Pharmacology 1 Flashcards
Define volume of distribution, and recite the equation.
The volume of distribution (Vd) describes the relationship between a drug’s plasma concentration following a specific dose. It is a theoretical measure of how a drug distributes throughout the body.
Vd= Amount of drug/ desired plasma concentration
Vd assumes two things:
* the drug distributes instantaneously (full equilibration occurs at t=0)
* the drug is not subjected to biotransformation or elimination before it fully distributes
What are the implications when a drug’s Vd exceeds TBW? What if Vd is less than TBW?
If Vd> TBW (>0.6 L/kg or >42L) the drug is assumed to be lipophilic.
* It distributes into TBW + Fat
* It will require a higher dose to achieve a given plasma concentration
* examples: propofol and fentanyl
If Vd< TBW (0.6 L/kg or <42L), the drug is assumed to be hydrophilic:
* it distributes into some or all of the body water, but it does not distribute into fat.
* it will require a lower dose to achieve a given plasma concentration
* examples: NMBs (ECF), albumin (Plasma)
How do you calculate the loading dose for an IV medication? How about a PO medication?
Loading dose = (Vd x desired plasma concentration)/ bioavailability
For an IV drug, the bioavailability is always 1. This is because all of the drug enters the bloodstream.
A drug administration by any other route may not be absorbed completely and/or it may be subject to first-pass metabolism in the liver. These conditions reduce bioavailability and explain why the dose that achieves a given plasma concentration is dependent on the route of administration. Therefore, bioavailability will be less than 1.
what is clearance? What factors increase/decrease it?
Clearance is the volume of plasma that is cleared of a drug per unit time.
CL is directly proportional to: blood flow to cleaning organ, extraction ratio, drug dose
CL is inversely proportional to : Half-life, drug concentration in the central compartment
What is steady state?
Steady state occurs when the amount of drug entering the body is equivalent to the amount of drug eliminated from the body- there is a stable plasma concentration. Each of the compartments has equilibrated, although the total amount of drug may be different in different compartments
(SS) rate of administration = Rate of elimination
SS is achieved after 5 half-lives
Compare and contrast the alpha- and beta distribution phases on the plasma concentration curve
the plasma concentration curve graphically depicts the biphasic decrease of a drug’s plasma concentration following rapid IV bolus.
Alpha distribution phase:
* describes drug distribution from the plasma to the tissues
Beta distribution phase:
* begins as plasma concentration falls bellow tissue concentration
*the concentration gradient reverses, which causes the drug to re-enter the plasma
* the beta phase describes drug elimination from the central compartment
You have administered esmolol to a pt after a sudden (and profound) elevation in heart rate. After three half-lives, what percentage of you initial dose remains in the patients blood stream?
12.5% of the drug remains
Half-time amount eliminated amt remaining
0 0 100
1 50 50
2 75 25
3 87.5 12.5
4 93.75 6.25
5 96.875 3.125
What is context sensitive half-time?
the problem with half-life is that they do NOT consider time.
the context-sensitive half-time solves this problem. It is the time required for the plasma concentration to decline by 50% after discontinuing the drug.
Discuss the context sensitive half-times of fentanyl, afentanil, sufentanil, ad remifetanil. Which has the longest? which has the shortest? why?
The context-sensitive half-time for a fentanyl infusion increases as a function of how long it was infused. An extended infusion of fentanyl had more time to fill up the peripheral compartments; therefore, more fentanyl has to be eliminated, and it will have a longer elimination half-time. This is also true for alfentanil and sufentanil to lesser degrees.
Remifentanil is an exception. Even though hit is highly lipophilic, it is quickly metabolized by plasma esterases. It also has a similar context- sensitive half-time regardless of how long it is infused
What is the difference between a strong and weak acid or base?
the difference is the degree of ionization:
*if you put a strong acid or a strong base in water, it will ionize completely.
* if you put a weak acid or a weak base in water, a fraction of it will be ionized, and the remaining fraction will be unionized
an acid is a substance that donates a proton
a base is a substance that accepts a proton
what is ionization? What 2 factors determine how much a molecule will ionize?
ionization describes the process where a molecule gains a positive or negative charge.
The amount of ionization is dependent on two things:
* the pH of the solution
* the pKa of the drug
finish this sentence: when pKa and pH are the same..
50% of the drug is ionized, and 50% is non-ionized
comparing ionized vs non-ionized
Ionized: hydrophillic/lipophobic, not active, renal elimination, does not cross BBB/GI tract/placenta
Non-ionized: lipophilic/hydrophobic, active, hepatic biotransformation, does cross BBB/GI tract/ placenta
Can you tell if a drug is an acid or a base by looking at its name? how?
most drugs are weak acids or weak bases. They are usually prepared as a salt that dissociates in solution.
A weak acid is paired with a positive ion such as sodium, calcium, or magnesium.
* example: sodium thiopental
A weak base is paired with a negative ion such as chloride or sulfate.
Example: lidocaine hydrochloride, morphine sulfate
Name the 3 key plasma proteins. Does each bind acidic drugs, basic drugs, or both?
Albumin: primarily binds to acidic drugs; however, it also binds to some neutral and basic drugs.
Alpha 1 acid glycoprotein: binds to basic drugs
Beta-globulin: binds to basic drugs
What conditions reduce the serum albumin concentration?
liver disease
renal disease
old age
malnutrition
pregnancy
What conditions affect alpha 1 acid glycoprotein concentration?
Increase alpha1- acid glycoprotein concentration:
* surgical stress
* myocardial infarction
* chronic pain
* rheumatoid arthritis
* advanced age
Decreased alpha 1 acid glycoprotein concentrations
* neonates
* pregnancy
How do changes in plasma protein binding affect plasma drug concentration?
Decreased PP binding -> increased Cp
Increased PP binding-> decreased Cp
alcohol is cleared from the body via zero-order kinetics. How will this drug’s rate of elimination change as plasma drug concentration changes?
Zero order kinetics describes the situation where there is more drug than enzyme.
Under zero- order kinetics, a constant amount of drug is eliminated per unit time. Said another way, the rate of elimination is independent of plasma drug concentration.
Examples: aspirin, phenytoin, warfarin, heparin, and theophylline
What is the function of a phase 1 reaction? list 3 examples.
Phase 1 reactions result in small molecular changes that increase the polarity (water solubility) of a molecule to prepare it for a phase 2 reaction- it creates a location of the molecule that will allow phase 2 reaction to take place. Most phase 1 biotransformation are carried out by the P450 system.
There are three phase 1 reactions that you should understand:
Oxidation- removes electrons from a compound
Reduction- Adds electrons to a compound
Hydrolysis: adds water to a compound to split it apart (usually an ester)
what is the function of a phase 2 reaction? list 5 common substrates.
The phase 2 reaction conjugates (adds on) an endogenous, highly polar, water soluble substrate to the molecule. This results in a water-soluble, biologically inactive molecule ready for excretion.
Typical substrates for conjugation reactions include:
*glucuronic acid
* Glycine
* Acetic acid
* sulfuric acid
* methyl group
Some drugs do not require preparation by phase 1 reactions and many proceed directly to phase 2 reactions
Discuss enterohepatic circulation, and list 3 drug examples
Enterohepatic circulation- some conjugated compounds are excreted in the bile, reactivated in the intestine, and then reabsorbed into the systemic circulation
Examples: diazepam and warfarin
Regarding hepatic clearance, What is perfusion-dependent elimination?
For a drug with high hepatic extraction ratio (>0.7), clearance is dependent on liver blood flow.
Hepatic blood flow greatly exceeds enzymatic activity, so alteration in hepatic enzyme activity has little effect.
- increased liver blood flow= Increased clearance
- decreased= decreased
regarding hepatic clearance, what is capacity-dependent elimination?
For a drug with a low hepatic extraction (<0.3), clearance is dependent on the ability of the liver to extract the drug from the blood. Changes in hepatic enzyme activity or protein binding have a profound impact on the clearance of these drugs.
Since only a small amount of drug is removed per unit time, alteration in liver blood flow minimally affect clearance.
The amount of enzyme present influences changes in the liver’s intrinsic ability to remove the drug from the blood.
Enzyme induction -> increased clearance and vice versa
Whats the difference between a hepatic enzyme inducer and enzyme inhibitor? List examples of each.
the P450 system is the most important mechanism of drug biotransformation i the body. In the liver, these enzymes reside in the smooth endoplasmic reticulum.
A unique feature of the P450 system is that exogenous chemicals can influence the expression of these enzymes. This can be significant source of drug interactions.
Enzyme inducer: inducers increase clearance, decrease drug plasma level, dose increase my be required
* examples: tobacco smoke, barbiturates, ethanol, phenytoin (anticonvulsant), rifampin, carbamazepine (anticonvulsant)
Enzyme inhibitors: inhibitors decrease clearance, increase drug plasma level, Dose decrease may be required.
* ex: grapefruit juice, cimetidine, omeprazole, isoniazid, SSRI (citalopram, dapoxetine, sertraline), erythromycin, ketoconazole
Whats the difference between a hepatic enzyme inducer and enzyme inhibitor? List examples of each.
the P450 system is the most important mechanism of drug biotransformation i the body. In the liver, these enzymes reside in the smooth endoplasmic reticulum.
A unique feature of the P450 system is that exogenous chemicals can influence the expression of these enzymes. This can be significant source of drug interactions.
Enzyme inducer: inducers increase clearance, decrease drug plasma level, dose increase my be required
* examples: tobacco smoke, barbiturates, ethanol, phenytoin (anticonvulsant), rifampin, carbamazepine (anticonvulsant)
Enzyme inhibitors: inhibitors decrease clearance, increase drug plasma level, Dose decrease may be required.
* ex: grapefruit juice, cimetidine, omeprazole, isoniazid, SSRI (citalopram, dapoxetine, sertraline), erythromycin, ketoconazole
List 2 drug classes and 6 drugs that are metabolized by pseudocholinesterase.
Some neuromuscular blockers:
* succinylcholine (depolarizer)
* Mivacurium (nondepolarizer)
Ester-type local anesthetics:
* chloroprocaine
* Tetracaine
* benzocaine
* Cocaine (also metabolized by the liver)
List 6 drugs that are metabolized by non-specific plasma esterases.
- Esmolol
- Remifentanil
- Remimazolam
- clevidipine
- Atracurium (and hofmann elimination)
- Etomidate (and hepatic)
List 1 drug that is biotransformed by alkaline phosphatase hydrolysis.
Fospropofol (a propfol prodrug under the trade name lusedra)
Define Pharmacokinetics, pharmacobiophysics, pharmacodynamics. How do they relate to each other?
Pharmacokinetics: can be thought of as “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. This relationship is affected by absorption, Distribution, metabolism, and elimination.
Pharmacobiophysics: considers the drug’s concentration in the plasma and the effect site (biophase)
Pharmacodynamics: can be thought of as “what the drug does to the body.” it explains the relationship between the effect site concentration and the clinical effect
What is potency and how is it measured?
potency is the dose required to achieve a given clinical effect (x-axis of the dose-response curve)
The ED50 and ED90 are measures of potency. They represent the dose required to achieve effect in 50% and 90% of the population, respectively.
How is potency measure on the dose- response curve
Farther left = more potent and lower dose required, higher affinity for receptor
What is efficacy, an how it is measured on the dose-response curve?
Efficacy is a measure of the intrinsic ability of a drug to produce a clinical effect
The height of the plateau on the y axis represent efficacy
high plateau= high efficacy and vice versa
Once the plateau phase is reached, any additional drug does NOT produce an additional effect. Increase dosing will only increase the risk of toxicity.
What does the slope of the dose-response curve tell you?
The slope tells us how many of the receptors must be occupied to elicit a clinical effect.
*steeper slope= small increase in dose can have profound clinical effect
* Flatter slope= higher doses are required to increase the clinical effect
what are the differences between a full agonist, partial agonist, antagonist, and inverse agonist?
Full agonist: binds to a receptor and turns on a specific cellular response ( Heroin, oxycodone, methadone, morphine, hydrocodone, opium)
Partial agonist: binds to a receptor, but it is only capable of partially turning on a cellular response. It is less effective that a full agonist. (buprenorphine, butorphanol, and tramadol)
Antagonist: occupies the receptor and prevents an agonist from binding to it. It does not tell the cell to do anything, By definition, it does not have efficacy. (naltrexone and naloxone)
Inverse agonist: binds the the receptor and causes an opposite effect to that of a full agonist. It has negative efficacy.(nalmefene, benzodiazepine, digoxin, propranolol, all antihistamines)
What is competitive antagonism? Give an example
Competitive antagonism
* competitive antagonism is reversible
* increasing the concentration of the agonist can overcome competitive antagonism
* examples: atropine, vecuronium, rocuronium
What is noncompetitive antagonism? give an example
Noncompetitive antagonism
* noncompetitive antagonism is NOT reversible. The drug binds to a receptor (usually through covalent bonds) and its effect cannot be overcome by increasing the concentration of an agonist.
* only be creating new receptors can the effect of a noncompetitive agonist be reversed. This explains why these drugs have long durations of action.
Examples: aspirin and phenoxybenzamine (antihypertensive for pheochromocytoma)
Define therapeutic index
therapeutic index helps us determine the safety margin of a desired clinical effect.
Therapeutic index: Toxic dose 50/effective dose 50
A drug with a narrow TI has a narrow margin of safety and vice versa
what is chirality?
Chirality is a division of stereochemistry. It deals with molecules that have a center of three-dimensional asymmetry. in biological 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 created.
What is an enantiomer? What is the clinical relevance?
Enantiomers are chiral molecules that are non-superimposable mirror images of one another.
Different enantiomers can produce other clinical effects. For example: the side effect profile of one enantiomer of a drug can be different from another enantiomer of the same drug
What is a racemic mixture? List some commonly used examples.
A racemic mixture contains 2 enantiomers in equal amounts
About one-third of the drugs we administer are enantiomers, and just about all of these medications are racemic mixtures. Common examples include Bupivacaine, ketamine, isoflurane, and desflurane (not sevo)
MOA of propofol
Direct GABA- A agonist-> increased Cl- conductance-> neuronal hyperpolarization (prevent action potential)
What is the dose, onset, duration, and clearance mechanism of propofol?
Dose:
* induction: 1.5-2.5 mg/kg IV
* infusion: 25-200mcg/kg/min
Onset: 30-60seconds
duration: 5-10 min
Clearance: liver (P450 enzymes)+ extrahepatic metabolism (lungs)
What are the cardiovascular and respiratory effects of propofol?
Cardiovascular effects:
* decreased BP (due to decreased SNS tone and vasodilation
* decreased SVR
* decreased Venous tone-> decreased peload
* decreased myocardial contractility
Respiratory effects:
* shifts CO2 curve down and to the right (less sensitive to CO2)-> respiratory depression and/or apnea
* Inhibits hypoxic ventilatory drive
what are the CNS effects of propofol?
CNS effects:
* decreased cerebral oxygen consumption (CRMO2)
* decreased cerebral blood flow
* decreased intracranial pressure
*decreased intraocular pressure
* no analgesia
* anticonvulsant properties
What is the formulation of propofol? Is there a patient population where this is a problem?
Propofol is prepared as a 1% solution in an emulsion of egg lecithin, soybean oil, and glycerol
Despite concerns that propofol might precipitate anaphylaxis in pts allergic to egg, soy, and/or peanuts, there is a gross lack of evidence to justify these fears
Most people with egg allergy are allergic to the albumin in egg whites. Egg lecithin is derived from the yolk. There is no good evidence to support cross-sensitivity in egg- allergic patients, and propfol is probably safe to administer to patients with egg allergies
There is no cross-sensitivity between propofol and soy or peanuts.
what is propofol infusion syndrome
Propofol contains long chain triglycerides, and an increased LCT load impairs oxidative phosphorylation and fatty acid metabolism. This starves the cells of oxygen, particularly in cardia and skeletal muscle. Propofol infusion syndrome is associated with high mortality rate.
what are the risk factors for propofol infusion syndrome
Risk factors:
* propofol dose >4 mg/kg/hr (67mcg/kg/min)
* propofol infusion duration >48 hrs
* adults >children (used to be the other way around)
* inadequate oxygen delivery
* sepsis
* significant cerebral injury
What is the clinical presentation of propofol infusion syndrome?
Clinical presentation include acute refractory bradycardia -> asystole + at least one of the following
* metabolic acidosis (base deficit >10mmol/L)
* rhabdomyolysis
* enlarged or fatty liver
* renal failure
* hyperlipidemia
*lipemia (cloudy plasma or blood) may be an early sign
what preservatives are used in brand and generic propfol? What patient populations are at risk?
Diprivan (branded propofol) contains EDTA (disodium ethylenediamine tetraacetic acid) as a preservative. Its not a problem for any specific patient population
Generic propofol formulations contain different preservatives, and these can cause unique problems of their own.
* Metabisulfite can precipitate bronchospasm in asthmatic patients.
* Avoid benzyl alcohol in infants. There are a few reports of toxicity and death attributed to the benzyl alcohol preservative when used in other medications
How can propofol injection pain be minimized?
Propofol injection pain can be minimized or eliminated by:
* injecting inot a larger and more proximal vein
* lidocaine (before propofol injection or mixed with propofol)
* giving an opioid before the propofol
What dose of propofol can be used to treat PONV?
Propofol (10-20 mg IV) can be used to treat PONV
An infusion of 10 mcg/kg/min can also be used
how is fospropofol converted to its active form?
Forspropofol is a prodrug, and propofol is the active metabolite. Alkaline phosphatase converts fospropofol to propofol.
This mechanism of action explains why it has a slower onset (5-13 min) and longer duration (15-45 min)
Fospropofol -> converted by alkaline phophatase to propofol + formaldehyde + phosphate
What is the primary MOA for anesthesia produced by ketamine?
Ketamine is an NMDA receptor antagonist ( antagonizes glutamate)
- secondary receptor targets include opioid, MAO, serotonin, NE, muscarinic, and Na+ channels
- ketamine dissociates the the thalamus (sensory) from the limbic system (awareness)
what are the potential routes of administration for ketamine? Include the doses for each.
IV
* Induction- 1-2 mg/kg
* analgesia =0.1-0.5 mg/kg
IM- 4-8 mg/kg
PO- 10mg/kg
What is the onset, duration, and clearance mechanism for ketamine?
Onset:
IV- 30-60 seconds
IM- 2-4 min
PO- variable
Duration- 10-20 min (may vary 60-90 min to return to full orientation)
Clearance: liver (P450 system)
* it produces an active metabolite- norketamine (1/3-1/5 the potency of ketamine)
* chronic ketamine use induces liver enzymes (ex burn pts)
What are the cardiovascular effects of ketamine?
Cardiovascular effects:
* Increase SNS tone (useful if the pt is hemodynamically unstable, but harmful if severe CAD)
* increased cardiac output
* increased heart rate
*increased SVR
* increased PVR (caution with RV failure)
* Subhypnotic doses (<0.5 mg/kg) usually don’t activate the SNS
Its important to understand that ketamine is actually a myocardial depressant. The cardiovascular effects discussed above require and intact SNS. The myocardial depressant effects are unmasked in patients with depleted catecholamine stores (sepsis) or sympathectomy.
What are the respiratory effects of ketamine?
- bronchodilation (a great choice if the patient is actively wheezing)
- upper airway muscle tone and airway reflexes remain intact
- maintains respiratory drive, although a brief period of apnea may occur following induction
- does not significantly shift the CO2 response curve
- increased oral and pulmonary secretions -> increased risk of laryngospasm (glycopyrrolate helps reduce secretions)
What are the CNS effects of ketamine
- increased Cerebral Oxygen consumption (CRMO2)
- increased cerebral blood flow
- increased intracranial pressure
- Increased EEG activity (caution if hx of seizure)
- Nystagmus ( caution during ocular surgery that requires a still eye)
- emergence delirium
Discuss ketamine emergence delirium (presentation, tx, and risk factors)
Emergence delirium:
* presents as nightmares and hallucinations (risk persists for up to 24 hrs)
* benzodiazepines are the most effective way to prevent emergence delirium (midazolam is better than diazepam)
* risk factors: age >15 yrs, female gender, ketamine dose >3 mg/kg, hx of personality disorder
Discuss the analgesic properties of ketamine.
- Provides good analgesia and opioid-sparing effects (the only induction agent that does this)
- relieves somatic pain >visceral pain
- blocks central sensitization and wind-up in the dorsal horn of the spinal cord
- prevents opioid induced hyperalgesia (after remifentanil infusion)
- is excellent for burn pts (frequent dressing changes) and those with preexisting chronic pain syndrome
what is the dose, onset, duration, and clearance mechanism for etomidate?
Dose: 0.2 - 0.4mg/kg
Onset: 30-60 seconds
Duration: 5-15min
Clearance: hepatic P450 enzymes +plasma esterases
Cardiovascular and respiratory effects of etomidate?
Cardiovascular:
* etomidate’s key benefit is hemodynamic stability (minimal change in HR, SV, or CO)
* SVR is decreased, which accounts for a small reduction in BP
* it does not block the SNS response to laryngoscopy. An opioid or esmolol will help.
Respiratory effects:
* mild respiratory depression ( less than propofol and barbiturates)
what are the CNS effects of etomidate?
- Decreased cerebral oxygen consumption
- decreased cerebral blood flow (cerebral vasoconstriction)
- Decreased intracranial pressure
- cerebral perfusion pressure remains stable
- no analgesia
what is the relationship between etomidate and myoclonus?
myoclonus is involuntary skeletal muscle contractions, dystonia, or tremor
Although the exact mechanism of myoclonus is unclear, it is likely due to an imbalance between excitatory and inhibitory pathways in the thalamocortical tract. It is NOT a seizure.
What is the relationship between etomidate and seizure activity?
if the pt does not have a history of seizures, then etomidate does not increase the risk of seizures.
If the pt has a history of seizures, then etomidate can increase epileptiform (seizure-like) activity and possibly increase the risk of seizures. This property can make it useful for mapping seizure foci
what is the relationship between adrenocortical suppression and etomidate?
Cortisol and aldosterone synthesis are dependent on the enzyme 11-beta-hydroxylase (located in the adrenal medulla). Some texts also add 17-alpha-hydroxylase.
*etomidate is a known inhibitor of 11-beta-hydroxylase and 17-alpha-hydroxylase
* a single dose of etomidate suppresses adrenocortical function for 5-8 hrs (some books say 24hrs)
* for this reason, avoid etomidate in pts reliant on the intrinsic stress response (sepsis or acute adrenal failure), These pts need all of the cortisol they can muster.
* Mortality may be increased by etomidate, particularly in pts with sepsis.
which induction agent is most likely to cause PONV?
etomidate, as high as 30-40%
what does FA/FI curve tell us? How does anesthetic solubility affect the FA/FI curve for each agent?
The FA/FI curve allows us to predict the speed of induction
* low solubility -> less uptake inot the blood -> increase rate of rise -> faster equilibration of FA/FI-> faster onset
- High solubility -> more uptake into the blood-> decrease rate of rise -> slower equilibration of FA/FI-> slower onset
