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)
Cardiovascular effects of propofol:
- Decreased BP (d/t decreased SNS tone and vasodilation)
- Decreased SVR
- Decreased Venous tone–> decreased preload
- Decreased myocardial contractility
Respiratory effects of propofol:
- Shifts CO2 response curve down and to the right (less sensitive to CO2–>respiratory depression and/or apnea
- Inhibits hypoxic ventilatory drive
CNS effects of propofol:
- Decreased cerebral O2 consumption (CMRO2)
- Decreased cerebral BF
- Decreased intracranial pressure
- Decreased intraocular pressure
- No analgesia
- Anticonvulsant properties
Formulation for propofol:
1% solution in an emulsion of egg lecithin, soybean oil and glycerol.
- There’s a lack of evidence that propofol might precipitate anaphylaxis in pts allergic to egg, soy, and/or peanuts.
- Most people w/ egg allergies are allergic to albumin in egg white. Lecithin is derived from the yolk. Safe to administer.
What is propofol infusion syndrome?
Propofol contains long chain triglycerides, and an increased LCT load impairs oxidative phosphorylation and fatty acid metabolism. This starves cells of O2, particularly in cardiac and skeletal muscle.
-Associated with high mortality rate.
What are the risk factors for propofol infusion syndrome?
- Dose > 4mg/kg/hr (67 mcg/kg/min)
- infusion duration >48hr
- Children > adults
- inadequate O2 delivery
- sepsis
- significant cerebral injury
Clinical presentation of propofol infusion syndrome?
Acute refractory bradycardia –> asystole + at least one of the following:
- Metabolic acidosis (base deficit > 10)
- Rhabdomyolysis
- Enlarged or fatty liver
- Renal failure
- hyperlipidemia
- lipemia (cloudy plasma or blood) maybe early sign
when must a propofol syringe be discarded?
Within 6 hours.
*propofol supports bacterial and fungal growth. Vial and stopper must be cleansed with 70% isopropyl alcohol.
when must a propofol infusion be discarded?
within 12 hours (includes tubing)
What preservatives are used in Diprivan?
EDTA (Disodium ethylenediamine tetraacetic acid)
What preservatives are used in generic propofol?
- Metabisulfite: can precipitate bronchospasm in asthmatic patients.
- Benzyl alcohol: should be avoided in infants. reports of toxicity/death attributed to benzyl alcohol when used in other medications.
How can propofol injection pain be minimized?
- Injecting into a larger, more proximal vein
- Lidocaine before propofol or mixture
- Opioid prior to propofol
Antipruritic effects of propofol:
10mg IV can reduce itching caused by spinal opioids and cholestasis.
Antiemetic effects of propofol:
10-20 mg IV can be used to treat PONV.
An infusion of 10mcg/kg/min can also be used.
How is Fospropofol converted to its active form?
Fospropofol is a pro-drug and propofol is the active metabolite.
Alkaline phosphatase converts Fos to Prop.
Fos—(alkaline phos)–>prop+ formaldehyde + phosphate.
This explains why it is slower to onset (5-13mins) and longer duration (15-45min).
Ketamine MOA:
NMDA antagonist (antagonizes glutamate)
Secondary receptor targets: opioid, MAO, serotonin, NE, Muscarinic, Na+ channels.
Ketamine dissociates the thalamus (sensory) from the limbic system (awareness)
Ketamine dose:
IV Induction: 1-2 mg/kg
IV Analgesia: 0.1-0.5 mg/kg
IM: 4-8 mg/kg
PO: 10 mg/kg
Ketamine Onset and duration:
Onset:
IV= 30-60 sec
IM= 2-4 min
PO= variable
Duration: 10-20 min (may require 60-90 min to return to full orientation)
Ketamine Clearance:
Liver (P450)
Produces active metabolite- norketamine (1/3-1/5 the potency of ketamine)
Chronic ketamine use induces liver enzymes (ex: burn patient)
Cardiovascular effects of ketamine:
- Increased SNS tone (useful if pt is hemodynamically unstable, but harmful if severe CAD)
- increased CO
- Increased HR
- Increased SVR
- Increased PulmVR (caution in RV failure)
- Subhypnotic doses ( <0.5mg/kg) usually don’t activate SNS
*ketamine is actually a myocardial depressant. the SNS effects discussed above require an intact SNS. myocardial depression will be unmasked in pt with depleted catecholamines stores (sepsis) or sympathectomy.
Respiratory effects of ketamine:
- Bronchodilation (great for active wheezing)
- upper airway muscle tone and airway reflexes remain intact
- maintains respiratory drive, although brief period of apnea may occur following induction.
- Doesn’t significantly shift CO2 response curve
- increases oral and pulmonary secretions–> increase risk of laryngospasm (glycopyrrolate helps reduce secretions)
CNS effects of ketamine:
- increased cerebral oxygen consumption (CMRO2)
- increased cerebral blood flow
- increased intracranial pressure
- increased intraocular pressure
- increased EEG activity (caution if h/o seizures)
- nystagmus (caution during ocular surgery)
- emergence delirium
Ketamine and emergence delirium:
- Presents as nightmares/hallucinations (risk persists for up to 24hrs)
- Benzodiazepines are most effective way to prevent ED (midazolam > diazepam)
- Risk factors: age > 15, female, dose >2mg/kg, h/o personality disorder
Analgesic properties of ketamine:
- Good analgesia and opioid-sparing effects (only induction agent that does this)
- Relieves somatic pain > visceral pain.
- Blocks central sensitization and wind-up in the dorsal horn of spinal cord.
- prevents opioid induced hyperalgesia (after Remi infusion)
- good for burn patients (frequent dressing changes) and those with pre-existing chronic pain syndrome.
Etomidate dose:
0.2-0.4 mg/kg IV
Etomidate onset and duration:
Onset: 30-60 sec
Duration 5-15 min
Etomidate clearance:
Hepatic P450 + plasma esterases
Cardiovascular effects of Etomidate:
- Hemodynamic stability (minimal changes in HR, SV, or CO.
- SVR is decreased, which accounts for a small reduction in BP.
- Does NOT block the SNS response to laryngoscopy. and opioid or esmolol will help.
Respiratory effects of Etomidate:
-Mild respiratory depression (less than propofol and barbiturates)
CNS effects of Etomidate:
- Decreased CMRO2
- Decreased cerebral BF (cerebral vasoconstriction)
- Decreased intracranial pressure
- cerebral perfusion pressure remains stable
- no analgesia
Relationship between Etomidate and myoclonus?
involuntary skeletal muscle contractions, dystonia, or tremor.
Exact mechanism is unclear, it is likely d/t imbalance between excitatory and inhibitory pathways in the thalamocrtical tract. NOT a seizure.
Relationship between etomidate and seizure activity?
If no h/o seizures then Etomidate does NOT increase risk of seizures.
If h/o seizures, Etomidate increases epileptiform (seizure like) activity and possibly increase risk of seizures. This can make it useful in mapping seizure foci.
Relationship between Etomidate and adrenocortical suppression?
Cortisol and aldosterone synthesis are dependent on 11-beta-hydroxylase enzyme (in adrenal medulla). (some text add 17-alpha-hydroxylase)
- Etomidate is known inhibitor of 11BH and 17AH.
- Single dose suppresses adrenocortical function 5-8hrs (some say up to 24hr)
- Etom should be avoided in pts reliant on intrinsic stress response (sepsis or acute adrenal failure). They need all of their cortisol.
- Mortality may increase by etomidate, particularly in sepsis.
Which induction agent is most likely to cause PONV?
Etomidate
30-40% incidence
2 sub-classes of barbiturates:
list 2 examples of each:
Barbs derived rom barbituric acid. Substitutuions on the ring can midfy the PK/PD profile for each drug.
(see photo in Pharm1: Intravenous anesthesia)
Thiobarbiturates: sulfur molecule in 2nd position (increases lipid solubility and potency)
ex: Thiopental, thiamylal (T’s)
Oxybariturates: Oxygen molecule in 2nd position
ex: methOhexital, pentObarbital (O’s)
Thiopental MOA:
GABA-A agonist –>depresses the reticular activating system in the brainstem.
- low/normal dose: increases affinity of GABA for binding site
- High dose: directly stimulates GABA-A receptor
Thiopental Dose:
Adult: 2.5-5 mg/kg
Child: 5-6 mg/kg
Thiopental onset and duration:
onset: 30-60sec
duration: 5-10min
Thiopental clearance:
liver (p450)
- awakening is determined by redistribution (not metabolism)
- repeated doses–>tissue accumulation–>prolonged wake up time+hangover effect
Cardiovascular effects of Thiopental:
- Hypotension is primarily result of ventilation and decreased preload; myocardial depression is secondary.
- non-immunogenic histamine release. Can contribute to hypotension (effect is short-lived)
- Baroreceptor reflex is preserved, so reflex tachycardia helps restore CO.
- Compared to propofol, thiopental produces less hypotension.
Respiratory effects of Thiopental:
- Respiratory depression (shifts CO2 response curve to right)
- histamine release can cause bronchoconstriction (caution with asthma)
CNS effects of Thiopental:
- Decreased CMRO2
- Decreased Cerebral BF (cerebral vasoconstriction)
- Decreased intracranial pressure (used in tx of intracranial hypertension)
- Decreased EEG activity (can cause burst suppression and/or isoelectric EEG–> neuroprotection)
- No analgesia (low dose may increase the perception of pain)
IN what circumstances can Thiopental be sued for neuroprotection?
Focal ischemia: YES (ex: carotid endarterectomy, temporary occlusion of cerebral arteries)
Global ischemia: NO (ex: cardiac arrest)
Pathophysiology of acute intermittent porphyria:
Heme is key component of hemoglobin, myoglobin, and cytochrome P450.
Porphyria is caused by a defect in heme synthesis that promotes the accumulation of heme precursors (ALA induction).
Succinyl-CoA + Glycine –> ALA synthase –> Precursors –> Heme
Porphyrias can be classified as acute or cutaneous.
Acute intermittent porphyria is the most common (and dangerous) type.
What drugs should be avoided in Acute Intermittent Porphyria? why?
Avoid any drug or condition that induces ALA synthase which will accelerate the production of heme precursor.
Drugs to avoid: barbs, etomidate, glucocorticoids, and hydralazine
Conditions to avoid: emotional stress, prolonged NPO status
Tx for Acute Intermittent Porphyria:
- Liberal hydration
- Glucose supplementation (reduces ALA synthase activity)
- Heme arginate (reduces ALA synthase activity)
- Prevention of hypothermia.
What is the risk of intra-arterial injection of Thiopental?
What is the treatment?
Intra-arterial injection –> intense vasoconstriction + crystal formation (occludes blood flow) + inflammation –> tissue necrosis.
Tx: injection of vasodilator: phentolamine or phenoxybenzamine
Sympathectomy: stellate ganglion block or brachial plexus block
What induction agent is the gold standard for ECT? Why? What’s the does?
Methohexital
It decreases the seizure threshold and produces a better quality seizure.
Induction dose: 1-1.5mg/kg
Dexmedetomidine MOA:
Alpha-2 agonist–> decreases cAMP –> inhibits the locus coeruleus in the pons (sedation)
Dexmedetomidine Dose:
Loading = 1mcg/kg over 10 min
Maintenance infusion= 0.4-0.7 mcg/kg/hr
Dexmedetomidine onset and duration:
onset: 10-20 min
duration: 10-30 min (after infusion stopped)
Dexmedetomidine clearance:
Liver (p450)
Cardiovascular effects of Dexmedetomidine:
Most common SE: bradycardia and hypotension
*rapid administration can cause HTN (alpha-2 stimulation in the vasculature–> temporary vasoconstriction –> HTN).
Usually short-lived.
Why is Dexmedetomidine attractive for procedural sedation?
Doesn’t cause respiratory depression (also why its attractive for sedation during difficult airway management)
- No change in oxygenation
- No change in blood pH
- No change in slope of CO2 response curve
CNS effects of Dexmedetomidine:
*Produces stimulation that resembles natural sleep.
- Sedation result of decreased SNS tone and decreased level of arousal.
- Patients are easily aroused.
- Do NOT provide reliable amnesia.
- decreased CBF
- no change to CMRO2
- no change in ICP
How does Dexmedetomidine produce analgesia?
Produced by Alpha-2 stimulation in the dorsal horn of the spinal cord (decreased substance P and decreased glutamate release)
Other routes of Dexmedetomidine and their doses?
Nasal and buccal routes have high degree of bioavailability.
Useful for preoperative sedation in children (3-4 mcg/kg 1 hour prior to surgery)
Midazolam contains an imidazole ring. How does this affect its solubility?
Imidazole ring can assume the open or closed position depending on the environmental pH.
- Acidic pH–> ring opens–> increases H2O solubility
- Physiologic pH–> ring closes–> increased lipid solubility
Because midazolam is water soluble inside the vial, it does NOT require a solvent such as propylene glycol (diazepam and lorazepam require it).
Midazolam MOA:
GABA-A agonist–> increases frequency of channel opening–> neuronal hyperpolarization.
*Most GABA-A agonist increase channel open time, but Benzes increase open frequency.
Midazolam doses: IV and PO
IV sedation 0.01-0.1 mg/kg
IV induction 0.1 -0.4 mg/kg
PO sedation in children 0.5 -1mg/kg
*PO bioavailability = 50% d/t first pass metabolism
Which inductions agents produce an active metabolite?
- Midazolam= 1-hydroxymidazolam (0.5 potency parent compound)
- Ketamine= norketamine (0.33-0.5 potency parent compound)
- Fospropofol= propofol
- propofol, etomidate, dexmed do NOT produce active metabolites.
- Always think about active metabolites when a patient has kidney/liver dysfunction or prolonged administration.
Cardiovascular effects of Midazolam:
sedation dose: minimal effects
Induction dose: decreased BP and SVR
Respiratory effects of Midazolam:
- Sedation dose: minimal effects
- Induction dose: respiratory depression
- Opioids potentiate respiratory depression
- Pts with COPD more sensitive to resp depression
CNS effects of Midazolam:
- Sedation dose: minimal effects on CMRO2 and CBF.
- Induction dose: decreased CMRO2 and CBF.
- Can’t produce isoelectric EEG (propofol and Barbs can)
- Anterograde amnesia (not retrograde)
- Anticonvulsant
- Anxiolysis
- Spinally mediated skeletal muscle relaxation (antispasmodic- useful for pts with cerebral palsy)
- No analgesia
What reverses Benzodiazepines?
Flumazenil
Flumazenil MOA:
- Competitive antagonist of GABA-A receptor.
- Has very high affinity, but short duration (30-60 min)
- Repeat dosing maybe necessary.
- Initial dose is 0.2mg IV and titrated in 0.1mg increments q1min.
Potential side effects of Flumazenil:
Unlike post-operative opioid reversal with naloxone (which can cause a profound increase in SNS tone), post-op benzo reversal with Flumazenil does NOT increase SNS tone, anxiety, or neuroendocrine evidence of stress.
In benzo dependent pts, Flumazenil cna precipitate withdraw, including seizures.
How can you tell the difference between the chemical structures of the halogenated agents?
(see photo in pharm1: VA 1)
Count the halogens.
- Iso has 5 fluorine atoms + 1 Cl-
- Des has 6 fluorine atoms
- Sev has 7 fluorine atoms (sevo=7)
How does fluorination affect the physiochemical characteristics of halogenated anesthetics?
Adding fluoride ions tends to:
- decrease potency
- increase vapor pressure
- increase resistance to biotransformation
*Even though Sevo is heavily fluorinated, it’s 3x potent as Des. most likely d/t bulky propyl side chains.
What is vapor pressure? and how is it affected by ambient temperature?
the pressure exerted by a vapor in equilibrium with its liquid or solid phase inside of a closed container.
Vapor pressure is directly proportional to temperature (increased temp–> increased vapor pressure)
How is the anesthetic delivery affected by altitude?
Depth of anesthesia is determined by the partial pressure of anesthetic agent in the brain, NOT the volume of percent.
Partial pressure of a gas = vol% X total gas pressure
Atm pressure decreases at higher elevations, vol% of gas remains the same, PP of the gas decreases. Risk is undedosing the agent.
Sevo or Iso at elevation underdosing is NOT a problem. B/c conventional variable bypass vaporizer automatically compensates for the change in elevation.
Des= underdosing is a problem (unless vaporizer has been calibrated to lower atm pressure) bc of injector design of Tec6 vaporizer does NOT compensate for elevation.
6% Des at sea level = 45.6mmHg (0.06 x760mmHg=45.6)
6% Des 1mile above SL = 37.2mmHg (0.06 x 620=37.2)
(18.4% reduction)
What is the vapor pressure of Sevo, Des, Iso, and N2O?
Sevo= 157 Des= 669 Iso= 238 N2O= 38,770
*Halogenated agents VP is less than atm pressure. This is why they exist as liquids. N2O has VP > atm pressure, so its a gas. (unless its compressed in a cylinder)
Which inhalation anesthetics are stable in soda lime?
What byproducts can each agent produce in SL?
SEVO: Not stable/ Compound A (happens in functional SL- worse if soda lime is desiccated)
DES: Not stable/ Carbon monoxide (only a problem if SL is desiccated)
ISO: Not stable/ Carbon monoxide (only a problem if sodalite is desiccated)
N2O: stable/ None
What is solubility, and how do we measure it?
The tendency of a solute to dissolve into a solvent. IN the case of inhalation anesthetics, it’s the ability of the anesthetic agent to dissolve into the blood and tissues.
The blood:gas coefficient (lambda) describes the relative solubility of an inhalation anesthetic in the blood vs in alveolar gas when the PP between the 2 compartments are equal.
(lambda)= [anesthetic dissolved in blood]/[anesthetic inside the alveolus]
What is the blood:gas solubility for Sevo, Des, Iso, and N2O?
Sevo= 0.65 Des= 0.42 Iso= 1.45 N2O= 0.46
How do we establish an anesthetic concentration inside the alveolus?
- Vaporizer on. Creates concentration gradient that pushes anesthetic agent from vaporizer to alveoli. (Fi).
- Ventilation washes the anesthetic agent into alveoli (FA).
- Buildup of anesthetic PP inside the alveoli is opposed by continuous uptake of agent into blood (uptake).
- CO distributes the agent through out the body. (Distribution)
What does the FA/FI curve tell us?
How does anesthetic solubility affect the FA/FI curve for each agent?
(see photo in Pharm1: VA)
FA/FI curve allows us to predict the speed of induction.
- low solubility–> less uptake into the blood–> increase rate of rise–> faster equilibration of FA/FI–> faster onset
- High solubility–> more uptake into the blood–> decreased rate of rise–> slower equilibration of FA/FI–> slower onset
What factors affect agent delivery to and removal from the alveoli?
Determinants of delivery:
- setting on vaporizer
- time constant of delivery system
- anatomic dead space
- alveolar ventilation
- functional residual capacity
Determinants of uptake:
- solubility of anesthetic in blood (blood:gas partition coefficient)
- CO
- PP gradient between alveolar gas and mixed venous blood
What conditions increase FA/FI?
Which conditions decrease it?
(see photo in Pharm1: VA)
For FA/FI to increase, there must be greater wash in and/or reduced uptake.
For FA/FI to decrease, there must be a reduced wash in and/or increased uptake.
Things that increase FA/FI wash in:
decrease uptake:
increase wash in:
- high fresh gas flow
- high alveolar ventilation
- low FRC
- Low time constant
- Low anatomic dead space
Decrease Uptake:
- Low solubility
- Low CO
- Low Pa-Pv difference
Things that decrease FA/FI wash in:
Increase uptake:
Decrease wash in:
- Low fresh gas flow
- Low alveolar ventilation
- High FRC
- High time constant
- High anatomic dead space
Increase uptake:
- high solubility
- high CO
- high Pa-Pv difference
In which pt will Sevo onset be the fastest?
Pt A with HR of 55, SV of 100.
Pt B with HR of 60, SV of 85.
(assuming all other factors are equal)
Patient B.
Anesthetic uptake is directly proportional to CO. A high CO removes more anesthetic agent from alveoli, so it slows the rate of rise of FA/FI (slows anesthetic induction).
Pt A has CO of 5.5L/min
Pt B has CO of 5.1L/min.
Onset of Sevo (rate of induction) will be faster in B (smaller CO)
What are the 4 tissue groups?
How much CO does each receive?
Vessel rich group: 75%CO, 10%Body mass
Muscle/skin 20%CO, 50%BM
Fat: 5%CO, 20%BM
Vessel poor group: <1%CO, 20%BM
*Each group is defined by how much CO is receives relative to a percentage of body weight.
How are inhaled anesthetics removed from the body?
- Elimination from the alveoli (most important)
- Hepatic biotransformation
- Percutaneous loss (minimal)
For each agent, what percent is attributed to hepatic metabolism?
N2O: 0.004%
Des: 0.02%
Iso: 0.2%
Sevo: 2-5%
*rule of 2’s (0.02, 0.2, 2)
Halogenated agents are in alphabetical order (DIS)
Discuss the FDA recommendations for minimum fresh gas flow requirement for SEVO?
Compound A is a halogenated vinyl ether. While it’s associated with renal tubular necrosis in rats, there’s no supporting evidence that this complication occurs in humans. The FDA recommends a minimum FGF go 1L/min for up to 2 MAC hours and 2L/min after 2MAC hours.
What is a MAC hour?
1 MAC hour =
1% sevo x 2hrs
2% sevo x 1hr
4% sevo x 30min
Which VA agents are metabolized to trifluoroacetic acid?
What is the potential consequence of this?
UP to 40% of halothane undergoes hepatic biotransformation, and a high concentration of TFA in the liver is the mechanism for halothane hepatitis.
Although Des/Iso undergo much smaller degree of hepatic biotransformation, there remains a very minute possibility that TFA could precipitate an immune mediated hepatic dysfunction, especially in pts with previous TFA exposure.
What are the theoretical consequences of Sevo metabolism?
Sevo NOT metabolized to TFA, but its biotransformation does result in liberation of inorganic fluoride ions.
B/c Sevo has higher degree of metabolism, there are theoretical concerns of fluoride induced high output renal failure (no solid human evidence for this).
*CompoundA is produced inside circuit and F- inions are produced by hepatic metabolism. (both can cause renal problems)
What are signs of high output renal failure:
Polyuria Hypernatremia Hyperosmolarity Increased plasm creatinine Inability to concentrate urine
What is the concentration effect?
Describes an increased rate of alveolar uptake as concentration of gas is increased.
What are the 2 mechanisms of the concentration effect?
Concentrat’ing’ effect: When N2O introduced into lungs, the volume of N2O from alveolus to pulmonary blood is much higher than amount of nitrogen moving in the opposite direction. This causes alveolus to shrink and the reduction in alveolar volume causes a relative increase in FA.
Augmented gas inflow: on subsequent breath, concentrating effect causes increased inflow of tracheal gas containing anesthetic agent to replace lost alveolar volume. This increases alveolar ventilation and augments FA. Alveolar volume is restored quickly, so this is only temporary phenomenon.
When compared to nitrous oxide, Des has a lower blood-gas partition coefficient. Why does the FA/Fi ratio for N2O rise faster than Des? (see photo in Pharm1: VA)
The concentration effect.
Despite sightly higher B/G partition coefficient, the alveolar PP of N2O rises faster than Des. This is because we can safely deliver a much higher inspiratory concentration, and this negates the fall difference imposed by slightly higher B/G partition coefficient.
Anesthetic overpressure results in more profound effect for agents with a higher or lower blood solubility?
Higher.
The concentration effect says that an anesthetic’s onset of action is directly proportional to the concentration of inhalation anesthetic delivered to the alveolus.
When applied to the halogenated agents, overpressure will have a more profound effect with agents of higher blood solubility. (we can offset the effects of a higher blood solubility by increasing the inspired concentration on the vaporizer.) it helps us read FA/FI equilibration faster.
How does N2O affect the uptake of halogenated anesthetic during induction?
N2O during induction will hasten the onset of a second gas. (aka the second gas effect)
Explain diffusion hypoxia:
*Risk at emergence.
N2O moves from the body towards the lungs–> dilutes alveolar O2 and CO2–> decreased respiratory drive and hypoxia.
Diffusion hypoxia can be prevented by administering 100% O2 for 3-5 minutes after N2O has been turned off.
Which inhalation anesthetics are most greatly affected by a right to left shunt?
(see photo in Pharm1: VA)
In the presence of a right to left shunt, the FA/FI of an agent with lower solubility (DES) will be more affected than an agent with higher solubility (ISO).
Which inhaled anesthetics are most greatly affected by a left to right shunt?
L to R shunt will not have a meaningful effect on anesthetic uptake or induction time.
Why does N2O accumulate in closed air spaces?
N2O is 34x more soluble than nitrogen. This means it will enter a space 34 times faster than nitrogen can exit that space.
- N2O B:G partition coefficient = 0.46
- Nitrogen B:G PC = 0.014
- this can be problematic because N2O can accumulate in closed air spaces (middle ear, bowel, pneumothorax).
N2O and a compliant airspace:
N2O and a fixed air space:
*Compliant airspace= N2O increases volume* Fast equilibration between space and blood: -Pulmonary blebs -Air bubbles in blood -Sulfa hexafluoride bubble in eye Slow equilibration btwn space and blood: -Bowel -Pneumoperitoneum
Fixed airspace= N2O increases pressure
Fast equilibration btwn space and blood:
-Middle ear
-Brain during intracranial procedure.
How does N2O affect pts with an ocular gas bubble?
Gas bubble is placed over retinal break during retinal detachment surgery. Functions as a “splint” to hold retina in place while healing. N2O can diffuse into bubble faster than other gases can diffuse out, expanding the SF6 bubble, compromising retinal perfusion and causing permanent blindness.
When can N2O be used in patients with SF6 bubble?
- Discontinue N2O 15minutes before SF6 bubble is placed.
- Avoid N2O for 7-10 days after SF6 bubble is placed.
Alternatives to SF6 bubble and when to use N2O:
Air: 5 days
perfluoropropane: 30 days
Silicone oil: No contraindication to N2O
What is the relationship between N2O and anesthesia equipment?
N2O can increase volume and pressure in a/an:
- ETT cuff
- LMA cuff
- Balloon-tipped pulmonary artery catheter.
What is the most reliable way to check the internal pressure of a ETT or LMA cuff?
attaching a manometer to pilot balloon.
Palpation is grossly inaccurate.
How do we quantify anesthetic potency?
What is this value for each inhaled agent?
Minimum alveolar concentration (MAC)
(same thing as ED50)
MAC for 40y/o and relative potency: Iso: 1.2 ++++ Sevo: 2.0 +++ Des: 6.6 ++ N2O: 104 +
What is MAC-bar?
Alveolar concentration required to block autonomic response following supra maximal painful stimulus. ~1.5MAC
What is MAC-awake?
Alveolar concentration at which a patient opens his or her eyes. This shows hysteresis in that MAC-awake is ~0.4-0.5 during induction but during recovery MAC-awake is as low as 0.15MAC.
What factors increase MAC?
Drugs:
- Chronic alcohol
- Acute amphetamine intoxication
- Acute cocaine intoxication
- MAOIs
- Ephedrine
- Levodopa
Electrolytes: Hypernatremia
Age:
- increased in infants 1-6 months
- Sevo is same for neonates and infants
Body temperature: hyperthermia
Other: Red hair
What factors decrease MAC?
Drugs:
- Acute alcohol intoxication
- IV anesthetics
- N2O
- Opioids (IV and neuraxial)
- Alpha-2 agonists
- Lithium
- Lidocaine
- Hydroxyzine
Electrolytes: Hyponatremia
Age:
- Older age (decreased 6% per decade after 40)
- Prematurity
Body temperature: Hypothermia
Others:
- Hypotension (MAP <50)
- Hypoxia
- Anemia (<4.3 mL O2/dL blood)
- Cardiopulmonary bypass
- Metabolic acidosis
- Hypo-osmolarity
- Pregnancy–> postpartum (24-72 hrs)
- PaCO2 > 95
What factors do NOT affect MAC?
Electrolytes:
- Hyper- or hypokalemia
- Hyper- or hypomagnesemia
others:
- hyper- or hypothyroidism
- gender
- PaCO2 15-95mmHg
- HTN
How does Hyper- and hypothyroidism affect MAC? why?
Hyper- and hypothyroidism do NOT directly affect MAC, however changes in CO associated with these conditions may affect anesthetic uptake and subsequent onset of action.
EX: profoundly hypothyroid patients have a reduced CO leading to decreased uptake into the blood and faster rate of rise FA/FI. B/c of this, these pts are more susceptible to anesthetic overdose.
What is the Meyer-Overton rule?
Liquid solubility is directly proportional to the potency of an inhaled anesthetic. This theory implies that depth of anesthesia is determined by the number of anesthetic molecules that are dissolved in the brain.
What is the unitary hypothesis?
The unitary hypothesis states that all anesthetics share a similar mechanism of action, although each may work at a different site.
What is the most important site of halogenated anesthetic action in the brain?
GABA-A receptor
It’s a ligand gated chloride channel.
Stimulation of GABA-A receptor increases chloride influx and hyper polarizes neurons. This impairs neurotransmission.
VA most likely increase the duration that the chloride channel remains open.
How do halogenated anesthetics produce immobility?
In the spinal cord, VA produce immobility in the ventral horn.
Which cerebral receptors are stimulated by N2O?
NMDA antagonism
Potassium 2P-channel stimulation
(Does NOT stimulate GABA-A)
In which regions of the brain do halogenated anesthetics produce unconsciousness?
Cerebral cortex
Thalamus
Reticular activating system
In which regions of the brain do halogenated anesthetics produce amnesia?
Amygdala
Hippocampus
In which regions of the brain do halogenated anesthetics produce autonomic modulation?
Pons
Medulla
How do halogenated agents reduce BP?
Decrease MAP in dose dependent fashion. At equivalent doses, there is little difference between agents.
- Primary cause: decreased intracellular Ca++ in vascular smooth muscle–> systemic vasodilation–> decreased SVR and decreased venous return
- Secondary cause: decreased intracellular Ca++ in myocyte–> myocardial depression–> decreased isotropy
How do halogenated anesthetics affect HR?
Directly affect cardiac conduction in dose dependent fashion.
- Decrease SA node automaticity
- Decreased Conduction velocity through AV node, His-Purkinje system, and ventricular conduction pathways.
- Increase duration of myocardial depolarization by impairing the outward K+ current (prolongs action potential duration and the QT interval)
- Altered baroreceptor function
Why do Des and Iso sometimes increase HR?
Des and Iso increase HR from baseline by 5-10%. Most likely d/t SNS activation from respiratory irritation.
Rapid increase in Des (and to a lesser degree Iso) cause tachycardia. Pulmonary irritation–> SNS activation–> increase NE release–> beta-1 stimulation
(Tachycardia can be minimized with opioids, alpha-2 agonists, or beta-1 antagonists)
What is the relationship between Iso and coronary steal?
Iso is most potent coronary artery dilator.
This means iso might contribute to coronary steal syndrome. The underlying principal is that atherosclerotic vessels can’t dilate, while normal vessels can. This would preferentially divert blood away from areas of higher resistance, starving those regions of O2.
(More theoretical than real world problem)
How does N2O by itself affect hemodynamics?
N2O activates SNS –> increases MAP as function of increased SVR. CVP and right atrial pressure may increase.
N2O is also myocardial depressant, but the increase in SNS stimulation outweighs the physiologic consequence of this.
-Myocardial depression is more likely when N2O is used in combination with an opioid.
How do halogenated anesthetics contribute to hypercarbia?
VA cause dose dependent depression of central chemoreceptor and respiratory muscles. This contributes to hypercarbia. Mechanism includes:
- Altering the respiratory pattern (decreased Vt and compensatory increase in RR –> decreased Ve and increased Vd)
- Impairing the response to CO2 (slope CO2 response curve shifts down and right)
- impairing motor neuron output and muscle tone to upper airway and thoracic muscles.
How do halogenated anesthetics affect cerebral metabolic rate?
CMRO2 is a function of:
- Electrical activity (60%)
- Cellular homeostasis (40%)
VA reduce CMRO2, but only to the extent that they reduce electrical activity. Once the brain is isoelectric, VA cannot reduce CMRO2 any further.
-Isoelectricity on EEG occurs at 1.5-2 MAC.
Compare and contrast the effects of halogenated anesthetics and N2O on cerebral blood flow:
Brian matches its blood flow with its metabolic requirement.
- When metabolic demand increases, the blood vessels dilate (cerebrovascular resistance decreases).
- When metabolic demand decreases, the blood vessels constrict (cerebrovascular resistance increases).
VA uncouple this relationship: CMRO2 decreases and CBF increases. This can increase ICP as well.
N2O is different. It increases CMRO2 and CBF appropriately.
How do halogenated anesthetics affect evoked potentials? How about N2O? (see photo in Pharm1: VA)
Des, Iso, and Sevo produce a dose-dependent effect on evoked potentials.
- Decrease amplitude (signal is not as strong)
- Increase latency (signal is slower to conduct)
The addition of N2O to a halogenated anesthetic agent can lead to a more profound amplitude reduction.
Therefore, N2O should not be used during evoked potential monitoring.
Which type of evoked potential is most sensitive to the effects of VA? which is the most resistant?
Sensitivity ranking:
- Visual evoke potentials are most sensitive to VA
- Brainstem evoked potentials are the most resistant to VA
- SSEPs and MEPs are somewhere in between
What is the relationship between N2O and bone marrow depression?
Nitrous oxide inhibits methionine synthase and folate metabolism. This can cause megaloblastic anemia.
