What is the definition of pharmacokinetics and what are the components?
What happens to the drug following administration
What is the definition of pharmacodynamic and what are the components?
How the drug works in the body
The Big Picture
Bioavailability--> Drug Action--> Drug Effect
Name the components for each part as well as what consists of pharmacokinetics versus pharmacodynamics
Routes of administration
Absorption and Distribution
~ lipid solubility
Drug Action (pharmacodynamics)
~ Dose-Response Relationship
Drug Effects (pharmacodynamics)
~ratio of therapeutic agent that reaches therapeutic level over lethal dosage
Drug action vs Drug effect for LSD
Drug action: inhibits cellular activity in brain stem areas (pons and medulla)
Drug effect: widespread, including increased heart rate, blood pressure, sweating and chills, sometimes vomiting and nausea
Drug action vs drug effect for carbachol versus morphine
Drug effect: reduction in the size of the pupil
Drug action: carbachol: acts at the nerve endings in the iris (topical)
Drug action: morphine: in the brain areas that modify pupillary responses to light, but has no effect when applied directly to the eye
What are localized drug effects?
Drugs applied to a targeted area
Minimum absorption into the bloodstream
What are systematic drug effects?
Drugs are admninistered through the prescribed route and are absorbed into the blood stream
Effects and side effects may be seen in many body systems
What is the key with Pharmacokinetics
Drugs typically go through the body: depending on route of administration
Drugs can and will act at sites that were not intended: not only in the brain but..
~ Other organs
What are the processes in the body for Pharmacokinetics
What are routes of administration?
How and where a drug enters the body determines how much drug reaches the site of action, therefore the magnitude of its drug effects
Routes of administration affects drug absorption by determining...
Absorbing surface (available blood supply)
Number of membranes needed to cross
Amount of drug destroyed (metabolism)
Amount of depot binding
Name the types of routes of administration
Intravenous injections (iv)
Intramuscular injections (im)
Intraperitoneal injections (ip)
Subcutaneous administration (sc)
Oral Administration (po)
Other (topical, transdermal, Sublingual)
Absorption and Distribution: What influences the rate and amount of drug that enters the bloodstream and therefore the brain?
Transportation across membranes (key issues is difussion, lipid solubility, & ionization)
Age, Sex, and Body size (dilution and available depot sites)
Blood-brain barrier (numerous mechanism for limiting access to brain)
Transportation across membranes: What is the Law of Diffusion and what influences the ability of diffusion to act?
Dissolved substances move from an area of higher concentration to an area of lower concentration
This is the power behind the absorption of drugs
The ability of diffusion to act is influenced by: how easily a molecule dissolves across a membrane (lipid solubility) and whether or not a molecule is electrically charged (ionization)
Transportation across membranes: What is lipid solubility?
membranes are composed of lipid molecules
the lipid solubility of a drug is given by its Partition Coefficient
Drugs that dissolve in fat (lipid soluble) diffuse across membranes easier then drugs that dissolve in water (water soluble)
Membranes are composed of?
Drugs that dissolve in fat diffuse across a membrane______ then drugs that dissolve in water (water soluble)
The lipid solubility of a drug is given by its...
What are ions?
Atoms or groups of atoms (molecules) that gain an electrical charge (+/-) after dissolving in a solution
What is ph?
the negative logarithm of the concentration of hydrogen ions in a solution
7 is neutral: meaning that the number of hydrogen ions equals the concentration of OH- (hydroxide ions)
a lower ph, more hydrogen ions
higher ph, less hydrogen ions
What are the rules of Ionization?
Molecules become less charged (unionization) when in the same ph environment and become more charged (ionized) when in different ph environments
The less charged a molecule the easier it will move across membranes
If the drug as well as the environment are the same then the charge will be ____, (less, more), the lipid solubility will be_____ (greater, less), and the potential absorption will be _____ (greater or less)
less, greater, greater
If the drug and the environment are different the charge will be _____ (less, more), the lipid solubility will be______ (greater, less) and the potential absorption will be (greater, less)
more, less, less
Will aspirin (a weak base) be more absorbed in the bloodstream of the stomach or intestines? Why?
stomach- more similar environment because the stomach is acidic
In order for a drug in the blood to enter the brain it must...
unionized at blood ph
have a fairly high partition coefficit (lipid soluble)
Or, existing transport mechanisms (e.g LDOPA)
How does depot binding affect the bioavailability of a drug? Give 3 examples
1 Slowed actionMany drug actions will be slowed by depot binding
1. drug A bings readily to "silent receptors" (depot sites)
2. drug A quickly reaches equilibrium between bound and unbound forms
3. blood concentration is dependent on the drugs release from depot sites
4. As drug leaves the bloodstream it is slowly released from depot sites
2. drug interactions
Drug interactions can be affected by depot binding:
Ex) imipramine ( antidepressant), diazepam (Valium), and phenytoin (antiepeleptic) all readily bind to depot sites
Consequently, the effective dose of one will be greatly influenced by the presence of the others
Effects of valium on 2 different patients:
one on imapramine (antidepressant); depot sites are already bound
one not on imapramine; depot sites need filling first
3 Drug termination:Depot binding may terminate a drug's action
Thiopanel used as IV anasthesia: highly lipid soluble, easily passed from the blood to the brain (rapid drug effects), almost instantaneous sleep
Meanwhile, blood levels quickly fall due to depot binding
As blood levels fall, thiopanel moves back from the brain to the blood to maintain equilibrium
Within 90 minutes, brain gives up its initial peak levels due to various depot sites (muscles, fat)
What is depot binding?
the binding of drugs to inactive sites (blood proteins, muscles, bone, fat, liver)
drug effects are related to the concentration of the drug at its site of action (receptor)
only unbound drugs can pass easily through membranes (i.e reach site of action: receptor)
bound and unbound drugs are within equilibrium in the blood
What is biotransformation?
the process of drug metabolism that involves breakdown, detoxification, and removal of chemicals from the body.
liver is primary site of drug metabolism
oxidation: drug conversion to more water soluble compound
What are the factors influencing biotransformation?
Each person metabolizes drugs in a unique way
Age: reduced metabolism, nutrition, disease
enzymes: increased, decreased, absent
Environmental factors: psychological effects
What is metabolism?
the chemical process inwhich any drug maybe transformed or changed in the body
This results in metabolites
Metabolites are formed by enzyme interactions which alters the drug's chemical composition, forming compounds which differ from the original drug
Metabolites have unique properties which have different effects then the original drug.
Metabolites may be helpful, harmful, or neutral
What are the different types of metabolites?
unchanged with regards to activity
can last longer than the original drug
may influence the rate at which the drug is metabolized
Drugs and metabolites have associated half lifes: what are half-lifes?
the amount of time it takes for one half of an administered drug to be lost through biological processes (biotransformation: metabolism, and elimination)
each drug will have an associated half-life
Half-lifes will impact
Drug effects: sustained drug effects,relapse, and side effects emergence
Drugs cleared through kidneys will have prolonged half-lifes in patients with renal failure (kidney failure)
What is first pass metabolism?
Drugs administered orally will go directly to the liver before getting into the blood that supplies the rest of the body
Within the liver, specialized enzymes transform the drug into metabolites
Water soluble metabolites are quickly and easily excreted
This can dramatically influence the plasma level of many drugs (therapeutic dosage)
What is first order kinetics?
the rate of metabolism is proportional the plasma concentration of the drug (exponential)
e.g 50 % of the drug in blood is removed during each given interval of time
What is zero order kinetics?
rate of metabolism is fairly constant regardless of amount taken (e.g ethanol)
What is steady state metabolism?
Drug absorption equals drug elimation during the dosing interval: therapeutic level
What is enzyme induction?
the increase of enzyme levels with repeated use of a drug- smoking increases p450 enzymes which also metabolize antidepressants
What is enzyme inhibition?
Reduction of enzyme levels through repeated use of a drug
MAO-I in both brain and liver
this blocks the mao enzymes that break down seratonin
How does drug competition change the rate of metabolism?
Drugs that share a common enzyme may reduce the metabolism of each by using up the available enzymes
What factors influence the rate of metabolism
How do drug-food interactions affect metabolism?
Increased or decreased absorption
Reduced GI irritation
~ grapefruit juice
~ Vitamin K
What issues affect drug elimination?
~ acidity of urine can facilitate reabsorption
~ poorer in very young and very old
~ Metaabolites can affect renal excretion
Additional drug effects of same drug
Why is excretion important?
Required to completely terminate effect of drug
prevents accumulation of drug in system (including metabolites)
What are the sites of elimination?
Renal: kidneys (primary site)
GI tract (intestines)
exocrine glands (sweat, saliva, milk)
What are the major issues of aging populations and pharmacokinetics?
Physiological changes with aging
~ increased fat (decreased lean body mass)
Decreased GI motility and blood flow
Decreased liver function
Decreased renal function
Medication issuescumulative drug effects
~ memory issues
~ medication refusal (side effects, lack of knowledge, ideaology)
Aging and Pharmacokinetics: What is an indication of drug toxicity?
do not assume mental status changes are a normal part of aging
what is a receptor?
a molecule, usually a protein, that is present on the surface or within a cell and which is the initial site of action of a biologically active agent.
What are dose response curves?
graphical representation of the amount of biological or behavioral effect (response) for a specific drug concentration (dose)
with increasing drug concentrations (x-axis) there is an increase in biological or behavioral effect (y-axis) until the maximum effect is achieved.
for each drug, increasing the dose produces greater analgesia (elevations in pain threshold) until the maximum response is achieved.
Dose response curves: mechanisms of action
despite great differences in potency among the 3 opiate drugs, their maximum effectiveness and shapes are the same.
this similarities indicate that the 3 drugs are acting at the same receptors, but with different assessibility, affinitiy, and efficacy
What can the dose response curve tell us?
The relative effectiveness of a drug across biobehavioral responses
drugs are absorbed and distributed all over the body and may act at multiple receptors having multiple actions.
Receptor Antagonism: Drug Interactions?
Many drugs will act at a given receptor and each drug may have a host of of effects, all of which potentially influencing the ability of other drugs or neurotransmitters to do their job.
What is an antagonist?
( general terms for actions/interactions)
A drug that binds to a receptor, but has no intracellular effect. consequently, they may block the effects of neurotransmitters or agonists drugs for this receptor.
what is an agonist?
A drug that binds to the same receptor as a neurotransmitter and does initiate intracellular changes.
what is irreversible antagonists?
an antagonist that does not follow the rules of reversible binding and forms an almost inseperable bond with the agonist receptor site
A drug that binds reversibly to a region of a a receptor in common with an agonist but occupies the site without activating the effector mechanism
the effects of a competive antagonist maybe overcome by increasing the concentration of a an agonist, thereby increasing the proportion of receptors which the agonist occupies.
an antagonist thar reduced the effectiveness of a neurotransmitter or agonist through a mechanism other than binding to the agonist receptor site.
For example, pcp: reduces the eficacy of Glutamate receptor, but rather by binding to a separate receptor site on the same receptor molecule.
a drug which produces an effect opposite to that of an agonist, yet acts at the same receptor
If receptor X opens the door to the house when activated by its agonist, then the inverse agonist would cause the receptor to now shut the door
the inverse agonist still activates the receptor, but with the opposite consequences in regard to drug action
Adverse drug reactions: harmful effects of a drug due to high levels of the drug in the body
Iatrogenic effects: illness caused by medical txt.
adverse side effects
Adverse drug reaction?
high drug dose
dosing too frequently
narrow margin of safety (therapeutic index).
What influences desirable versus undesirable side effects?
will differ from patient to patient
must guide prescribing decisions
Drugs are chosen to take advantage of side effects that may benefit the patient:
I.e. when choosing an antidepressant, if patient is having trouble sleeping, may avoid drugs that cause insomnia like Prozac and choose a drug that causes drowsiness such as nortryptilline, a tricyclic antidepressant, giving it at bedtime