Pharmacology

Pharmacodynamics I

- When you give a patient a drug you see the effects with being efficacy or toxicity
- Dose is given to the patient and within the patient’s body there builds a concentration which results in either efficacy or toxicity
- You need to have drug concentration to have certain effect in the body
- Pharmacokinetics= relationship between dose and concentration in different fluid –CSF, blood- of a drug
- Pharmacodynamics = qualitatively relates the relationship between the concentration of the drug in different fluid to the efficacy or
toxicity

Pharmacokinetics = what the body does to the drug

- When we look at pharmacokinetics, we look at four things that the body can do to the drug
o Absorption
o Distribution
o Metabolism
o Excretion

Pharramcodynamics = is what the drug to the body

- Inhibitor = prevent/reduce a physiologic, biochemical or pharmacologic activity at the level of receptor, cell, organ/tissue or whole body
- Activator = opposite effect than the inhibitor
- Agonist = produce an action at a receptor system
- Antagonist= prevent an agonist from having its action at the same receptor system

- Levels of drug action

o Molecular
o Cellular
o Tissue
o System
- MOLECULAR LEVEL DRUG EFFECT
o Drug must bind to molecular targets to produce their actions
 Drug can have effect on one tissue and none on another
o Some molecular drug targets include
 Hormones and neurotransmitter receptors
 Enzymes
 Transporters
 Ion channels
 Nucleic acids
 Idiosyncratic targets = metal ions, surfactant proteins gastrointestinal contents
o Some drugs do not have molecular targets
 Buffers
 Osmotic diuretics or laxatives
 Gaseous and volatile

MAIN MOLECULAR TARGETS

 Receptors
o Agonist and antagonist
o Agonist = leads to response
o Antagonist stays at the receptor and blocks the action of the agonist
 Enzymes
o The drug can bind to the enzyme and inhibit its activity
o False substrate will be processed by the enzyme and if given in a higher concentration than the endogenous enzyme then it
would compete and reduces the activity of the endogenous enzyme
 Channels
o Ion channels – 2 kinds
 Receptor operated ion channels
 Similar to the receptors that work with agonist and antagonist drugs
 Voltage operated ion channels
 It is not a receptor interaction since the membrane interaction is triggered by voltage difference (membrane
potential)
 The drug cannot control the opening and closing of the channel
 But it can bind to the channel and close the pore and block the membrane potential change
 Transport carriers
o Facilitate the transport of endogenous compounds
o Examples of transport carriers
  Antiport
 One goes in and one goes out –exchange of compounds –co transport
 The drug can bind and inhibit the transport activity
 Symport
 Two molecules travel in the same direction together – co-transport

MOLECULAR ACTIVITY of DRUGS

- Prerequisites for receptor interaction

o #1 Recognition -receptor protein must exist in a conformational state that allows for recognition and binding of a compound and
must satisfy:
 Saturability – receptors exist in finite numbers
 Reversibility – binding must occur non-covalently due to weak intermolecular force – H-bonding, van-der-waal forces
 Stereoselectivity – receptors should recognize only one of the naturally occurring optical isomers
 Agonist specificity – structurally related drugs should bind well, while physically dissimilar compounds should bind
poorly
 Tissue specificity – binding should occur in tissue known to be sensitive to the endogenous ligand and should occur at
physiological relevant concentration
o #2 Transduction: binding of an agonist must be transduced into some kind of functional response – biological or physiological
- Classes of receptors
o 4 hormonal neurotransmitter receptor superfamilies
 Receptor operated channel
 G- protein coupled receptor
 Tyrosine kinase receptor (receptor that is an enzyme)
 DNA – coupled receptor
 Intercellular receptor
- Receptor theory
o Lock and Key model
 Receptor (large proteins) contain a site at which drugs can be recognized and bound
 Binding of a ligand –drug- results in conformational –allosteric-change in the three dimensional structure
 Complex formed
 Transduction within the cell
- Classes of ligands
o Full agonist – optimal tissue response
o Competitive Antagonist- binds to receptor without initiating molecular response, blocks agonist access to receptor
o Partial Agonist – similar to the agonist, produces a molecular response but do not get the optimal tissue response like the full
agonist, this allows it to act as functional antagonist since both of them are similar and have the same affect on the tissue,
competes with the full agonist
o Inverse Agonist – binds to receptor that is in activated state(basal activation in the absence of ligand) in the absence of ligand,
and inactivate or stabilizes inactive form
- Receptor reserve
o Tissue response to drug is not directly proportional to molecular response
o Most cells reach maximum cellular response to an agonist reached when only a small fraction of receptors is occupied
o Basically, small fraction of receptors need to be activated to get the maximum response
o Example
 Partial agonist – can overcome
 If the cell doesn’t have spare receptor
o The partial agonist does not achieve the same maximum cellular response as full agonist
 If there are spare receptors
o Partial agonist needs to interact with more receptor than the full agonist to get the same maximum
result
o If the concentration of the partial agonist is increases it will give it the opportunity to bind to the
spare receptors and give the optimal response observed in full agonist
- Antagonism
o They reduce the number of receptors available for agonist binding
 Competitive antagonism
 Binds where the agonist normally binds
 Non competitive antagonism
 Binds to an allosteric site= different from the binding site of the agonist, only if the agonist is not already
bound
 This binding results in conformation change of receptor that changes agonist binding = no agonist binging or
no signal transduction
 Uncompetitive antagonism
 Binds allosterically even if the agonist is already bound
 Reverse and irreversible antagonism (covalently or non-covalently bound)
 Physiological antagonism
 They work through different receptors and have antagonist physical effect on the system/tissue
  Example
o Acetylcholine and noradrenalin on arterioles
- Drug-receptor binding
o Binding occurs when ligand and receptor collide with the proper orientation and energy
o Interaction is reversible
o Rate of association or dissociation depends solely on:
 The number of receptors
 The concentration of ligands
 The rate constants Kon and Koff
 At equilibrium, the rate of formation equals that of dissociation
 KD = Koff/ Kon
 KD= dissociation constant
o Is an inverse measure of receptor affinity
o KD = [D] produces 50% receptor occupancy
 Drug affinity to receptor
- Dissociation constant
o Used to describe the affinity-how tightly a ligand binds-between a ligand (drug) and protein (receptor)
o The formation of the ligand-protein complex = C = P + L
o KD = [P] [L]/ [C]
 The smaller the dissociation constant the more tightly bound the ligand is to its protein receptor = higher affinity
between the ligand and the protein
o Law of mass action
 All receptors are equally accessible to ligand
 no partial ligand occurs, receptors are either bound or free
 ligand is not altered by binding, just the enzyme is
 binding is reversible
 KD is an inverse measure of receptor affinity
- Fractional occupancy
o % of drugs that are occupying the receptor
- Competitive antagonism
o When there is a competitive antagonist is present, K D changes, since we have to take into account the agonist and the competitive
agonist that have attached to the receptor
o KD’ is the new dissociation value for the agonist and the competitive antagonist
o We can decrease the competitive antagonist by increasing the concentration of the agonist
o The presence of the competitive antagonist shift the curve to the right
o KD’ is going to be bigger than KD

Drug effect on the organ/system level

- Receptor operated channel

o Causes depolarization/hyerpolorization and leads to tissue response
o Takes milliseconds
- G- protein coupled receptor
o Change in excitability
o Or activate second messengers who cause changes within the cell leading to tissue response
o Takes seconds
- Tyrosine kinase receptor (receptor that is an enzyme)
o Leads to protein phosphorylation which leads to tissue response
o Takes minutes
- DNA – coupled receptor
o Goes into the nucleus to cause change in protein synthesis leading to tissue response
o Take hours

Doses-Response Relationship

- Sigmoid curve resembling drug-receptor binding

- Translation of agonist-receptor interaction into tissue response
o Often non-linear relationship due to multiple transduction/translation steps
- Intrinsic activity
o Relative maximum effect of a drug in a particular tissue preparation when compared to the natural, endogenous ligand
 Full agonist acts equal to the endogenous ligand, intrinsic activity = 1
 Antagonist – intrinsic activity = 0
 Partial agonist – intrinsic activity = 0~1, (product less than the maximum response, but with maximum binding to
receptors)
 Inverse agonist – intrinsic activity = eg. -1
- Potency
 o The ability of a drug to cause a measured functional change at a certain does/concentration
o Characterized by E50 TD 50LD 50 , the smaller the number the more potent the drug is
- Efficacy
o Relationship between receptor – occupancy and the ability to initiate a response at the molecular, cellular, tissue, or system
level

Potency measures

- Efficacy dose
o For continuous or graded response: dose level at which 50% the maximum effects has been reached
o For binary response (all or nothing): dose level at which 50% of individuals experience efficacy
- Toxic effect
o 50% for undesired – toxic effect
o Used in animal experiment to determine the dose level at which 50% of animals show signs of toxicity
o TD50 does not contain information on the seriousness of the toxic effect
- LD –death
o Dose level at which 50% of the exposed animals die
o LD50 highly dependent on the species
o For most drugs ED50 < TD50 < LD50

Therapeutic index

- is the ration of the does that produces toxicity to the does that produces a clinical desired or effective response in a population of
individuals
- drug safety margin must be >1 to be used
- therapeutic range includes variability in concentration-effect relationship
- therapeutic range- is a range of drug where the probability of desired response is high and unacceptable toxicity if low

Theophylline- therapeutically effects

- has different effect on different concentration in adults and has different affect on children
- also has adverse effect at different concentration and depends on the individual – mild to severs
- therapeutic range also differs between different populations –adults and children

Adverse Drug reactions

- drug may interact with not only with the intended target structure but also with the same, similar unrelated receptors or other target
structures in the same or other tissues
- ADR accompany the desired reaction – unintended reaction

Classification of ADR

- Type A ADR
o So called side effects
o They are dose related and are predictable reaction to the drug- based on the pharmacologic activity of the drug
o ADR are expected to occur in certain fraction of treated individuals
 Frequency and severity of type-A ADR is directly related to therapeutic range and selectivity
 The more selective the drug is with its receptor the larger its therapeutic range and the less likely is the
occurrence of type A ADR
 Examples
o Sildenafil
 Has partial selectivity to phosphodiesterase 6 and its selectivity to PDE6 which is found
in the eye has caused visual disturbances in some individuals
o Tadalafil
 Higher selectivity to PDE5 when compared to PDE6 which allows it to have higher
therapeutic index and lower frequency of visual side effects as seen in sildenafil which
was causing visual issues since it was partially selective to PDE6
- Type B ADR
o Idiosyncratic (individual) reaction
 Examples
 Hepatotoxicity
o Associated with the formation of toxic metabolites or intermediates only in certain individuals with
certain genetic
 Nephrotoxicity
o Related to protein binding, transport, rate of water vs. drug reabsorption
 Pancreatitis
 Hypersensitivity (allergic) reactions
 o Immunologically mediated
o Asthma, rhinitis, urtikaria
o Type I-IgE,

o Type II-IgG,IgM,
o TypeIII-IgG, IgM
o Type IV –Tcell
o Non-dose related, unexpected such as allergic reaction, carcinogenic and teratogenic effects
o Genetically determined abnormal reactivity to a drug
 Does independent and unpredictable
 Not related to the pharmacological properties of the drug
 Occurs in a subset of the population at therapeutic doses and do not occur in the rest of the population despite
increasing the does to otherwise toxic level
 It is host depended, no simple does response relationship, not reproducible in animal or controlled studies, usually rear
dissect

Tolerance

- Diminishing effect to a repeated stimulus (dose)

- Can be due to metabolic tolerance and functional tolerance
- Metabolic tolerance = time-dependent change in pharmacokinetics –clearing
o Decreasing drug concentration after repeated administration of the same dose= diminishing drug effects in response to these
doses
- Functional tolerance = time-dependent change in pharmacodynamics
o Reduction in effect intensity at concentrations that earlier produced greater effect
o Or decrease in drug effect over time despite constant effect site concentrations
o Decrease in response could be due to decrease in receptor number or receptor desensitization
 Desensitization – the receptors are tired
 Receptor down regulation
 receptor internalized using endosomes and lysosomes
 net loss in total cell receptor number
o Emax decreases = Kd stays the same
o Clockwise hysteresis loop
- Tachyphylaxis
o Is a special form of functional tolerance
o Rapid tolerance development
 Within minutes to hours
 Also rapidly reversible
 Examples
 Indirect sympathomimetics (amphetamines, ephedrine)
o Indirectly releases stored neurotransmitters
o Overtime reduction of stored neurotransmitters leads to reduced or no response
o Overtime, the stored neurotransmitters will run out and you will get reduced-to no response
o Reversible, take away the drug the storage will fill up again
 Nitrate (Nitroglycerin)
o Depletion of SH-groups containing compounds necessary for the conversion of nitrates to
pharmacologic active NO
o SH-pool replenished within hours after discontinuation of nitrate
- Depends
o Produced by rewards within the brain
o Repeated compulsive drug use to receive its rewarding effect = psychological dependence
o Or- avoid punishing effects of withdrawal = physiological dependence
 Usually they are present together to various degrees
 It starts with psychological dependence and lead to physiological dependence
o Rewards lead to operant conditioning
o The brain initiates adopted mechanism which is called neuroadaptation to restore physiological homeostasis
 Neuroadaptation can cause physiological dependence
 Physiological adaptation is unpleasant and sever effect in case of withdrawal or abstinence =this occurs when
there is no stimulation
o Mechanism of dependence
 Receptor downregulation
 Agonist and neurotransmitter present at the same time, this will cause the receptor to be over stimulated, to
establish homeostasis, receptors will be reduced = downregulation
 Drug withdrawal
 o in this situation, there is low concentration of the neurotransmitter and low number of receptor,
when the agonist is taken away there will still be low number of neurotransmitter concentration but
the number of receptors will return leading to withdrawal symptoms
 ratio of transmitter and receptor upset
 upregulation
 in the presence of antagonist
 the antagonist will inhibit some of the receptors of the neurotransmitters, to compensate, the brain will
increase the number of receptors
 when the antagonist is taken away, the number of available receptors are not activated leading since the
concentration of the transmitter and antagonist has decreased, this will lead to withdrawal symptoms
 Affinity
 Similar to desensitization
 This is a much lesser problem when compared to receptor upregulation
 Here the receptors change conformation in the presence of the agonist and transmitters
 When the agonist is taken away, the transmitter will weakly bind to the receptor and lead to symptoms of
withdrawal

Variability of pharmacodynamics across the lifespan

- There are several things that can affect pharmacokinetics

Pediatric pharmacodynamics = developmental pharmacology – CHANGE IN RECEPTOR SYSTEM

- Pediatric development can alter the action of and response to drug

- True age dependent differences either in the interaction between a drug and its specific receptor are rare
- Ex
o Cyclosporine
 Immune suppressant drug
 1 yr old = E50= 30
 4 yrs old
 12 yrs old =E50 = 80-90
 12-18 yrs old
 The graph shifts to the right
 Different in potency of the drug based on age
 Lower E50 translate into higher end of sensitivity to the drug
o The drug has a higher potency in younger patients =higher sensitivity (INR)
 The same drug concentration will have different effect in different age groups
 Neonates are more sensitive to drugs than other age group
 ELDERLY
 Changes in receptor density- reduction in density
 The change in receptor density will correlate with physical change = diminished memory in the brain ,
decrease rate and contraction of the heart

Drug development

The food drug and cosmetic Act of 1938

- Requires drug to be effeicacious and safe

- Provides the FDA with authority to regulate development manufacturing use and marketing of drugs and medical devices to ensure their
safety and efficacy
- some role of the FAD
o new drug application
 submission and approval by FDA are prerequisites for marketing a drug in the US
o abbreviate new drug application
 for generic versions of a brand name drugs
 need to show bioequivalent between the brand name drug and generic new drug
o investigational new drug application
 for the first use of the drug in human

Phase of drug development

- identify a lead compound that target a specific biochemical pathway/receptor that interferes with pathogenesis, symptoms or progression of
a disease
o selecting target that is relevant to the receptor (specific to the target)
o designing compounds that interact with the target in the desired fashion
o understanding the molecular mechanism of the disease
o optimize the initial hits to obtain leads for further development
- Pre-clinical development I
o evaluation and optimization of chemical leads in in vitro and in vivo animal models with regard to efficacy and safety
 in vitro
 cell line based and cell free assay = isolated receptors
 identify mechanism of action
 assess potential for off-target effects = undesired drug targets
o drug manufacturing and formulation development
 how the drug is going to be manufactured
 good manufacturing practice= set by the FDA that controls the method of drug manufacturing
- pre clinical development II
o in vivo pre-clinical studies in animal species
 attempt to establish drug efficacy
 establish PK and PD relationships including the bioavailability, penetration into different organs and tissues, and the
dose-concentration effect relationship
 toxicity studies
 acute toxicity
o tested at least two species and non can be rodents
 multi-does toxicity
 reproductive toxicity
 mutogenicity
 carcinogenicity
 all these tests will be submitted to FDA before testing can move on to human
 this is called good laboratory practice conditions
 animal scale up
 move testing to humans
 define the first in man dose- effective does
 then establish toxic dose
o pre clinical to clinical transmission
 investigational new drug application (IND)
 need to be filled with the FDA before resting of drug in humans
 intended to ensure reasonable safety for initial use in humans
 contains
o animal pharmacology and toxicology studies
o manufacturing information= composition, manufacturer stability and contains
o clinical protocols and investigator information
 FDA has 30 day to object to an IND after it has been filed
 Research in human subject is regulated by federal laws and each investigational study in humans requires approval by
an institutional review board (IRB)
 Subjects have to give consent to testing in written form

o Clinical Development – phase I and II

 Phase I studies
 Comprise small numbers of healthy subjects (<100)
 Solely intended to establish the tolerability and safety of a new drug product
 Secondary aims include characterizing the pharmacokinetics in humans
 Efficacy is NOT an objective in phase I studies:
o For drugs with inherent toxicity: performed in patients with the targeted disease. Tolerability and
safety remains the primary objectives in these studies
 Phase II studies
 Performed in patients with the illness, 24-300 subjects
 Early phase II (phase IIa)
o Proof of concept studies- show that the hypothesized therapeutic concept is working in vivo in
humans
 Late stage phase II (phase IIb) studies
o Identify appropriate patient populations in which the drug works best, determine the
appropriate dosing regimens
  Phase III studies
 To confirm efficacy and safety in a large patient population – 250 - >1000 patients
 Detect and evaluate adverse drug events that may be encountered in clinical use
 For submission of a New Drug Application (NDA)
o Efficacy and safety results need to be replicated with the same dosage regiment in two
independent double- blind randomized placebo-controlled clinical trials (pivotal trails)
o Depending on the indication placebo control might need to be replaced by the current standard of
care for ethical reasons
 Phase IV studies
 Post market studies
o Conducted after approval to further refine the use of the drug in different patient populations,
different indication, or different formulation
o Pharmacovigilance and risk mitigation strategies: growing efforts in post-marketing drug
development intended to identify new information about side effects and adverse events

Pharmacokinetics I

Who’s responsibility?

- The prescriber
o Should warn their patient about the risk associated with taking the drugs

Pharmacology = how the drug acts on the body

- Use blood concentration of drug-since its most accessible-as a surrogate marker for the tissue concentration
- The maximum rate on the graph is where the absorption rate of the drug equals the body’s elimination rate
o This does not mean that absorption is complete, it just means that the two rates are equal
o In the time against drug concentration graph
 The maximum rate - rate of absorption = rate of elimination
 Then it starts to decline
 This decline is drug and individual dependent
o AUC= area under the curve
 Concentration time profile = response to intensity and duration
 The higher the curve the higher the intensity
 The longer the area under the curve the longer the duration of the drug
o AUC = f is (drug that is administrated that reaches the systemic circulation) * DOSE /CL

Route of administration

- Most common are oral and IV

- They both have advantages and disadvantages

Oral administration advantage

- Most common, safe, convenient, economical method

- Self administration
- Quick onset (10 -60 minutes)
- Duration 30 minutes -12 hrs
- Immediate release
o Tablet or capsule available readily

Oral administration disadvantage

- GI mucosal irritation
- Compliance – patient cooperation
o Patient might have other factors that might prohibit them from taking their medications
- Degradation
o Digestive enzymes or low gastric pH
o The drug might not be available to the site that is needed due to being metabolized by the enzymes of the mucosa, the intestinal
flora, or the liver (limit the absorption of the drug)
- Altered absorption profile
o The diet can change the absorption rate of the drug
o Blood flow is increased to the gut when medication is taken with a meal, it will be cleared at a higher rate and might not reach the
area of interest

Immediate vs. sustained release

 - Immediate release tablets
- Sustained release tablets

Pharmacokinetics – what the body does to the drug

- Absorption
o Movement of the drug from the site of administration to the site of measurement- plasma
- Distribution
o Reversible transfer of drug from the site of measurement and the tissue
o Where the drug goes
- Metabolism
o Conversion of one chemical entity to another
o The liver
- Excretion
o Irreversible loss of chemically unchanged or parent drug
o Kidney

The body

- Can be thought as compartment s

- Drug at the absorption site=oral to the vascular space
o Vascular space
 The drug can go through reversible distribution into tissues
 It can undergo irreversible metabolism in the liver
 escape through the urine after being metabolized by the liver
 It can be excrete as parent molecule in the urine

Biopharmaceutics: Principles of membrane permeability

Drug absorption - Movement of the drug from the site of administration to the site of measurement- plasma

- Plasma = aqueous, used to determine drug concentration

- Blood = RBC and aqueous
o Top is plasma
o Bottom is blood
- Movement of drug
o Drug can move between cells but it is limited because of gap junction
o It can move through transport protein that are located on both ends of the cell
o Some transport proteins limit the drug absorption, only let certain amount in while taking some right back out
o Other protein transport take it from the gut back to the circulation
o Other proteins metabolize the drug and send it to the circulation or send it to the gut lumen
o Some proteins metabolize the drug and send it back to the lumen
- Passive diffusion
o From an area of high concentration to low concentration of the material
- Absorption time
o Hydrophilic (lipophobic) = soluble in water, poorly soluble in non-polar lipids
o Hydrophobic (lipophilic) = soluble in non-polar lipids, but poorly soluble in water
o Partition coefficient (oil: water) = higher partition coefficient means higher lipophilicity
 Oil and water = separated
 Place drug in it and shake it, the drug will move more into the philic phase it has
o More lipophilic = inside lipid phase
o More hydrophilic= inside water phase
- Passive diffusion
o Is controlled by Fick’s first law
o Absorption can be though as net
 rate of penetration is fast the faster the drug is absorbed and the faster the patient feels the effect of the drug
o rate of penetration = P * SA X (Ch – C1)
 P = permeability
 SA = surface area
 Cu1 – Cu 2+ = concentration gradient
o Three major determinants of drug penetration
 Size
 Lipophilicity
 Charge (degree of ionization)
o Size and lipophilicity on permeability
 From the graph, we can conclude that as we increase the lipophilicity of the drug we increase the permeability also
  Molecular weight
 Low molecular weight is associated with increase in permeability
o pH partition hypothesis
 weak acids: HA are in equilibrium with free acids and H+ (hydrogen ions)
 at low pH, weak acid is less ionized = more absorption
 at high pH, weak acid is more ionized, less absorption
 weak bases = NH4 – NH3 + H
 at low pH, weak base is mores ionized, less absorption
 at high pH, weak bases is less ionized, more absorption
 The drug that will be administrated to the body are either weak base or weak acids, this will determine the drug
administration since the drug will move through different pH environment
 pH variability
o Gastric fluid = 1.5 – 7.0
o Intestinal fluid = 6.2 – 7.5
o Urine 4.5 – 7.5
o pH partition hypothesis
 Only unionized nonpolar drug penetrates the membrane and at equilibrium, the concentrations on either side of the
membrane are equal. But, the total drug concentration may be different on either side of the membrane

Barrier types

- Blood-brain barrier – cells form tight junctions between the blood and the brain
o Prohibit transcellular movement of drugs/toxins
o Active efflux mechanisms (p-glycoprotein) limit penetration of polar compounds
o Smaller lipophilic molecules –general anesthetics diethyl ether and halothane- can easily enter the brain across the cellular
membrane
- Renal tubules
o Its membranes are relatively non-porous
o only drugs which are lipophilic or non-ionized can be reabsorbed
 depended on pH and pKa
- Hepatic blood vessels
o Capillaries are lined with a basement membrane broken in part by sinusoids and fenestrations interspersed with cells held
together with tight junctions
- Blood capillaries and renal glomerular membranes
o Porous allowing non-polar and polar molecules

Carrier mediated transport

- Facilitated diffusion, is the movement of molecules across the cell membrane via transport proteins that are embedded within the cellular
membrane
- Doesn’t rely on concentration of drug
- It can move against concentration gradient
- Requires energy
- The graph
o Passive diffusion- linear transport between the concentration and rate of transport
o carrier mediated – the rate of transport will level off= saturation = if the concentration of the drug is increased, the system might
be overwhelmed

Efflux transporters

- well studies is the P-glycoprotein –P-gp

o human multi-drug resistance gene MBR1 which is encoded by protein P-glycoprotein –P-gp contributes to organ penetration
and elimination
- protective mechanism in the body

Drug movement

- gut lumen-gut wall-portal vein-liver-systemic circulation

- when drug is in the gut wall (enterocytes), it can be met with efflux transporters or metabolizing enzymes
o If the drug is a substrate for the efflux transporter then it is kicked back
o It can also be metabolized by the enzymes and inactivated
o the drug has to escape the enzymes, P-gp, go through the liver (encounter same enzymes in the liver) before it is absorbed in the
systemic circulation

Factors prescriber should take into consideration

- food and dietary interactions

 o consider patient diet
 grape fruit juice inhibits P450 3A4 – family of drug metabolism of drugs
 a greater fraction of the drug is going to escape this protection mechanism and hit systemic circulation and
cause higher effect
o herbal drug interactions
 drug interaction and potential side effects
 some of the herbal drugs might have similar effect as synthesized drugs since their affects are not studied we should be
careful
 treat herbal as another form of drug
o Individual variability
 Age dependent and individuals dependent of drug metabolism

Profile of IV drug

- No absorption phase
- Terminal slop shows the half life of the drug

Volume of distribution and clearance

- C0 = dose / volume
- When a drug is going through the organ, certain amount is removed each time it circulates
- The higher the concentration, the greater amount will be removed even though the elimination rate stays the same
- Clearance of any organ is the product of its blood flow X its extraction ration
- Organ blood flow is important to drug eliminations
o Reduce rate will cause the blood to stay longer so we might not have to give higher concentration
- K (terminal slope/elimination rate constant) = rate of elimination n / amount in reservoir
- K = clearance / volume
o The higher the volume of the drug the longer it will take to be eliminated
o The higher the clearance of the drug the fastest it is eliminated
o Half life
 Drug’s half life =
 If K is higher the slope is higher the drug is going to stay around longer , half life is shorter
 Inverse relationship between rate of elimination and half life
 Proportionally to how rapidly it is removed
 Inversely proportion to the extend how it is distributed outside the vascular space
- K = CL/V
- Rate of elimination = CL * Concentration
- Dose = CL * AUC
- CL = Dose/AUC
- AUC = Dose/CL
- K = 1/half life
-

Distribution and Elimination: Competing Processes

- Where the drug goes and how it is eliminated from the body are separate and competing process

Volume distribution

- Relationship between blood flow and permeability

o What determines tissue distribution?
 #1. Perfusion-rate limited
 Drug in the blood and in tissue is in equilibrium with that in interstitial fluids and cells
 Blood and tissue seen as one compartment
 Membrane offers no resistance
 #2 permeability-rate limited –limited by the movement of the drug into the tissue
 There is membrane resistance to drug movement
 Drug in blood exiting tissue is not in equilibrium with that in interstitial fluid and cells
 The drug can go easily into the interstitial fluid but it barely enter the cell membrane
 Blood and tissue view as separate compartments

Total body water

- Total body water is 60% of total in lead adult male

- TBW = 42 liters
- Extracellular fluid is approximately 1/3 of TBW or 14 liters
- Plasma represents 1/3 of ECF or 3 liters
Effect of protein binding on volume

- Only drugs that are not unbound are available for distribution
- Unbound drug gives us the pharmacologic effect
- Unbound drug is also that is eliminated
- Bound drugs have longer half life in the plasma, less of it is going to be removed
- Drug into the tissue that is bound with proteins will have longer half life as well
- High unbound fraction in the plasma means the higher the drug is going to be distributed outside the vascular
- Low unbound fraction in the tissue means the volume distribution is high
- Volume of distribution can be higher than total body water because it is a product of the different affinity of the plasma protein binding and
tissue protein volume binding

Albumin: an acute phase reactant protein

- Acute phase reactant proteins are liver proteins whose production changes by at least 25%
- Albumin is a negative acute phase reactant protein
- More drugs will be available since less protein are there to bind them during a disease state within a particular patient - half life goes down
- Will determine the amount and frequency of the drug administrated since the response will change with protein concentration with the
patient
o Different patients will have different disease

Elimination mechanisms

- The role of the liver and the kidney

- Liver
o There are enzymes that are responsible for metabolizing
o It’s a defense mechanism
o Cytochrome P450 enzymes are the enzymes in the liver
o One mechanism of the liver is to hydroxylate – which makes the compound inactive and water soluble so it can be excreted easily
- Cytochrome P-450 phase reactions
o Phase I – lots of P 450 in this phase
 Most common routes are oxidation, reduction and hydrolysis
 THC is prone to phase I metabolism which means its metabolized in the gut and in the liver before it has a chance of
reaching its target
 THC is not administrated by oral, but by passing these systems and into the systemic circulation
o Phase II
 Conjugation reactions
 Glucuronidation and sulfation are primary conjugation pathways

Hepatic biotransformation

- Not all drug metabolism leads to inactivation of the drug some metabolites (active drugs-good and bad) are still active
- Some patients need the metabolites for their improvement and if they lack the enzyme that metabolize it
- With age our ability to metabolize decreases
o Some patients metabolize things much differently than other at various age, we are individuals, genetic variance
- The goal of the liver is to inactivate the drug

Alcohol and Acetaminophen (Tylenol)

- Alcohol upregulated 2E1 subfamily of P450

- Tylenol is metabolized by 2E1 to toxic level
o Do not stop consuming ethanol with the medication
o

Renal Excretion

- Metabolism into water soluble compounds stops reabsorption of drugs molecules from urine through renal tubular membranes back into
plasma
- Lipophilicity is the determination of the drug to cross membrane= water soluble it will be less likely to cross the membrane= reabsorption

Additivity of Clearance

- When giving drugs, understand how they get out of the body of the patient
- If the patient has kidney issue you would not give them drug that is eliminated thru kidney, give them drug that is metabolized through
liver

Bioavailability (F)
 - Fraction of drug reaching the systemic circulation following extravascular administration
- IV = 100% of the drug reaches systemic circulation
- Oral = what fraction of the drug reaches the systemic circulation
- Fraction and rate of absorption
- Food effect
o Food, especially fat slows down emptying time, slow absorption
o Drug requiring fast onset of action should be give on an empty stomach
- Bioavailability
o Dependent on three processes
 #1 fraction of drugs that is absorbed (Fa)
 #2 fraction of drugs that escape gut metabolism
 #3 fraction of drugs that escape liver metabolism

Generic substitution

- The drug and its generic products should be superimposable if interested in using generic over brand name
- This is the bioavailability
- The drug must be bioequivalent
o The absence of significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical
equivalent or pharmaceutical alternatives become available at the site of drug action when administrated
o Bioequivalent
 Same drug
 Same bioavailability
 Same route of administration
 Same strength
o Therapeutic e equivalence
 Bioequivalent
 Pharmaceutical equivalent
 Same dosage form = capsule, tablet
 Same salt form = acid or base

KEEP YOUR EYE ON THE UNBOUND DRUG

- Drug that comes from the gut is dumped into the portal vein and it comes in the sinusoid of the liver
- In the sinusoid, both drug and drug bound protein passed
- The unbound drug will pass to the hepatocyte
- When the unbound drug comes in contact with p450 it can be metabolize
- Phase II reaction
o When we have high molecular weight we make it more able to be excreted in the bowel
- Some drugs re-circulate, in the liver – back to the liver, it is so readily absorbed in the small intestine it is reabsorbed back to the liver
o Administrate the drug, the concentration decreases and there is a second bump which shows the drug is re-circulating – this is the
mechanism how the biliary excretion affects concentration X time profile

Organ clearance

- Pass – absorbed –
- The first time, the second time it is not affective bioavailability because the drug is being absorbed in time

Fraction escaping first pass metabolism

- If 50% of the drug is extracted that means that 50% the drug escapes first pass metabolism
- The overall bioavailability is how much is absorbed, how much is escaping gut metabolism and how much is escaped the first pass
-

What determines hepatic clearance?

- Liver blood flow- several things can affect liver blood flow
o CHF
o Shock – loss of blood to vital organs
o Food intake
o Drugs
o Cirrhosis – changes in the liver, slow blood flow down
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