Exam 1 Flashcards
What is a drug?
Any chemical agent that affects living protoplasm
What is pharmacology?
The study of drugs and their interactions with the human body
What is an adverse drug reaction?
- Any response to a drug which is harmful and unintended at a normal therapeutic dose
- Occurs at doses used in man for prophylaxis, diagnosis, or treatment
- Side effects, drug allergies, and drug interactions
What is pharmacokinetics?
- The absorption, distribution, metabolism, + elimination of drugs
- The action of the body on a drug
- The study of the fate of drugs in the body
What can understanding and applying pharmacokinetic principles do?
Increase the probability of therapeutic success and reduce the occurrence of adverse drug effects in the body
Tools used to design optimally beneficial drug therapy regimens
- Proper drug
- Route of administration
- Dosing schedules
What is absorption?
Movement of a drug from its site of administration into the central compartment and the extent to which this occurs
For solid dosage forms, absorption first requires
Dissolution of the tablet or capsule, thus liberating the drug
The clinician is primarily concerned w/ bioavailability or absorption?
bioavailability
A drug should be _____ for absorption and site access
lipid soluble
Absorption occurs by
passive or active transport
Passive transport in absorption
Diffusion from higher to lower concentration
Active transport of absorption
Against a concentration gradient requiring energy
Absorption can occur as
ionized/non-ionized
Their is a high probability for drug interactions to occur during movement through
the GI tract
An example of a drug interaction in the GI tract
Theo-24 + food = ir and toxic levels
What is distribution?
After absorption, drug transported to site where it reacts w/ various bodily tissue, and/or receptors
Following absorption/systemic administration into the bloodstream, a dug distributes into
interstitial + intracellular fluids
What are things that effect distribution?
Cardiac output, regional blood flow, capillary permeability, + tissue volume determine the rate of delivery and potential amount of drug distributed into tissues
Initially during distribution, which organs receive the most amount of the drug
Liver, kidney, brain, + other well-perfused organs
Is the second distribution phase faster/slower?
slower
In the second distribution phase, delivery is made to
muscle, most viscera, skin, + fat
The second distribution phase involves a far larger fraction of
body mass
What accounts for most of the extravascularly distributed drug
second distribution phase
What are two important determinants for distribution
lipid solubility + transmembrane pH gradiets
What limits the concentration of free drug during distribution?
Binding of drug to plasma proteins + tissue macromolecules
In distribution, lipid soluble drugs have
A high affinity for adipose tissue where stored and since their is low blood flow here, lipid soluble drug reservoir causes prolonged drug effects
What are some highly lipid soluble drugs
Phenothiazines, benzodiazepines, barbiturates
What is metabolism in pharmacokinetics?
Convert active lipid soluble compounds to inactive water-soluble substances primarily excreted by the kidney
Most drugs are metabolized in the
liver, but also kidneys, lungs, + intestinal tract
The two metabolic processes are
Phase 1 and phase 2
Phase 1 of metabolism hepatic microsomal enzymes first
oxidize, demethylate, + hydrolize drugs
More clinically significant drug interaction are cause by which phase of metabolism?
Phase 1
Drugs w/ short half-lives and inactive metabolites almost entirely metabolize during
first pass, therefore less effected by drug interactions
What is phase 2 of metabolism
Large water soluble substances are attached to the drug (glucuronic acid, sulfate)
Compounds may circulate through one/both phases multiple times until
the water-soluble characteristic is present
Hepatic microsomal enzymes of phase one are
mixed function oxidases characterized by the cytochome p450 isoenzymes
Hepatic microsomal enzymes of phase 1 metabolism is more commonly _______ by other drugs
induced/inhibited
There are numerous forms of the hepatic microsomal enzymes of phase 1 metabolism about _________ different genes
20-200
The CP450 system which is how hepatic microsomal enzymes of phase 1 metabolism are characterized are responsible for
Oxidation of many drugs
CYP450 system of phase 1 metabolism oxidizes these drugs:
- warfarin
- phenytoin
- tolbutamide
- quinidine
- cyclosporin
The CYP in the CYP450 stands for
the superfamily
The number 4 in the CYP450 system stands for
the family
The 5 in the CYP450 system stands for the
subfamily-letter/arabic number
The 0 in the CYP450 system is the
individual gene
What are the families that are primarily involved with drug metabolism in the CYP450 system
CYP1, CYP2, CYP3, + CYP4
Drugs have been identified as ______, ______, + _____ of CYP metabolism
substrates, inhibitors, + inducers
Enzyme inhibitors decrease the rate of
metabolism of object drug by obstructing metabolizing enzymes
Enzyme inhibition leads to a _____ in enzyme concentration, and an ______ half life, accumulation, and side effects/toxicities
increase, increase
Examples of enzyme inhibitors
allopurinol, erythromycin, amidarone, fluoxetine, azoles, isoniazid, cimetidine, MAO inhibitors, ciprofloxain, metronidazole, bactrim, omeprazole, diltiazem, quinidine, ethanol, sulfonamindes, verapamil
Enzyme induction
stimulates the increase of CYP450 enzyme activity
Enzyme induction _____ the clearance of each drug and ____ the concentration available to site of action
increase, decrease
What is the prototype inducer
Phenobarbital
Enzyme inducers and substrates
Inducers: barbiturates, carbamazepine, ethanol (chronic), phenytoin, primidone, rifampin, rifabutin, + cigarette smoking
Substrates: warfarin, quinidine, verapamil, keto/itraconazole, cyclosporine, steroids, OCP’s, methadone, metronidazole
Excretion/elimination is
the process that removes the drug and its metabolites from the body primarily through urine mostly done in the kidneys
Excretion can also occur through
feces, lungs, + skin
Drugs are eliminated from the body either _____ by the process of excretion or _______
unchanged, converted to metabolites
Excretory organs, excluding the lungs, eliminate
polar compounds more efficiently than substances w/ high lipid solubility
*Lipid soluble drugs are NOT readily eliminated until they are metabolized to MORE POLAR compounds
Substances excreted in the feces are principally _______ orally ingested drugs/drug metabolites excreted either in the _____ or secreted directly into the ______ and not reabsorbed
unabsorbed, bile, intestinal
Excretion of drugs in breast milk is important not because of the _________, but because the excreted drugs are potential sources of ______ in he nursing infant
amounts eliminated, unwanted pharmacological effects
Excretion from the lung is important mainly for
The elimination of anesthetic gases
All four pharmacokinetic principles can __________, making it difficult to predict reactions to the medications
vary from patient to patient
Factors that affect the pharmacokinetic principle
age, sex, weight, disease states, genetic factors
Pharmacodynamics is
- the action of the drug on the body
- The study of the biochemical + physiological effects of drugs + their mechanisms of action
The most common mechanism for drug interactions by pharmacodynamics include:
Synergism (additive effect), antagonism, altered cellular transport, + effects on receptor sites
Understanding pharmacodynamics can provide the basis for the ________ and ____________
rational therapeutic use of a drug, desin of new and superior therapeutic agents
The four most important parameters governing drug disposition in pharmacodynamics:
- Bioavailability
- Volume of distribution
- Clearance
- Elimination
Bioavailability(F) in pharmacodynamics is the
fractional extent to which a dose of drug reaches its site of action
Factors that decrease bioavailability (F)
- GI absorption
- First pass effect
- Metabolism (enzymes, active transport)
- Route of administration must be based on understanding of these conditions
Volume of distribution (V)
- second fundamental parameter useful in considering processes of drug disposition
- relates the amount of drug in the body to the concentration of the drug (C) in the blood or plasma depending on the fluid measured
Volume of distribution (V) does not necessarily refer to an identifiable physiological volume but rather
the fluid volume that would be required to contain all of the drug in the body at the same concentration measured in the blood or plasma
Half-life (t) is
the time it takes for the plasma concentration to be reduced by 50%
Half-life (t) reflects the
decline of systemic drug concentrations during a dosing interval at steady-state
State state is when ______=_______
rate in, rate out
Steady state is
the amount of drug administered in a given period (maintenance dose) is equal to the amount eliminated in that same period
Approximately how many half-lives does it take to reach steady state
5-7
If the half life of prozac is 7 days how long does it take to reach steady state?
35 days/5 weeks b/c 7*5=35
Drug interactions are
- pharmacological results either desired/undesired
- the effect of one drug (object drug/substrate) is changed by another drug (precipitant drug)
What are the two classifications of drug interactions
Pharmacokinetic/pharmacodynamic
What are the types of drug interactions?
- Drug-drug
- Drug-food
- Drug-disease
Pharmacokinetic drug interactions occur when
Absorption, distribution, metabolism, + excretion (ADME) of one drug is affected by another drug/agent
How can absorption cause a drug interaction
- GI
- pH
- Binding
- Increase/decrease in motility (chrones/diabetes)
- Changes in GI flora (OCP’s absorbed by bacteria in Gi tract so if given w/ ABX that wipe out that bacteria, OCP’s are ineffective)
How can distribution cause a drug interaction?
- Plasma protein
- Bound vs. unbound (free drug)
How can metabolism cause a drug interaction?
- Hepatic (liver) enzymes: CYP450, CYP3A4
- Inducers: in addition to meds like cigarettes/phenytoin
- Inhibitors: grapefruit juice (inhibits CYP4A4), + Tagamet
How can elimination cause a drug interaction?
- Urinary pH
- Competition: Probenecid + PCN= increased PCN in the body (blocks PCN elimination in the case of syphilis), Lithium
Pharmacodynamic causes of drug interactions
- Action of drug on the body
- Additive effects (synergism): Beer+valium
- Opposing effects: Tenormin+Sudafed (but heads may not get any effects)
Potentiation/synergism things that can cause drug interactions from pharmacodynamics are
interactions between two + drugs/agents resulting in a pharmacologic response greater than the sum of individual responses to each drug
Antagonism, a pharmacodynamic effect that can cause a drug interaction is
opposition in action/smaller combined effect than individual agents: 2+2=1 (opposite of synergism/potentiation)
Principles of pharmacodynamics apply to all biologic systems
- In vivo, patients w/ specific disease
- In vitro, isolated receptors
A receptor is
A molecule to which a drug binds to bring a change in function of he biologic system
A receptor site is
the specific region of he receptor molecule which the drug binds
Inert binding molecule/site
Molecule to which a drug may bind w/out changing any function
Spare receptor
- receptor that doesn’t bind drug when the drug concentration is sufficient to produce maximal effect
- Present when K(d)>EC50
Effector
Component that accomplishes the biologic effect after the receptor is activated by an agonist (i.e. channel/enzyme molecule)
Efficiency, maximal efficiency (Emax)
The maximum effect that can be achieved w/ a particular drug regardless of dose
Potency
Amount of drug needed to produce a given effect, determined mainly by the affinity of the receptor for the drug, and # of receptors available
Graded dose-response curve
A graph of increasing response to increasing drug concentration/dose
Quantal dose-response curve
A graph of the fraction of a population that shows a specified response at progressively increasing doses
EC50
The CONCENTRATION hat causes 50% of the maximum effect/toxicity
ED50
The DOSE that causes 50%of the maximum effect/toxicity
TD50 (TC50)
The median toxic dose/concentration at which toxicity occurs in 50% of cases
LD50 (LC50)
The median lethal dose/concentration required to kill half the members of a tested population after a specified test duration
Kd
The concentration of drug that binds 50% of the receptors in the system
Bmax
Max # of receptors bound
Agonist
Drug that activates its receptor upon binding
Partial agonist
Drug that binds to its receptor but produces a smaller effect at full dosage than a full agonist
Allosteric agonist
A drug that binds to a receptor molecule w/out interfering w/ normal agonist binding but alters the response to the normal agonist
Antagonist
Pharmacologic antagonist that binds w/out activating its receptor + thereby prevents activation by an agonist
Competitive antagonist
A pharmacologic antagonist that can be overcome by increasing the concentration of the agonist
Irreversible antagonist
A pharmacologic antagonist that cannot be overcome by increasing agonist concentration
Physiologic antagonist
Drug that counters effects of another by binding to a different receptor + causing opposing effects
Chemical antagonist
A drug that counters the effects of another by binding the agonist drug NOT THE RECEPTOR
Allosteric anagonist
A drug that binds to a receptor molecule without interfering w/ normal antagonist binding but alters the response to the normal antagonist
Therapeutic index (TI)
Td50/LD50:ED50
Signaling
Once an agonist drug has bound to its receptor, some effector mechanism is activated
What are the receptor-effector systems of signaling
Enzyme in intracellular space:
-cyclooxygenase, target for NSAIDS
Neurotransmitter reuptake transporters:
-NE + DA transporters for cocaine
Voltage-activated ion channels:
-Antiarrythmic drugs target Na+, K+, + Ca2+ calcium channels
Classic drug-receptor interactions of signaling
- drug is present in the extracellular space, effector mechanism resides inside the cell + modifies some intracellular process
- Involves signaling across the membrane
5 major types of transmembrane-signaling mechanisms
- transmembrane diffusion of drug to bind to an intracellular receptor
- transmembrane enzyme receptors, whose outer domain provides the receptor function + inner domain provides the effector mechanism converting A to B
- Transmembrane receptor that after activation by an appropriate ligand, activate separate cytoplasmic tyrosine kinase molecules (JAKs) which phosphorylate STAT molecules that regulate transcription (Y, tyrosine, P, phosphate)
- transmembrane channels that are gated open/closed by the binding of a drug to receptor site
- G protein-coupled receptors, which use coupling protein to activate a separate effector molecule
Receptors that are intracellular
- More lipid-soluble/diffusible agents (steroid hormones, nitric oxide)
- May cross membrane + combine w/ an intracellular receptor that affects an intracellular effector molecule
- Receptor + effector may/may not be the same molecule, but no specialized transmembrane signaling device is required
Receptors located on membrane-spanning enzymes
-Drugs that affect membrane-spanning enzymes combine w/ a receptor site on the extracellular portion of the molecule + modify its intracellular activity (insulin + tyrosine kinase)
Receptors located on membrane-spanning molecules binding seperate intracellular TK molecules
- Appropriate drug (cytokine) activates extracellular receptor site
- Associate but separate tyrosine kinase molecules (JAKS) activated
- Results in phosphorylation of STAT molecules (signal transducers + activators of transcription)
- STAT dimers (effectors) then travel to the nucleus + regulate transcription
Receptors located on membrane ion channels
- Directly cause opening of channel (ACh at nicotinic receptor)
- Modify channel’s response to other agents (BZD’s at GABA-activated Cl- channel)
- The channel molecule acts as both receptor + effector (resulting in a change in transmembrane electrical potential)
Receptors linked to effectors via G Proteins
- Drug bind to receptors that are linked by coupling proteins to intracellular/membrane-bound effectors (sympathomimetics-activate/inhibit adenylyl cyclase (effector) by multistep process)
- When G-coupled receptors bind agonist, G-protein activated
3 most important G-proteins
- receptor: M2, M3, a1 G protein: GQ Effector: phospholipase C Effector substate:membrane lipids second messenger response: increased IP3, DAG Result: Increased CA2+ and protein kinase activity
- receptor: B, D1 G protein: GS effector: adenylyl cyclase Effector substrate: ATP second messenger response: ^cAMP result: ^Ca2+ influx + enzyme activity
- receptor: a2, M2 G protein: GI effector:adenylyl cyclase effector substrate:ATP second messenger response: dec. cAMP result: decreased CA2+ influx + enzyme activity, ^ K+ efflux
Receptor regulation in
number, location, + sensitivity
Receptor regulation can have changes that occur
over a short time (minutes) or longer periods (days)
Tachyphylaxis of receptor regulation
- An acute (sudden) decrease in the response to a drug after its administration
- Frequent/continuous exposure to agonists, resulting in short-term reduction of receptor response
- Can occur via several mechanisms
Mechanisms of tachyphylaxis the sudden decrease in the response to a drug after its administration
- Blockage of G proteins responsible for receptor activation + sensitization
- Agonist-receptor complexes may be internalized, removing them from further exposure/activation by agonists
- Continuous activation of the receptor-effector system that may lead to depletion of essential substrates needed for effect expression
Down regulation
Long-term reduction in receptor number which occur in response to continuous exposure to agonists
Up-regulation
Increases in receptor number which occur when receptor activation is blocked for prolonged periods (several days) by pharmacologic antagonists/denervation
Do you want a high or low TD50?
high b/c takes longer to produce signs of toxicity
Do you want a high or low TI?
High because it gives you a high therapeutic window which means there is a large difference of a drug giving a desired effect + toxic effects
Don’t ever compare potency w/out
efficiency
What is the base value of TI?
100
Is T1 always reliable?
No sometimes ED50 + LD50 overlap
Pharmacokinetics helps decide
instructions of using a drug
Only ______ drugs can diffuse through capillary walls + produce a pharmacological effect + be metabolized + excreted
unbound free
What type of molecules can enter into the brain
Nonionized molecules not easily bound to plasma proteins b/c lipid-soluble
A decreased bioavailability would mean that
poorly absorbed in GI tract or partially metabolized in the liver
Pharmacodynamics is the relationship between _____ and ___+___
drug concentration and therapeutic and toxic effects
Pharmacokinetics is the relationship between ____ + _____
dosage regimen + drug concentrations
Kinetic interactions are changes in effect that are the result of changes in the relationship between _____ + ______
dose, concentration
Dynamic interaction changes in effect are the result of changes in relationship between ___ + ___
concentration, effect
The pharmacological effect of kinetic interactions has changes as a result in the change in the
drug concentrations
The pharmacological effect of a dynamic interaction has changed despite the lack of change in the _______
concentration
Is this a pharmacodynamic/pharmacokinetic reaction and why? Drug C (50mg) --> Cp peak 100mcg/ml--> efficiency w/out toxicity Drug C (50mg) + Drug D--> Cp peak 100mcg/ml--> toxicity
Pharmacodynamic because the concentration stays the same but their must be an interaction at the receptor level that is producing toxicity
Is this a pharmacokinetic/pharmacodynamic relationship + why? Drug A (10mg) --> drug A cp peak 8mcg/ml --> Efficiency w/out toxicity Drug A (10mg) + Drug B --> Drug A cp peak 16 mcg/ml --> toxicity
Pharmacokinetic because the concentration changes with the same dose administered probably due to drug B inhibiting the metabolism of drug A
The more _____ substances may move more freely across the membrane
lipid-soluble because they must pass through the phospholipid “barrier”
Substances that are less lipid soluble may need to cross the membranes via
Other mechanisms (protein channels/carrier proteins) because they are polar substances, relatively insoluble, including ionized substances
What is the only administration method which bypasses the absorption process?
IV b/c administered directly into systemic circulation
An increase in bioavailability is equal to an _____ in systemic drug exposure
increase
The area under the curve that is that is produced w/ a graph of serum concentration vs. time (AUC) is
bioavailability
What is the pharmacokinetic parameter which quantifies drug exposure?
Bioavailability
An increased AUC means an ______ in systemic drug exposure?
increase
How is bioavailability expressed?
As a percentage/fraction of the drug administered which reaches th systemic circulation
If 90% of the drug from an administered dose reaches the systemic circulation, the drug in that dose form has a ____ bioavailability?
90%
With oral administration, the fraction reaching the systemic circulation (bioavailability) is dependent on
- absorption characteristics of the drug dose form
- amount of metabolism that occurs prior to the drug reaching the systemic circulation (intestinal wall/liver hepatic first pass metabolism)
- Presence of interacting substances (drugs, food, type of food)
With a first pass effect you would ____ a lot of the drug
lose
CPmax ng/ml is
maximum concentration
Tmax (hrs)
time to achieve maximum concentration after administration
AUC
area under the curve produced by graphing the drug concentrations over time
What is the approximate absolute bioavailability of a 30mg tablet if the AUC for the tablet is 27.3 and the AUC for IV is 4290?
0.64% because 27.3/4290=x/100
What is the approximate bioavailability of a 30mg dose of oral aqueous solution if the AUC is 26.1 and the AUC for IV is 4290?
0.61% b/c 26.1/4290=x/100
What is absolute bioavailability?
One of the AUC’s is being compared to a dose form where there is 100% absorption (IV 100%)
What is relative bioavailability?
How two dose forms compare in terms of the relative amount of the drug that reaches systemic circulation
*Used when we don’t have a gold standard like IV to compare to
What is the relative bioavailability of the tablet relative to solution if the AUC of the tablet is 27.3 and the AUC of the solution is 26.1?
104.6% b/c 27.3/26.1*100
What is the relative bioavailability of the solution relative to the tablet if the AUC of the solution is 26.1 and the AUC of the tablet is 27.3?
95.6% b/c 26.1/27.3*100
What to do with relative/absolute bioavailability?
Determine whether to give a drug in a certain form based on the AUC and peak in case your method of form doesn’t provide relief of symptoms
Volume of distribution (Vd) is used to account for
observed initial drug concentrations following administrations so researches calculate an “apparent” volume into which the drug is distributed
When a researcher administers a drug, he measures the maximum concentration + calculates the volume of distribution with this equation
Cp max = dose/Vd
CPmax= Dose/Vd allows the calculation of the ______ that should e produced when a certain dose is put into a certain volume
concentration
If the researcher administers a drug and the concentration is very high, then the volume of distribution of that drug is
very small
If the researcher administers a drug and the concentration is very low then the volume the drug appears to occupy is
very large
Is the volume of distribution a true physiologic volume?
No it is “apparent”
Physiologic volumes are used to help us understand
where the bulk of a drug resides in the body
The volume of distribution provides an indication of
the extent of distribution
The reason drugs have different Vd’s is a function of the drugs chemical characteristics which dictate its
lipid solubility, protein binding, + tissue binding
For a given drug there is variability in Vd from pt to pt b/c of the pt characteristics + conditions like
pregnancy, fluid status, + disease states (CF, trauma)
A high volume of distribution is due to
increased lipid solubility, decreased protein binding, and increased tissue binding
Dose is calculated by
CP max*vd
Average 70 kg person
A drug w/ <= 0.25 L/kg distributes into an apparent volume of 18L (70kg*0.25L/kg) means that the drug is primarily distributed in
extracellular fluid (interstitial fluid + plasma/blood)
Average 70 kg person
Drug w/ 0.55-.70L/kg Vd distributes into an apparent volume of approximately 40-50L (70*.55-.7L/kg=40-50L) these drugs have a greater tendency to distribute
out of extracellular fluid compartment and into total body water
70kg person
Drug Vd is >.7L/kg (>50L) is distributed
Extensively throughout the body and is NOT being allowed to reenter the central compartment due to tissue bind/affinity for specific cells/ion trapping
Biotransformation (metabolism)
drug is chemically altered to form a metabolite that is more “excretable” then parent drug
The byproduct of biotransformation (metabolism) is
a metabolite
A prodrug
When the parent drug has no actiity and the metabolite does
In phase 1 hepatic biotransformation either a ___ is added or a ___ is removed
oxygen, hydrogen
Cytochrome P450 which primarily mediates oxidation in phase 1 hepatic biotransformation are most sensitive to substances that have the ability to ___ or ___ biotransformation
inhibit, induce (alcohol, drugs, smoking)
An inducer ____ action and their is ____ metabolism and ____ concentrations
induce, more, less
An inhibitor is ___ active, ____ metabolism, and ___ concentrations
less, less, more
In phase 2 reactions of hepatic biotransformation the parent drug/metabolite is conjugated w/
glucuronic acid, a methyl group, an acetyl group, or a sulfate group
Phase 2 reaction of hepatic biotransformation are primarily mediated by a group of enzymes known as
transferases
Phase 2 reactions of hepatic biotransformation produce a metabolite which is more _____ and less ____. The more ____ molecules will be more likely to stay in the blood stream + be available for excretion via the kidneys
polar, lipophilic, polar
Relatively polar substances made in phase 2 reactions of hepatic biotransformation are less likely to undergo
renal tubular reabsorption which means it will more likely stay in the renal tubule + be excreted
How are drugs filtered through the kidney?
At the nephron, filtered at the glomerulus + pass into the renal tubule + excreted in urine
Some drugs may also be secreted into the tubules via
active transport proteins
Drugs can also be excreted via other organs and of most relevance to kinetics is via
bile ducts
What is enterohepatic recirculation?
When a metabolite may be excreted into the small intestine via bile and some may be reabsorbed and re-enter the systemic circulation
These are less susceptible to change in the liver
Enzymes
Drug elimination rate may be gleaned from two parameter
Clearance, elimination half-life
Clearence
the volume of blood that is cleared of drug per time
150ml/min clearance means
150ml of blood is cleared of drug every minute
Elimination half-life
The time it takes for the concentration of drug to reduce by one-half and for most it is a constant value for a given drug
A drug with a faster clearance or shorter elimination half-life will probably need to be dosed ______ frequently
more
For a dug whose elimination processes are NOT easily maximized (Pk verbiage = NOT easily saturated) the elimination of that drug increases in _______ to the serum drug concentration (referred to as _______). For such a drug, the serum drug concentrations are _______ to the dose administered.
direct proportion, first pass elimination, directly proportional
Half-life for first pass elimination is _____ and is _____ of drug serum concentrations
constant, independant
First order reaction equation
elimination rate= serum concentration*constant
Dose-serum concentrations hold true w/ IV administration but ____ with oral drug administration
May/may not be true b/c the AUC may not be directly proportional to dose b/c % absorption may decline w/ higher doses (maximized/saturated the absorption process)
First order elimination is a linear relationship between
drug concentration + elimination, and dose + concentration
For drugs whose elimination processes ARE easily maximized (PK verbiage=easily saturated) the elimination rate of that drug is ____ (referred to as ______). For such a drug, the serum drug concentration produced are _____ to the dose administered. Instead, small increases in dose will produce ______ increases in serum drug concentrations.
constant, zero-order elimination, disproportional, large
Equation for zero-order elimination
Elimination rate = constant
Half-life for zero-order elimination is
Dependent, the half-life changes based on serum concentrations
The relationship of concentration and elimination in a zero-order elimination process is
non-line curves to the right where it plateaus, so even with high concentrations the elimination stays the same
The relationship of serum concentration and dose in a zero-order elimination process is
non-linear, you may only increase the dose a little bit but the serum concentrations sky rocket so the curve goes far up to the right
Neurotransmitters
transfer information from nerve terminals across the synaptic cleft and bind receptors to pass on the message
Drugs have been found in nature + modified to
mimic or block the message getting to these receptors to cause a specific response
Classification methods of the nervous system
Physical location: Peripheral vs. CNS (separates brain + spinal cord from everything else)
Function: Autonomic vs. somatic nervous system (actions that require conscious thought or not)
Autonomic nervous system
Involves actions that are not under conscious control (visceral functions like cardiac output, blood flow to vital organs, + digestion)
Somatic nervous system
conscious function: movement, respiration, posture
Two major sections of the autonomic NS
sympathetic (thoracolumbar)
parasympathetic (craniosacral)
Both sympathetic + parasympathetic originate in the
CNS
Sympathetic NS fiber exit through
thoracic and lumbar spinal nerves
Parasympathetic fibers of the autonomic NS exit through
cranial nerves + 3rd + 4th sacral spinal routes
Efferent nerves
- are preganglionic neurons that originate in the CNS + connect to ganglia in the peripheral NS
- Ganglia act as relay stations to pass messages on to postganglionic nerves
- Postganglionic neurons terminate on effector organs
Afferent nerves of the autonomic nervous system
- Regulate the autonomic nervous system by sensing actions + providing feedback to the CNS
- Bring information from effector organ to CNS
- CNS can then adjust its message to efferent nerves
Two neurotransmitters of autonomic NS
Acetylcholine + norepinephrine
Acetylcholine is released from
- Cholinergic nerve fibers
- Include almost all efferent nerve fibers leaving CNS sympathetic and parasympathetic
Norepinephrine is released from
- adrenergic nerve fibers
- Include most postganglionic SYMPATHETIC nerve fibers
The sympathetic portion of the nervous system have the ganglionic neurotransmitter ______ and a neuroeffector neurotransmitter ______ with a _____ receptor
ACh, Norepinephrine, Adrenergic receptor
The parasympathetic portion of the autonomic nervous system includes ____ as the ganglionic neurotransmitter and he neuroeffector neurotransmitter ____ which has a _____ receptor
ACh, ACh, muscarinic
Acetylcholine is made from
acetyl-CoA using the enzyme choline O-acetyltransferase
Synthesis of ACh occurs in the nerve fiber
mitochondria
Once formed ACh is transferred to neuronal terminal by a
choline transporter
ACh is stored ass packages of
“quanta” in vesicles located on the surface of the nerve terminal facing the synapse
Release of ACh
- An action potential is generated in the nerve + reaches the terminal
- Causes an influx of Ca++ into the nerve terminal
- Calcium interacts w/ the vesicle membrane triggering fusion of the membrane to the terminal membrane
- A pore opens into the synapse + subsequent release of hundreds of quanta into synaptic cleft
Released ACh
- ACh binds to and activates acetylcholine receptors (reversible)
- Acetylcholinesterase present in the synaptic cleft breaks down unused ACh into choline + acetate in seconds
- Terminates ACh action
- Any ACh present in synapse will continue to interact with receptors until broken down
NE is only on the
postganglionic side and through the sympathetic portion of the autonomic nervous system
Adrenergic nerve fibers
- Make up the postganglionic neurons of the sympathetic nervous system
- Release norepinephrine
- Make adjustments in response to stressful situations
Adrenergic nerve fibers that release norepinephrine’s actions
- Increase hr + BP
- Mobilize energy stores
- Increase blood flow to skeletal muscles
- Divert blood flow from skin + internal organs
- Dilate pupils + bronchioles
Termination of adrenergic action occurs in three ways
- NE metabolized by catalytic enzyme (monoamine oxidase MAO)
- Diffusion away from receptor site (then metabolized)
- Reuptake into terminal by norepinephrine transporter (NET) or other cells
Receptors
- Structures made of protein that are designed to bind endogenous molecules
- Upon binding, the receptors pass on the message using signaling proteins
- Highly specific + require special interaction w/ the molecules for proper binding
- Many drugs are based on receptor-ligand interaction
Cholinergenic receptors are named after
alkaloids that bind them (muscarinic + nicotinic)
Norepinephrine receptors are based on
agonist + antagonist selectivity (a1 and B1 ad dopamine but not usually in the ANS)
There is more to ANS then just norepinephrine + ACh
nitric oxide synthase, purines, substance P, calitonin gene-related peptide, cholecytokinin, dynorphin
The parasympathetic system is sometimes referred to as
trophotopic which means leading to growth by resting + digesting conserving + storing energy and stimulating digestive activity
The sympathetic system is sometimes referred to as
ergotrophic which means leading to energy expenditure activated in “fight or flight” stimulating heart, increasing blood sugar, + mediating vasoconstriction of blood vessels
What is a major target of the autonomic NS
Cardiovascular system
What are parasympathetic effects on the cardiovascular system
-bradycardia:decreased hr
What are the sympathetic effects on the cardiovascular system
- Alter peripheral vascular resistance to manage BP
- Heart rate
- Contraction force to manage cardiac output
- Venous tone
- Renin production to manage renal blood flow
Control of autonomic function is done in order to
- prevent overstimulation
- maintain effector organ functions w/in a narrow window of tolerance
Control of autonomic function is done by
- Presynaptic regulation
- Postsynaptic regulation
Receptors on presynaptic nerves control
output of neurotransmitter
- a1 receptors
- B receptors
A1 recetors
- present on noradrenergic nerve terminals
- Activated by binding of NE released from same nerves
- Binding results in decreased release of NE
- Example of autoreceptor b/c responds to NE released from same neuron
B receptors
- Present on some neurons
- Facilitate release of more NE
2 mechanisms of postsynaptic regulation
- Up or down regulate receptors
- Action of one receptor is affected by action of other receptors
Up or down regulate receptors
Response to high or low activation from neurotransmitters or drugs that mimic neurotransmitters
Effector organs
- Multiple sites throughout the body sensitive to adrenergic/cholinergic action
- Actions of NE + ACh are often opposite each other
