Pharm 1 Flashcards
Define Volume of distribution (Vd):
the relationship between a drug’s plasma concentration following a specific dose.
A theoretical measure of how a drug distributes throughout the body.
What does Vd assume:
- Drug distributes instantaneously (full equilibration occurs at t = 0)
- Drug is not subjected to biotransformation or elimination before it fully distributes.
What is the Vd equation?
Vd= amount of drug/ desired plasma concentration
What are the implications when a drug’s Vd exceeds TBW?
The drug is assumed to be lipophilic.
- It distributes into TBW + fat
- It will require a higher dose to achieve a given plasma concentration.
- ex: propofol, fentanyl
What are the implications when a drug’s Vd is less than TBW?
The drug is assumed to be hydrophilic.
- It distributes into some or all of the body water, but it doesn’t distribute into fat.
- it will require a lower dose to achieve a given plasma concentration.
- Ex: NMBs (ECF), Albumin (plasma)
Calculate the loading dose for an IV medication:
and a PO medication:
Loading dose = (Vd X desired plasma concentration)/ Bioavailability
For IV, bioavailability is always 1 because all of the drug enters the blood stream.
For PO medications it will be <1 d/t distribution and first pass metabolism and other conditions that reduce bioavailability.
What is clearance?
The volume of plasma that is cleared of drug per unit time.
Clearance is directly proportional to:
Blood flow to clearing organ
Extraction ratio
Drug dose
Clearance is inversely proportional to:
Half-time
Drug concentration in the central compartment
What is steady state?
(SS) Rate of administration = rate of elimination
- there is a stable plasma concentration.
Each of the compartments are equilibrated, although the total amount of drug in each compartment may differ.
Steady state is achieved after how many half-times?
5
What is the plasma concentration curve?
It graphically depicts the biphasic decrease of drug’s plasma concentration following a rapid IV bolus.
Describe the alpha- and beta- distribution phases on the plasma concentration curve:
Alpha- drug distribution from the plasma to the tissue
Beta- drug elimination from the plasma by the clearing organs.
Begins as plasma concentration falls below tissue concentration.
The concentration gradient reverses, which causes the drug to re-enter the plasma.
What is half-time?
The amount of time required for the drug concentration to decrease by 50%.
Half-time; Amount of drug eliminated %; Amount of drug remaining %
HT 0-- E 0%-- R 100% HT 1-- E 50% --R 50% HT 2-- E 75% --R 25% HT 3-- E 87.5%--R 12.5% HT 4-- E 93.74%--R 6.24% HT 5-- E 96.875%--R 3.125%
What is context sensitive half-time?
The time required for the plasma concentration to decline by 50% after discontinuing the drug.
*the problem with half-time is that they do NOT consider time. CSHT solves this problem.
Discuss the context sensitive half-time of fentanyl, alfentanil, sufentanil, and remifentanil.
(see photo in Pharm 1: Pharmacokinetics)
CSHT of Fentanyl increases as a function of how long it was infused. longer infusion has more time to fill up the peripheral compartments, therefore more fentanyl has to be eliminated and it will have a longer elimination half-time.
Remifentanil is the exception. It is highly lipophilic, however it is quickly metabolized by plasma esterase and has similar CSHT regardless of how long its infused.
Fentanyl»_space;> Alfentanil>Sufentanil>Remifentanil
What is the difference between a strong and weak acid or base?
The difference is the degree of ionization.
[AH] –> [A-] + [H+] Acid donates H+
[BOH] –> [B+] + [OH-] Base donates OH-
If you put a strong acid or a strong base in H2O it will..
ionize completely.
If you put a weak acid or weak base in H2O…
a fraction of it will be ionized and the remaining fraction will be unionized.
What is Ionization?
Ionization describes the process where a molecule gains a positive or negative charge.
What 2 factors determine how much a molecule will ionize?
The amount of ionization is dependent on 2 things:
- the pH of the solution
- the pKa of the drug
When pKa and pH are the same…
50% of the drug will be ionized and 50% will be unionized.
How does ionization affect solubility?
Ionized: water soluble (hydrophilic; lipophobic)
Unionized: lipid soluble (hydrophobic; lipophilic)
How does ionization affect Pharmacologic effects?
Ionized: Not active
Unionized: Active
How does ionization affect hepatic biotransformation?
Ionized: less likely
Unionized: Morel likely
How does ionization affect Renal elimination?
Ionized: More likely
Unionized: Less likely
How does ionization affect Diffusion across lipid bilayers (BBB, Gi tract, placenta)?
Ionized: Not diffused
Unionized Diffuses
What happens when you put an Acid in a Basic solution?
- An acidic drug will be highly ionized in a basic pH.
- Acid drug wants to donate protons and basic solution wants to accept protons.
- Acid donates protons becomes ionized.
What happens when you put an Acid in a Acidic solution?
- An acidic drug will be highly unionized in an acidic pH.
- Acid drug wants to donate protons and acid solution wants to do the same.
- No proton acceptors, drug retains its protons and remains unionized.
*Remember that “like dissolves like”
Are most drugs weak or strong acids or bases?
Most drugs are weak acids or weak bases. They are usually prepared as a salt that dissociates in solution.
Can you tell if a drug is an acid or a base by looking at its name? If yes, how?
A weak acid is paired with a positive ion such as Na+, Ca++, or Ma++
ex: sodium thiopental
A weak base is parted with a negative ion such as Cl- or sulfate (SO4–).
ex: Lidocaine hydrochloride, morphine sulfate.
3 key plasma proteins:
Does each bind acidic drugs, basic drugs, or both?
Albumin: primarily binds acids however binds to some neutral and basic drugs.
alpha1-acid glycoprotein: binds basic drugs
Beta-globulin: binds basic drugs
What conditions reduce albumin concentration?
Liver disease Renal disease Old age Malnutrition Pregnancy
What conditions effect Alpha1-acid glycoprotein concentration?
Increased A1AG: Surgical stress MI Chronic pain RA Advance age
Decreased A1AG:
Neonates
Pregnancy
How does changes in plasma protein binding affect plasma drug concentration?
Decreased PP binding = increased plasma concentration
Increased PP binding = decreased plasma concentration
How do you calculate changes in plasma protein binding?
[free drug] + [unbound protein binding sites] [bound drug]
you must calculate the % changed to complete this question
if a drug is 98% bound and the its reduced to 96%, then the unbound (or free fraction) has increased by 100%.
(The free fraction was 2% now it’s 4%)
A new anesthetic drug is cleared from the body at a rate proportional to its plasma concentration. What kinetic model best describes the elimination of this drug?
First-order Kinetics: a constant fraction of drug is eliminated per unit time.
(see photo in pharm 1: pharmacokinetics)
Alcohol is cleared from the body via zero-order kinetics. How will this drug’s rate of elimination change as plasma drug concentration changes?
a constant amount of drug is eliminated per unit time.
The rate of elimination is independent of plasma drug concentration.
Ex: ASA, phenytoin, warfarin, heparin, theophylline
(see photo in pharm1: pharmacokinetics)
What is the function of phase 1 reaction?
Phase 1 –> small molecular changes that increase polarity (H2O solubility) of a molecule to prepare it for a phase 2 reaction.
- Creates a location on molecule that will allow phase2 reaction to take place.
- Most phase 1 bitransformations are carried out by the P450 system
List 3 Phase 1 reactions:
Oxidation- adds oxygen molecule to compound.
Reduction- adds electrons to compound
Hydrolysis- adds H2O to compound to split it (usually an ester)
What is the function of a phase 2 reaction?
Conjugates (adds on) an endogenous, highly polar, water soluble substrate to the molecule.
Results in water soluble, biologically inactive molecule ready for excretion.
*Some drugs do not require preparation by phase 1 reactions and may proceed directly to phase2.
5 common substrates for phase 2 conjugation reactions:
Glucuronic acid Glycine Acetic acid Sulfuric acid Methyl group
Discuss enterohepatic circulation:
list 1 drug example.
Some conjugated compounds are excreted in bile, reactivated in the intestine, and reabsorbed into systemic circulation.
Ex: Diazepam
What is the extraction ratio?
A measure of how much drug is delivered to a clearing organ versus how much drug is removed by the organ.
What does an extraction ratio (ER) of 1.0 mean?
that 100% of the drug delivered to the clearing organ is removed.
What does an extraction ratio (ER) of 0.5 mean?
that 50% of the drug delivered to the clearing organ is removed.
Calculate extraction ratio:
ER = (arterial concentration - venous concentration)/ arterial concentration
Regarding hepatic clearance, what is flow limited elimination?
- A drug with a high hepatic ER (> 0.7), clearance is dependent on liver blood flow.
- Hepatic blood flow greatly exceeds enzymatic activity, so alterations in hepatic enzyme activity has little effect.
increased liver BF = increased Cl
decreased liver BF = decreased Cl
Regarding hepatic clearance, what is capacity limited elimination?
- A drug with a low hepatic ER (< 0.3), clearance is dependent on ability of the liver to extract drug from blood.
- Changes in liver enzyme activity or protein binding have a profound impact on clearance.
- Changes in liver’s intrinsic ability to remove drug from the blood is influenced by the amount of enzyme present.
enzyme induction = increased CL
enzyme inhibition = decreased CL
What will have a greater effect on the metabolism of a low hepatic ER drug: prolonged hypotension or CYP inhibition?
CYP inhibition.
List the 7 Low hepatic ER drugs:
Rocuronium Diazepam Lorazepam Methadone Thiopental Theophylline Phenytoin
List the 4 intermediate hepatic ER drugs:
Midazolam
Vercuronium
Alfentanil
Methohexital
List the 15 High hepatic ER drugs:
Fentanyl Sufentanil Morphine Meperidine Naloxone Ketamine Propofol Lidocaine Bupivacaine Metoprolol Propranolol Alprenolol Nifedipine Diltiazem Verapamil
What is the most important mechanism of drug biotransformation in the body?
Where do these enzymes reside?
P450 system
In the liver, in smooth endoplasmic reticulum.
What can influence the P450 system?
A unique feature of P450 is exogenous chemicals can influence the expression of these enzymes. This can be significant source of drug interactions.
What is a hepatic enzyme inducer?
give examples
-Inducers increase Clearance
-Decreased drug plasma level
-Dose increase may be required
Ex: tobacco smoke, phenytoin, barbiturates, Rifampin, Ethanol, Carbamazepin
What is a hepatic enzyme inhibitor?
give examples
-Inhibitors decrease clearance
-Increased drug plasma level
-Dose decrease may be required
Ex: Grapefruit juice, SSRIs, Cimetidine, Erythromycin, Omeprazole, Ketoconazole, Isoniazid
2 drug classes and 7 drugs that are metabolized by pseudocholinesterase:
Some NMBs:
- Succinylcholine
- Mivacurium
Ester-type LAs:
- Chloroprocaine
- Tetracaine
- Procaine
- Benzocaine
- Cocaine (also metabolized by the liver)
6 drugs that are metabolized by non-specific plasma esterases:
Esmolol Remifentanil ASA Clevidipine Atracurium (and Hofmann elimination) Etomidate (and hepatic)
1 drug that is biotransformed by alkaline phosphatese hydrolysis:
Fospropofol (propofol pro-drug; trade name Lusedra)
What is Pharmacokinetics?
how is it affected?
“what the body does to the drug”
It explains the relationship between the dose that you administer and the drug’s plasma concentration over time.
Affected by: absorption, distribution, metabolism, and elimination.
What is pharmacobiophysic?
Considers the drug’s concentration in the plasma and the effect site (biophase)
what is pharmacodynamics?
“what the drug does to the body”
It explains the relationship between the effect site concentration and the clinical effect.
How do pharmacokinetics, pharmacobiphysics, and pharmacodynamics relate?
pharmacokinetics = Drug dose + plasma concentration pharmacobiphysics = plasma concentration + effect site concentration pharmacodynamics = effect site concentration + clinical effect
what is potency?
The dose required to achieve a given clinical effect (x-axis of the dose response curve)
How is potency measured?
see photo in pharm1: Pharmacodynamics
ED50 and ED 90
They represent the dose required to achieve a given effect in 50% and 90% of the population respectively.
How is potency measured not on dose-response curve?
see photo in pharm1: Pharmacodynamics
Drug A: curve shifts left with –> increased affinity for receptor–> higher potency–> lower dose required
Drug B: Curve shifts right with –> decreased affinity for receptor–> lower potency–> higher dose requited
What is efficacy?
Efficacy is a measure of the intrinsic ability of a drug to produce a clinical effect.
How is efficacy measured on the dose-response curve?
see photo in pharm1: Pharmacodynamics
The height of the plateau on the y-axis represents efficacy.
Higher plateau = greater efficacy
Lower plateau = lower efficacy
*once plateau is reached, additional drug doesn’t produce additional effect. It will only increase risk of toxicity
what does the slope of the dose-response curve tell you?
How many of the receptors must be occupied to elicit a clinical effect.
Steeper slope = small increase in dose can have a profound clinical effect.
Flatter slope = higher dose are required to increase the clinical effect.
What is a full agonist?
see photo in pharm1: Pharmacodynamics
Binds to a receptor and turns on a specific cellular response.
What is a partial agonist?
see photo in pharm1: Pharmacodynamics
Binds to a receptor, but is only capable of partially turning on a cellular response.
Less efficacious than full agonist.
What is a Antagonist?
see photo in pharm1: Pharmacodynamics
Occupies the receptor and prevents an agonist from binding to it.
Does NOT tell the cell to do anything.
By definition, it does not have efficacy.
What is an inverse agonist?
see photo in pharm1: Pharmacodynamics
Binds to the receptor and causes an opposite effect to that of a full agonist.
Has negative efficacy.
What is competitive antagonism?
Give 3 examples
Reversible
Increasing the concentration of the agonist can overcome competitive antagonism.
Ex: Atropine, Vecuronium, Rocuronium
What is noncompetitive antagonism?
Give 2 examples
Not reversible
Drug binds to a receptor (usually through covalent bonds) and is effect cannot be overcome by increasing the concentration of agonist.
Can only be reversed by producing new receptors. (this explains why these drugs have long duration of action)
Ex: ASA and phenoxybenzamine
Define ED50
Effective dose 50 is the dose that produces the expected clinical response in 50% of the population.
A measure of potency.
Define LD50
Lethal dose 50 is the dose that will produce death in 50% of the population.
Define therapeutic index:
helps us determine the safety margin for a desired clinical effect.
TI = LD50/ED50
Drugs with narrow TI have narrow margin of safety.
Drugs with wide TI have wide margin of safety.
What is chirality?
a division of stereochemistry.
Deals with molecules that have a center of 3-dimensional asymmetry.
In biologic systems, this type of asymmetry generally stems from the tetrahedral bonding of carbon (carbon binds to 4 different atoms)
A molecule with 1 chiral carbon will exist as 2 enantiomers. the more chiral carbons in a molecule, the more enantiomers that are created.
What is an enantiomer?
What is the clinical relevance?
(see photo in pharm1: pharmacodynamics)
Enantiomers are chiral molecules that are non-superimposable mirror images of one another.
Different enantiomers can produce different clinical effects. For Example, the SE profile of 1 enantiomer of a drug can be different from another enantiomer of the same drug.
What is a racemic mixture?
Give 4 examples:
Mixture containing 2 enantiomers in equal amounts.
About 1/3 of the drugs we administer are enantiomers, and just about all of these are prepared as racemic.
Ex: bupivacaine, ketamine, iso and des (not sevo)
Propofol MOA:
Direct GABA-A agonist–> increases Cl- conductance–> neuronal hyperpolarization
Propofol dose:
induction 1.5-2.5mg/kg IV
infusion 25-200 mcg/kg/min
Propofol Onset and duration:
Onset: 30-60 seconds
Duration: 5-10min
Propofol clearance:
liver (P450) + extra hepatic metabolism (lungs)
