONENTIALLY with time.
Based on half life, most of the drugs are first order
drug half life
The time required for the PLASMA CONCENTRATION of a drug to DECREASE by 50%
The elimination half-life
Time required to metabolize and excrete 50% of the drug from the system
how many half days does it take to eliminate a Drug from the body?
About 4 1/2 -5
This is especially important for lactating mothers
Pharmacodynamics
what the Drug does to the body
it is the relationship between the CONCENTRATION of the drug at the site of action and the BIOCHEMICAL and PHYSIOLOGICAL effect
response of the receptors in pharmacodynamics is affected by
Presence of the drugs, competing for the same receptors
the functional state of the receptor
the pathophysiological factors, such as hypokalaemia
agonists
full agonist
The drug elicits, a full response by binding to the physiological, receptors and mimicking the regulatory effects of endogenous, signalling compounds in
Drug, gives the same physiological response
Example of a full agonist
beta two receptor agonist, Ventolin (salbutamol) , albuterol
Partial agonist
A drug that acts on the physiological receptor, but illicit an effect, which is only partially as effective as the agonist drug
Antagonist
A drug which binds to the physiological receptor, but does not trigger an effect
in the presence of an antagonist the agonist drug cannot reach the receptor site to produce an effect
Competitive antagonism
Not very strong response can be achieved by increasing the dose of the agonist in presence of the antagonist
Non-competitive antagonism
strong and very dangerous
when a response cannot be achieved with increasing the dose of the agonist in the presence of the antagonist
Inverse agonist
They r ACTIVE drugs.
not used really
it gives an opposite response.
They are not the same as antagonists.
Agonist antagonist
Yeah, the substances which act as an agonist at one site white acting as an antagonist on the other side
examples of agonist antagonist 
opioids (naltrexone)
pentazocine
Therapeutic index
It is a comparison off the Amount of an agent, or a drug that causes a therapeutic effect to the amount of the same agent that causes toxic effect
therapeutic index is equal to
LD 50 /ED 50
LD50 is equal to the lethal dose of a drug for 50% of the population
ED 50 is effective dose of a drug for 50% of the population
The drug with the higher therapeutic index
SAFE as you need increase lethal dose
Therapeutic window
Describe the range between the LOWEST therapeutic concentration, and the beginning of toxicity
Lowest level of therapeutic index and lowest level of toxicity
is wide therapeutic window, safe or narrow, therapeutic window safe
Wide therapeutic window is safe
Narrow therapeutic window
Drug is DANGEROUS example lithium, so monitoring the patient is very important
Efficacy
The number of RECEPTORS that must be ACTIVATED to yield a maximum RESPONSE
A Drug with high efficacy
Needs to stimulate only a small percentage of receptors
QQQ A drug that produces the greatest maximum affect
has highest efficacy
Factor determining the effect of a drug on physiological processes
Affinity
intrinsic activity

increased efficacy
Is equal to
increased affinity and
increase intrinsic activity
Define affinity
A measure of TIGHTNESS that a DRUG binds to the RECEPTOR
Intrinsic activity
A measure of the ability of a DRUG once bound to the RECEPTOR to generate an EFFECT
Drug formulation
it determines the AFFINITY and INTRINSIC ACTIVITY of a drug
The factors that determine the appropriate dosage of a drug
Patient’s medical history
age
bodyweight
NOT patient gender
potency
It is a relative CONCENTRATION of two or more drugs that produce the same drug effect
EC 50
It is an index .
It is the dose causing 50% of maximal effect
smaller the EC 50
greater the potency of the drug
determining factor for potency
AFFINITY of the receptor for the drug
additive affect
RESPONSE for the drug is NO GREATER than that which would be expected had the drug been given one at a time
there is NO ENHANCEMENT OF POTENTIAL of the individual drugs
example when we REPEATING the PRESCRIPTION of a drug.
Cumulative effect
When a drug is administered repeatedly, a HIGHER CONCENTRATION of the drug that is desired, will be achieved
this results in SIDE EFFECTS
A+A+A
Synergistic response
When the COMBINATION ACTION of two drugs is GREATER than the sum of their individual actions in synergism
A drug acts beneficially, when it is prescribed with another drug
1+1=4
Alcohol acts synergistic with
diazepam
narcotics
barbiturates,
phenothiazines
Theraupeutic dose
Has side effects
over the therapeutic dose
Toxicity
toxicity
When the dose of the drug is excessive in the blood for the particular patient
toxicity is OVERDOSE
Drug allergy
An adverse effect due to an immune reaction to a Drug
Side effects
Adverse effect that occurs WITHIN the therapeutic dose range of the drug
example atropine side effect is xerostomia
idiosyncratic reaction
Are reaction to a medication that is unusual and unpredictable specific to a particular person and like allergy it can occur on first exposure to the medication
it affects only a very few individual
example chloramphenicol causes aplastic anaemia
Teratogenicity
The capacity of a drug to cause foetal abnormalities when administered to a pregnant mother, by crossing through placenta
example thalidomide
hypersensitivity reaction type one immediate/anaphylactic
mediator: antibody
IGE antibody is induced by allergin and binds via the FC, receptors to mast cells and basophils
after encountering the antigen again the fixed IgE becomes cross-linked, introducing degranulation, and the release of the mediators example histamine
example anaphylaxis to penicillin
hypersensitivity reaction type 4 delayed
mediator—cell
helper, T lymphocytes, sensitized by an antigen release lymphokines . on second contact with the same antigen the lymphokines induce, inflammation and activate macrophages that in turn release various mediators
example poison ivy, TB test
drug abuse
Use of an illicit drug or a prescription or over-the-counter medication for purposes, other than that indicated for or
an amount is greater than prescribed
Habituation
Acquired TOLERANCE from REPEATED EXPOSURE to a particular STIMULUS
addiction
A compulsive,UNCONTROLLED DEPENDANCE on a substance or a habit for such a degree that cession results in SEVERE emotional, mental or psychological reaction
Tolerance
The need to increase the dose in order to achieve the same effects, originally achieved from a lower dose.
It is the phenomenon of DECREASED RESPONSIVENESS to a Drug following CHRONIC administration.
physical dependence
A condition in which CONTINUED ADMINISTRATION OF DRUG IS REQUIRED to prevent unpleasant withdrawal symptoms like nausea, severe headache, and body ache
Psychological or emotional dependence
Repeated use of substance, but WITHOUT the addictive physiological, need to increase the dose
Highest physical and psychological dependence
Narcotics(opioids)
amphetamines
cocaine
LSD
The criteria for including a Drug into one of the five schedules in the controlled substance act
- Potential for abuse, (most important) 2.medical usefulness
3.degree to which it produces physiological dependence
4.degree to which it produces physical dependence
schedule one drug examples
Highest abuse, potential
Ex: Heroin, LSD ,mescaline
Schedule I important points
- these drugs are NOT considered LEGITIMATE for medical use.
- They CANNOT be prescribed and made available.
- They are available only for SPECIFIC approved research projects.
- SPECIAL LICENSING procedure may be followed to use this or other schedule once of stances
Schedule II example
hi abuse, potential
example:
morphine, cocaine, pentobarbital, oxycodone,methadone, codeine and amphetamine, secobarbitol and straight codeine
Important points for scheduled ii
1.They have a strong potential for abuse or addiction but which have legitimate medical use
- these drugs can be prescribed, but they cannot be refilled.
3.A new prescription must be written for refills.
- Prescription for schedule II drugs cannot be called into the pharmacy over the telephone
- No refills
Schedule three examples
moderate abuse potential
example:
hydrocodone with acetaminophen( vicodin)
codeine with acetaminophen( Tylenol 3)
Schedule three important points
- these drugs may be called into the pharmacy over the telephone.
- The prescriber can authorize refills without need of a new written prescription.
- No greater than five prescriptions in six months
Schedule 4 examples
Less abuse potential
example
diazepam (Valium)
Lorazepam (Ativan )
triazolam (Halcyon)
Alprazolam (Xanax),
chloral hydrate
Dextroposition (Darvon)
Important points for schedule 4
- A category of drugs that have less potential for abuse or addiction than those of schedule 1 to 3.
2.prescription can be telephoned.
- No more than five prescriptions for six months
schedule five examples
Least abuse potential
example medication, containing a small amount of codeine
Properties of schedule five
A category of drugs that have a small potential for abuse or addiction.
They can be bought OTC in some states.
Prescription
The FDA determines which drugs are to be sold by prescription only
the prescription must have the address of the patient and dentist, as well as the DEA number of the dentist
Monitored drugs
Or any CONTROLLED SUBSTANCES under the federal control, drug and substance act,
example narcotic analgesics
example Tylenol #3 and OxyContin
Non-narcotic control drugs like methylphenidate (ritalin)
Benzodiazepines (valium)
Barbiturates (phenobarbital)
As well as other opioid medication’s, not listed in the Control Drug, in substance act, such as tramadol
which of the following factors does not affect the bioavailability of warfarin?
- Perfusion of G.I. system
- drug chemical, formulation
- route of administration
- Glomerular filtration rate
- hepatic first passed affect.
Answer GFR as it is related to excretion. All others are related to metabolism.
The distribution and use of all of the following agents is are controlled by the Control Drug, and substance act, except
- Amobarbital
- amitriptyline
3.amphetamine - diazepam
- hydrocodone
answer to it is a TCA -2
rule: Opioid, sedatives and amphetamines… most of these belong to Control Drug
amphetamine schedule three
diazepam is schedule 4
Hydrocodone is scheduled 3
concurrent intake of digoxin, with which of the following agents can result in digoxin toxicity
Ketoconazole
Rifampicin
codeine
propanolol
answer A
whenever you see the word toxicity look for the word inhibitor A is an inhibitor
B is an induser
C&D have no effect
Anaphylactic shock has three criteria
bronchospasm,
laryngeal oedema
CNS collapse
A drug with a greater efficacy
has greater affinity for the receptors .ie has more POTENCY
Greatest, maximal effect
Causes increased efficacy
Greater efficacy……. causes increased affinity for receptor……
so increased potency.
Tachyphylaxis
Tachyphylaxis is a medical term describing an acute, sudden decrease in response to a drug after its administration; i.e. a rapid and short-term onset of drug tolerance.
It can occur after an initial dose or after a series of small doses. Increasing the dose of the drug may be able to restore the original response
