FDN Exam 4 Flashcards
Define pharmacogenetics
New area; understanding the underlying genetic component that gives variance in drug response from person to person
Define toxicants
Toxic subtances produced by human activities (man-made)
What is phase II metabolism?
Usually involves biotransformation into a more polar form which is more readily excreted in the urine, feces or bile
More info via Google: glucuronidation, acetylation, and sulfation reactions: “conjugation reactions” that increase water solubility of drug with a polar moiety
phase II reactions convert a parent drug to more polar (water soluble) inactive metabolites by conjugation of subgroups to -OH, -SH, -NH2 functional groups on drug
In first-order metabolism, is the half-life dependent or independent of the concentration of the drug?
Independent
What are environmental sources of individuality?
Diet, habits like smoking and drinking, and physical things like sunlight
What is a prodrug?
a biologically inactive compound that can be metabolized in the body to produce a drug
Example: Acetanilide
What factors determine the extent of drug absorption?
Drug factors, biological factors, and formulation factors
Smaller or larger molecular weight improves the rate of drug absorption?
Smaller
What is an orphan drug?
Drugs intended to treat rare diseases
US government had to find a way to incentivize drug companies to create these since the ability to recoup R&D money would be nearly impossible.
What type of adrenergic receptor causes iris contraction?
a1
What is the difference in patient populations from Phase II/III and Phase IV trials?
Phase II/III are small, homogenous populations whereas Phase IV is the entire population and is heterogeneous
What factors affect drug distribution?
Blood flow, drug binding to plasma proteins, and the activity of P-glycoprotein
What has a predominant parasympathetic tone?
Heart, iris, ciliary muscle, GI, urinary bladder, salivary glands
What is potency?
Based on the interaction of a drug with a receptor. The concentration or dose that produces 50% of the maximal response
The higher the potency, the lower the concentration of the drug to achieve the same level of receptor occupancy
Which components of the Michaelis-Menten equation are constants?
Km and kcat
What is occupation theory?
In order for an agonist to activate a receptor, it must occupy the receptor
What is first order elimination? Provide a definition and the equation.
The rate of drug elimination is proportional to the drug concentration
First-order elimination rate = -kel[drug]
Most drug-receptor interactions are what kind of bonds?
Ionic and hydrogen (very few are covalent)
What is the primary neurotransmitter at the somatic (voluntary) skeletal muscle neuromuscular junction?
Acetylcholine
What are the average volumes (in a 70kg adult) of plasma? extracelluar space? intracellular space? Total body water?
Plasma = 3L
Extracellular = 9L
Intracellular = 29L
Total body water = 41L
How are ionized comounds and their metabolites excreted in the liver?
Via active transport systems
What considerations should you keep in mind when prescribing to a pregnant woman?
Increased renal blood flow (pharmacokinetic!)
Placental transfer
And then infant toxicity if/when mother breast feeds
Can drugs excreted in bile re-enter systemic circulation?
Yes, via the hepatic portal system these drugs and metabolites can re-enter system circulation where they can undergo phase I and phase II metabolism again
(same mechanism used for bile salt recycling!)
What is ED50?
The dose of drug for 50% response
List the steps in the biosynthesis of epinepherine including enzymes
What type of adrenergic receptor is present on the liver? What does it do?
B2
Increases glycogenolysis and gluconeogensis
Which nicotinic ganglionic blocker can penetrate the CNS and which one cannot?
Hexamethonium can’t penetrate the CNS
Mecamylamine can enter the CNS
Is zero-order elimination saturating or non-saturating?
Saturating
What effect do Amphetamine and Tyramine have one norepinephrine in the synapse?
They facilitate reuptake and re-packaging into vesicles
Phase II enzymes are all what type of enzyme class?
Transferase
What are the three endogenous catecholamines?
- Norepinepherine - principal transmitter of most postganglionic fibers
- Dopamine - found in extrapyramidal system & mesolimbic nd mesocortical pathways
- Epinepherine - major hormone of the adrenal medulla
What are three ways that individuals vary in their ability to metabolize and excrete drugs?
- Age
- Diet
- Genetic differences (ex: rapid acetylators vs. slow acetylators)
Why do some patients have an allergic reaction to a drug but others don’t?
The drug could get paired with a larger molecule, and the body may see the larger molecule as an allergen - this mounts IgE response
What is the passive filtration rate in the nephron?
125 mL/minute
What phase of metabolism is used in the design of inactive prodrugs?
Phase I
What type of adrenergic receptor is responsible for brochial muscle dilation?
B2
Where are a1 receptors found?
Effector tissues: smooth muscle, glands
What are the major classes of nicotinic receptors?
- Neuromuscular
- Neuronal/ganglionic
Why is thiopental a good rapid anethestic but not a good long-term one?
Because it immediately goes to the brain, but shortly thereafter it is sequestered in fat reducing its activity in the brain
What is the two-compartment model?
We have a central compartment (i.e. plasma) into which drug is added and removed, but then we also have a peripheral compartment (i.e. brain, lipid) into which the drug is sequestered
This is obviously more complicated than single-compartment elimination
A drug can also enter and exit these peripheral compartments at different rates, further complicating the elimination
What is kcat equivalent to?
Vmax
It’s the maximum rate an enzyme can metabolize a drug
If a drug is actively excreted into the proximal tubule, what can the clearance rate go up to?
600 mL/minute
True or False: doubling the dose of a first-order drug will double the duration time?
False
Doubling the dose increases the duration time by approximately one half life
Define half life and give the equation
The time it takes for the drug concentration to fall by 50%
t1/2 = 0.693 / kel
Which cholinergic receptor is a G-protein?
Muscarinic
What type of reaction is important for the removal of toxic metabolites?
Glutathionation
What effect do Cocaine and Imipramine have on norepinepherine in the synapse?
The antagonize the dopamine receptor and leave norepinephrine out in the synapse longer than it should be
Codeine is a prodrug of what?
Morphine
What is an antagonist?
A drug that binds to the receptor but produces no response
How do most drugs enter the blood?
Via simple diffusion
What are nicotinic receptors? Where are they specifically located?
They are located on Na+/K+ ion channels and respond to acetylcholine and nicotine by opening the ion channel. They are located post-synapse in somatic pathways (neuromuscular is the major class!!)
Located in the ganglia and in the skeletal muscle end plates
When do acidic drugs have a charge? Low pH or high pH?
High
They are neutral at low pHs
What two feedback loops control blood pressure?
- Autonomic
- Hormonal
What is a schedule 1 drug? What is its abuse/dependence rating?
Cannot be prescribed and no accepted medical use
High abuse/dependence potential
Examples: LSD, heroin, etc
What does a quantal dose response graph show us?
How many people are responding to the treatment at specific doses
The graph is cumulative; we add patients in until 100% of individual responses (the y-axis) are accounted for
What type of adrenergic receptor(s) increase SA and VA node activity + ventricle activity?
B1 (and some B2)
What is assessed during phase III clinical testing? Who are the subjects in this phase?
Additional information is gathered about safety and efficacy. Often compares new therapy to current standard of care
Subjects: Patients (> 300). Double blind, placebo controlled
What body compartment(s) have a pH generally higher than plasma pH?
Small intestine lumen
What is supersensitivity?
The rebound effect
If you take a drug like the beta blocker propranolol your body will up-regulate the receptors in an attempt to compensate for the inhibited action
When you remove yourself/the patient from the beta-blocker there will be an up-regulated amount of receptors and a supersensitive response. Gradual tapering is recommended to avoid this.
Is a high or low lipid:water (or oil:water, lipophilic/hydrophboic nature) more important for absorption?
High
Which line is more potent? The one on the left or right?
The left. You need less of that drug to elicit the same response
Will drugs targeting nicotinic ganglionic receptors affect any other components of the nervous system?
Yes, they will affect the entire autonomic nervous system. There is no selectivity for sympathetic or parasympathetic systems
How many half-lives until we’ve reach nearly 100% concetration in the plasma/tissue?
5t1/2 = 96.9%
In what state are nicotinic receptors most stable?
Desensitized (with ACh still bound)
What are two outcomes after rare adverse events are observed?
- Label warnings are developed (black box). Example: antidepressants tested in adults but then once prescribed to teens we see instances of suicide
- Market withdrawal (Vioxx/seldane example - cox 2 inhibitor that caused heart failure in patients)
What are the three main mechanisms by which antidotes work?
- Binding to the toxicant and inactivating it
- Blocking critical receptors
- Changing the toxicant metabolism
Define toxins
Toxic substances produced by biological systems such as plants and animals (ex: rattlesnake venom)
What is first pass metabolism?
a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation.
It is the fraction of drug lost during the process of absorption which is generally related to the liver and gut wall
How are majority of drugs eliminated: first or zero order?
First
What continuously maintains the concentration gradient necessary for passive diffusion to occur?
Local blood flow
For first-order elimination, the time to plateau (steady state) is determine solely by what?
kel
And if there is a shift in the plateau, the time to reach the new one is determinely solely by kel again
Where are muscarinic receptors present even though there is no parasympathetic innervation?
Arterioles
(Explanation from class: “Vagus nerve dumps a bunch of ACh into the blood stream and it causes arteriole dilation”)
In zero-order elimination, if you double the initial dose what happens to the elimination time?
It nearly doubles
This is an important distinction from first-order elimination where doubling the initial dose does NOT double the elimination time
Activated G proteins can act on what effectors?
Adenylyl cyclase, phospholipases C and A2, cGMP phosphodiesterase, potassium channels, and calcium channels
When does liver toxicity peak in acetaminophen toxicity?
72 to 96 hours after the dose
What does Leuprolide do?
It is an agonist for gonadotropin-releasing hormone (GnRH) used to treat prostate cancer
GnRH stimulates the release of lutenizing hormone (LH) which in turn stimulates testosterone synthesis
Leuprolide ultimately causes a decrease in testosterone due to desensitization of the pathway
What type of adrenergic receptor is responsible for constriction of blood vessels in skeletal muscle? For dilation of blood vessels in skeletal muscle?
Constriction: a1 (due to high levels of epinepherine)
Dilation: B2 (due to low levels of epinepherine)
What form of drugs readily diffuses across the plasma membrane?
The unionized form
What is the Single Compartment Model of drug distribution?
It assumes that a drug distributes evenly throughout a single homoegenous space in the body
It allows us to predict the general pharmacokinetic properties of the drug sufficiently well enough for clinical use
When does a steady state concentration of a drug in plasma/tissue occur?
Rate of drug infusion = rate of drug elimination
What foods induce P450?
Charcoal broiled foods and broccoli/sprouts
______ is the primary transmitter in all autonomic ganglia and the stanpses between parasympathetic postganglionic neurons and their effector cells
Acetylcholine
What are G-protein coupled receptors also known as?
7TMR (seven transmembrane spanning receptors)
What foods inhibit P450?
grapefruit juice and tropical fruits
Where are B2 receptors found?
Smooth muscle, liver, heart
Can the apparent volume of distribution (Vd) be greater than total body water?
Yes. This would indicate that the drug is highly distributed in the tissues
Ex: Digoxin has a Vd of 280 L
Define cholinergic
A nerve ending that released acetylcholine; also, a synpase in which the primary transmitter is acetylcholine
What are three symptoms/symptoms of Aresnic poisoning/toxicity?
- Blackfoot disease (gangrenous feet)
- Mee’s lines (white lines on finger nails)
- Rice water stools (due to sloughing of GI mucosa)
When considering individuality in drug response, what items fall under “condition or state of being”?
Physiological set-point, disease-induced alterations in PK and PD, age, reproduction (i.e. pregnancy), allergic reactions
What is a muscarinic receptor? What kind of protein is it?
These receptors respond to muscarine and acetylcholine & are located post-synapse in the parasympathetic pathway and the eccrine sweat sympathetic pathway
Located primarily on autonomic effector cells (including heart, vascular endothelium, smooth muscl, presynaptic nerve terminals, and exocrine glands)
They are G-protein-coupled receptors
What are the muscarinic cholinergic actions?
Salivation
Lacrimation
Urination
Defecation
“SLUD”
Also: decreased heart rate, vasodilation, bronchoconstriction, constricted pupils, increased GI motility. This all makes sense because muscarinic receptors are part of the parasympathetic system!
If you plot the logarithm of the drug concetration versus time for a first-order process, what type of graph/line do you expect to see?
A straight line
What are the four targets of ANS drugs?
- CNS
- Ganglions
- Neurons
- Effector Organ Receptors
What are nicotinic ganglionic receptor antagonists called?
Ganglionic blockers
Examples: hexamethonium and mecamylamine
What effect does Warfarin have on P450 metabolism?
Reduces it
What is EC50?
The concentration of drug for 50% response
Can a drug bound to a plasma protein leave systemic circulation?
No. Only unbound drugs can leave systemic circulation
What type of adrenergic receptor constrictrs blood vessels in skin, mucosa, arterioles and veins?
a1
What is the important exception to norepinepherine being the postganglionic transmitter in sympathetic neurons?
Eccrine sweat glands
They use acetylcholine
How many liters of fluid are in plasma, extracellular, and intracellular space?
Plasma: 3L
Extracellular: 9L
Intracellular: 29L
What are examples of sympatholytics? What step in the catecholamine biosynthesis does each block?
Metyrosine blocks tyrosine hyroxylase (stops L-DOPA formation)
a-methyl DOPA blocks the conversion of L-DOPA to dopamine
Guanethidine has a two prong approach: competes with NE for space in vesicles & then lack of NE in vesicles stop their fusion with the plasma membrane & release into the synapse
What are three methods of enteral drug administration?
- Oral - Non-invasive and good for chronic administration
- Sublingual - rapid entry of permeable drugs
- Rectal - useful when oral administration is impractical
Do the nicotinic receptors of autonomic ganglia and neuromuscular junctions have the same specificities for agonists and antagonists?
No, they have different specificities. This allows for drugs targeting just the neuromuscular nicotinic receptors, for example, to be used
Does carrier-mediated faciltated transport of drugs occur?
Sometimes
What are examples of ion channel receptors?
Acetylcholine (Ach), GABA, serotonin, glutamate
Involved in neurotransmission; high levels of expression in the brain
Define pharmacotherapeutics
The therapeutic use of drugs (clinical response: efficacy and toxicology)
Where is norepinepherine a vasoconstrictor?
The renal blood vessels
What are pharmacodynamic genetic sources of individuality?
Receptors, enzymes, ion channels
What is active efflux and what molecule accomplishes this?
Active transport of drugs out of a cell so the drug cannot reach its targeted receptor
This is accomplished by P-glycoprotein
Does a non-competitive inhibitor change the potency or efficacy?
Efficacy
The agonist can still bind, but it can’t produce the same maximal effect with the allosteric inhibitor present
What is a “loading dose”?
Administration of a large dose of a medication to provide immediate relief to the patient
Calculated by multiplying the drug’s apparent volume of distribution (Vd) by the desired steady-state plasma concentration (Css)
Initial Loading Dose = Vd * Css
What are two examples of non-cyp enzymes found in the liver that are used for alcohol metabolism?
alcohol and aldehyde dehydrogenases
What happens to patients deficient in acetylation capacity (aka slow acetylators)?
They may have prolonged or toxic responses to normal doses of certain drugs because of decreased rates of metabolism
What are pharmacokinetic genetic sources of individuality?
- A person can be a poor metabolizer of coedine (failure to convert to morphine) or they can be a rapid metabolizer and be at risk for respiratory distress
- A person can also be a slow vs. fast acetylator; important when considering Isoniazid (therapeutic level vs. toxicity)
As drug concentration falls and we get into the region where [drug] <<< Km, what type of elimination are in?
First order
How long does it take a drug to act on nuclear receptors?
Hours
What is a key factor in clearance rates?
Blood flow
What is bioavailability?
The measure of the drug available to the systemic circulation over time after administration (usually oral)
What can you inject into a patient to determine how well their kidneys are functioning/clearing drugs?
Inulin
Clearance rate of 7.8 L/hr
What G-protein subunit typically acts on effectors like adeneylyl cyclase?
Alpha
What is the equation for zero-order elimination?
elimination rate = -kel
(its just a constant!)
What G-protein subunit typically acts on ion channels?
BY (beta gamma)
What are symptoms of organophosphate poisioning?
Excessive muscarinic activity (aka too much parasympathetic action)
Nicotinic effects varibale due to desensitization and depolarization-block of the nicotinic receptors
What is assessed during phase I clinical testing? Who are the subjects in this phase?
Safety and pharmacokinetics are assessed (typically not efficacy because the subjects are healthy volunteers)
Subjects: healthy volunteers (20-100 subjects)
Does a competitive inhibitor change the potency or efficacy?
The potency
You will still get the same effect when the agonist binds, but you just need more of it/need it to be more potent to achieve the same effect
What is it called when rate of drug infusion = rate of drug elimination?
Steady state
Define Km
the amount of drug required to activate 50% of the enzyme
What does zero-order elimination depend on? Drug concentration or the enzyme?
The enzyme and how fast it can work
Zero-order elimination is indepdent of drug concentration (when [drug] >>> Km). The elimination rate is what it is
rate of catalysis = kcat[enzyme]
What does inhibition of the P-glycoprotein pump accomplish?
Improvement in the delivery of therapeutic agents
What are the two types of adrenergic receptors?
- Muscarinic
- Nicotinic
What are the three classes of sympathomimetics? Include examples for each
- Direct acting: act directly on a receptor- norepinephrine, epinephrine, Isoproterenol
- Indirect acting: effect catecholamine levels in the synapse - Amphetamine, Tyramine, Cocaine, Imipramine
- Combination: have mixed actions - dopamine, ephedrine
What is a schedule 5 drug? What is its abuse/dependence rating?
Lowest abuse/dependence potential
Example: diphenoxylate (anti-diarrhea medication)
What does EC50 indicate? Efficacy or potency?
Potency
What amino acid is norepinepherine derived from?
What is the rate limited enzyme in norepipherine’s production from this enzyme?
Tyrosine
Tyrosine hydroxylase
Where are a2 receptors found?
Nerve endings, some smooth muscle
What happens to GI motility/tone under the actions of the parasympathetic nervous system?
Increase
(sphincters relax)
What is the benefit of a loading dose?
It gets patients into the therapeutic range quickly
What is phase 1 metabolism?
Usually involves “activation” of the molecule so that it can be subsquently conjugated with a more polar group
More info via Google: Oxidation (via cytochrome P450), reduction and hydrolysis reactions
Convert a parent drug to a more polar, water-soluble, active metabolite by unmasking or inserting a polar functional group (-OH, -SH, -NH2)
How do you calculate the maintenance rate of infusion?
Cl * [drug]ss
What is the value of having molecules like estrogen be able to bind to a kinase receptor AND a nuclear receptor?
The body doesn’t need to make a bunch of different ligands for various receptors; we can utilize fewer genes to make molecules that then act on multiple receptors/pathways
In what method of drug administration will side effects develop rapidly?
IV administration
Define clearance and provide the equation
The amount of blood per unit of time that is completely cleared of the drug
Clearance (Cl) = kel * Vd
Or you can substitute in the half-life equation for:
Cl = (0.693 / t1/2) * Vd
Describe the mechanism of action of a ligand binding to a tyrosine kinase receptor
A ligand will bind to the extracellular side of the TKR. This will cause dimerization and autophosphorylation on the intracellular side
Example: EGF rceptor
How is steady state most accurately and rapidly achieved?
Via IV infusion
What determines the rate and extent of drug absorption?
Drug factors & biological factors
When does urinary manipulation of pH work?
It’s limited to alkalization (with IV sodium bicarb)
Only works for a few chemicals with the right pKa values (i.e. salicylates)
What are the four receptor drug targets?
- Ion channels
- G-protein coupled receptors
- Kinase-linked receptors
- Receptors linked to gene transcription (nuclear receptors)
What are the three mechanisms of catecholamine removal from the synapse?
- Reuptake (primary) and then storage or breakdown via MAO
- Diffusion into ciruclation
- Active transport and then breakdown via COMT or MAO
Do we get a half life value for zero-order elimination?
Not usually
(and he didn’t tell us how to)
What are the clinical uses of antimuscarinics?
Eye examinations (dilation), asthma (blocks cholinergic component of bronchoconstriction), MI (blocks vagal response to pain), insecticide poisoning (antidote for anticholinesterases), oral surgery (to inhibit salivation)
What is the liver blood flow per hour? Combined kidney blood flow per hour?
Liver = 90 L/hr
Combined kidney = 70 L/hr
Define toxicology
The study of the deleterious effects of chemical agents on living systems
What are two examples of desensitization?
- Phosphorylation of the g-protein stops it from binding again/maintains the uncoupled state
- Arrestin sequesters the receptor from the cell surface (it’s physically removed!)
What is the main reaction in phase 1?
Oxidation
What is better: a higher or lower therapeutic index?
Higher
What considerations should you keep in mind when prescribing to newborns and infants?
They have lower levels of plasma proteins, lower P450 enzymes, and lower GFR
Can you achieve similar effects by using an agonist and an antagonist?
Yes
The Leuprolide example demonstrates this. Continous use of Leuprolide desensitizes the pathway (GnRH to LH to testosterone) & inhibits testosterone synthesis. An antagonist would do the same thing.
So you can achieve the same effect by using different methods of attack
How long does it take a drug to act on ion channels?
Milliseconds
Does the plateau principle tell us how long until the plateau is reached or what the plateau is? Or both?
Just how long until it’s reached
Define pharmacodynamics
What the drug does to the body physiologically (mechanism, potency, efficacy, toxicity)
What is physiological set point?
From body temperature to blood pressure to levels of certain nutrients, each physiological condition has a particular set point. A set point is the physiological value around which the normal range fluctuates. A normal range is the restricted set of values that is optimally healthful and stable.
Most orally administered drugs have bioavailabilities in what range?
Greater than 10%
What patient population has difficulty with phase 1 metabolism?
geriatric patients
- drugs metabolized via phase I reactions have longer half-lives
- geriatric patients metabolism drugs by phase II reactions
What are our four sources of toxicology information?
- Human studies
- Animal studies
- In vitro studies
- COmputer modeling
What three things have a dominant sympathetic tone?
- arterioles
- veins
- sweat glands (don’t forget: cholinergic!!)
What are common phase I metabolism reactions?
Oxidation, epoxidaiton, o-dealkylation (and n-dealkylation), reduction, dehalogenation, and hydrolysis of esters and amides
What is a schedule 4 drug? What is its abuse/dependence rating?
Drugs like benzodiazepines
Can prescribe 5 refills within 6 months
Low abuse/dependence potential
What type of foods delay gastric emptying?
Fatty foods
What is a schedule 3 drug? What is its abuse/dependence rating?
Drugs like ketamine, low-dose codeine
Can prescribe 5 refills within 6 months
Moderate abuse/dependence potential
Define adrenergic
A nerve ending that releases norepinepherine as the primary transmitter; also, a synpase in which norepinepherine is the primary transmitter
What is the Apparent Volume of Distribution (Vd) and how is it measured?
Vd = IV dose/Co
IV concentration (100%) versus the concentration you can immediately measure in the plasma after ingestion
Idea is the affinity of a drug for a tissue. More affinity = larger volume in tissue
How are drugs metabolized via phase II excreted?
Renally excreted
What are three examples of zero-order elimination?
Ethanol
Salicylate
Phenytoin
(ESP)
After administering a chronic agonist, what happens to the receptors? Are they up-regulated or down-regulated?
Down-regulated
Define volume of distribution (Vd) and give the equation
An apparent (or theoretical) volume that measures the drug distribution between plasma and the rest of the body
Vd = dose/plasma concentration
What two organs have the highest blood flow rate? What two have the lowest?
Highest: lung and kidney
Lowest: Muscle, skin and adipose
What is a schedule 2 drug? What is its abuse/dependence rating?
Drugs like morphine, high-dose codeine, amphetamines
No refills are allowed, written prescriptions only
High abuse/dependence potential
Can various types of G-proteins couple to the same effector or is it a one G-protein/one effector system?
Different types of G-proteins can couple to the same effector
(And conversely, the same type of G-proteins can couple to different effectors)
What enzyme terminates the action of ACh in the synaptic cleft?
Acetylcholinesterase
What are the signs that a Muscarinic antagonist has been used?
“Hot as a hare (inhibition of sweating), red as a beet (vasodilation - CNS effect), dry as a bone (xerostomia/dry eyes), mad a wet hen (hallcuinations - CNS effects)”
Also pupil dilation, blurred vision due to loss of accommodation, and urinary retention
If the drug concentration is much greater than Km, what will you expect of the line on the graph?
It will approach an asyptompe as the enzyme is saturated and there can be no increase in the rate of metabolism
What does Emax indicate? Efficacy or potency?
Efficacy
What is the equation for calulating the loading dose?
Vd x desired plasma concentration
After adminstering a chronic antagonist what happens to receptor regulation? Is it up-regulated or down-regulated?
Up-regulated
What is the rate-limiting step in catecholamine synthesis?
Tyrosine to L-DOPA (tyrosine hydroxylase)
What can signal amplification do to potency?
Increase it (shift the curve to the left)
What happens to GI motility/tone under the actions of the sympathetic nervous system?
Decreases
(sphincters constrict)
What are three cellular responses that activation of the muscarinic receptors can accomplish?
- The activation of phospholipase C
- Opening or closing of ion channels
- The regulation of adenylyl cyclase
(remember, muscarinic receptors are G-proteins!)
At what molecular weight can molecules passively diffuse through channels?
150-200 MW
What is the most important tone and reflex controlled by the ANS?
Blood pressure
Name a nicotinic ganglionic receptor agonist
Nicotine
Stimulates ganglionic nicotinic receptor, stimulation followed by depression, also a CNS stimulant
What is “trapping” of a drug?
Excessive concentration of the ionized form of a drug in certain compartments
Example: cocaine can be readily detected forensically in gastric fluid due to the much higher concentration of the ionized form in the acidic stomach environment
What do adrenergic drugs elicit in addition to their primary effects?
Reflex effects (like baroreceptors increasing or decreasing BP)
What adrenergic receptor is responsible for increased renin secretion in the kidney?
B1
What is therapeutic index?
TD50/ED50
TD50 = The toxic dose (dose at which 50% of individuals exhibit a toxic effect like vomitting)
ED50 = the dose at which 50% of individuals exhibit the therapeutic effect
Define pharmacology
effect of small molecules or chemicals on biological systems
Which two methods of enteral administration avoid first-pass metabolism?
Sublingual and rectal
How can blood pressure be quickly regualated? Slowly?
Quickly: through ANS pathways
Slowly: through renal pathway/blood volume effect
What type of patient population do we typically see in phase II/III trials? Why is that?
A homogenous patient population so you can limit the confounding variables. You can achieve this via inclusion/exclusion criteria (i.e. select those breast cancer patients who have the exact receptor your drug is targeting)
“Stack the cards in your favor”
If your drug concentration is less than Km, what will you expect of the line on the graph on that area?
It will be a straight line when the drug concentration is less than Km
What are four sources of individuality?
- Condition or State of Being
- Genetics
- Enviornment
- Drug Combinations (drug interactions)
“C’s get GEDs”
How are controlled substances classified?
Into schedule groups: 1 - 5
For a first-order process, the higher the drug concentration, the _______ the rate of elimination
higher
If the rate of excretion of a drug is independent of the drug concentration then it is first or zero order?
Zero
If excretion is directly proportional to the amount of the drug is this first order or zero order?
First
_______ is the primary transmitter at the sympathetic postganglionic neuron effector cell synapses in most tissues
Norepinepherine
What is the mechanism of action of sympatholytics?
They deplete the stores of catecholamines, block sympathetic transmission
(Block some step in the biosynthesis)
What are the two methods of drug administration?
- Enteral
- Parenteral
What is a modulatory transmitter in the ENS and kidney?
Dopamine
What diseased-states can affect pharmacokinetics?
Impaired renal or hepatic function (ex: cirrhosis)
Circulatory insufficiency (ex: HF or shock)
Altered drug binding proteins (ex: too little or too much plasma proteins like albumin)
How do ganglionic blockers affect the tone in a given organ?
They act as an antagonist of the dominant tone
What is responsible for the differentiaton of a sympathetic progenitor cell into an adrenergic neuron?
NGF (neuron growth factor)
How is prognosis of acetaminophen toxicity assessed?
The Rumack-Matthew nomogram
What is assessed during phase II clinical testing? Who are the subjects in this phase?
Efficacy, safety, and pharmacokinetics (“is there a therapeutic benefit?”)
Subjects: Patients with the condition (< 300)
How can adrenergic receptors be subclassified?
- Alpha (1 and 2)
- beta (1, 2, and 3)
What two phase I transformations don’t involve cyp enzymes?
Reduction and hydrolysis
Which is saturating: first order or zero order?
Zero
What happens during phase IV clinical trials? What are the subjects?
Evaluate long-term effects of drugs over a lengthy period of time
No specific subjects, but heterogeneous patient population. Reporting is voluntary and usually done by physicians
Rare adverse events are observed & off-label uses are discovered
What enzyme is responsible for the synthesis of Acetylcholine?
Choline-acetyl transferade (CAT) from Acetyl-CoA and choline
What is responsible for the differentiaton of a sympathetic progenitor cell into an cholinergic neuron?
Ciliar neurotrophic factor
What is efficacy?
The maximum response produced by a drug
It is proportional to the number of receptors occupied and is reversible
When do basic drugs have a charge: low pH or high pH?
Low pH
They are neutral at higher pHs
What are the six methods of parenteral administration?
- Intravenous
- Subcutaneous
- Intramuscular
- Topical
- Transdermal
- Inhalation
Drugs eliminated by which type of elimination process will reach a plateau with repeated doses?
First-order
What is an agonist?
A substance that binds and activates a receptor producing a response
What two functional groups are readily conjugated in glucuronidation (the most common phase II rxn)?
Hydroxyl and carboxyl groups
How long does it take a drug to act on GPCRs?
Seconds
What is an antagonist?
A substance that produces no response when bound to a receptor
By binding to the receptor, the antagonist prevents the binding of an agonist and thus the agonist from activating the receptor
Where are P-glycoproteins active?
- They reduce entry into the systemic circulation from the GI tract
- Reduce entry from the blood into the nervous system
- Reduce entry from the blood into malignant cells
What amino acid do all endogenous catecholamines originate from?
Phenylalanine
Are drugs equally distributed to all tissues and organs?
No. Blood flow/perfusion rates vary greatly between organs
Where are B1receptors found?
Cardiac muscle, juxtaglomerular apparatus
What clinical use dose nicotine as a nicotinic ganglionic receptor agonist have?
Cigarette smoking withdrawal (transdermal or oral), Chantix/Varenicline
Define pharmacokinetics
What the body does to drugs (absorption, distribution, metabolism, and excretion)
What is the most important absorptive mechanism?
Passive lipid diffusion
What is an example of a cytokine receptor?
JAK-STAT signaling (JAK is bound intracellularly to the kinase-linked receptor)
Growth hormone
Leptin
Which phase of drug development often compares a new therapy to the current standard of care?
Phase III
What are the two types of antagonists?
- Competitive (reversible)
- Non-competitive (irreversible)
Where are B3 receptors found?
Adipose
What are the three classifications of drugs?
- OTC drugs: self administration
- Prescription drugs
- Orphan drugs: rare diseases
What is responsible for transforming a neural crest cell progenitor into a sympathetic progenitor?
FGF2 (Fibroblast Growth Factor)
What body compartment(s) have a pH generally lower than plasma pH?
Stomach, vaginal secretions, urine, milk, and prostatic secretions
What drug is acetylated at different rates depending on a person’s genetic make up?
Isoniazid
What are common phase II metabolism reactions?
Acetylation, glucuronidation, sulfation, glutathionation, glycination, and methylation
What suffix is given to beta-blocks?
-lol
Examples: metoprolol, timolol, bisprolol
How long does it take a drug to act on kinase-linked receptors
Minutes
Phase I enzymes generally begin with what prefix?
cyp-
What affects the extent of passive reabsorption of a drug in the distal tubules/collecting?
Drug ioniation
Ionizied, lipid-insoluble drugs are excreted in the urine
So ionized drugs can be “trapped” in this manner (ex: Aspirin)
What do most molecular drugs target?
Receptors (45%), then enzymes (28%), and hormones & factors (11%)
What is a catecholamine?
An adrenergic agonist
Substances which can produce a sympathomimetic response (mimics the sympathetic nervous system)
May be endogenous or synthetic
