Pharmacology I Flashcards
Volume of distribution
relationship between s drug’s plasma concentration after a specific dose (how a drug distributes throughout the body)
What does volume of distribution assume?
- the drug distributes instantly
- the drug is not subject to biotransformation or elimination before it fully distributes
Equation for volume of distribution
Vd = amount of drug/desired plasma conc.
What does it mean when a drug’s Vd is greater than TBW?
- the drug is lipophilic
- the drug distributes into TBW and fat
- will require a higher dose to achieve a given plasma concentration
ex: propofol, fentanyl
What does it mean when a drug’s Vd is less than TBW?
- the drug is hydrophilic
- it distributes into some or all of the TBW
- does NOT distribute into fat
- requires a lower does to achieve a given plasma conc.
ex: NMBs (ECF), albumin (plasma)
Loading dose calculation (IV and PO)
Loading dose = Vd x desired plasma conc / bioavailability
- for IV drug, bioavailability is always 1 (all of the drug goes into the bloodstream)
- PO drugs don’t get absorbed completely and subject to first pass by liver so bioavailability is reduced
Clearance
- volume of plasma that is cleared of a drug per unit time
Clearance is directly proportional to…
- blood flow to clearing organ
- extraction ratio
- drug dose
Clearance is inversely proportional to…
- half-life
- drug concentration in the central compartment
Steady state
- when the amount of drug entering the body is equivalent to the amount being eliminated
- rate of admin = rate of elim
- occurs after five half-times
What does the plasma concentration curve depict?
- shows the biphasic decrease of a drug’s plasma concentration after a rapid IV bolus
Alpha distribution phase of plasma concentration curve
- describes drug distribution from the plasma to the tissues
Beta distribution phase of plasma concentration curve
- starts when plasma concentration falls below tissue concentration
- concentration gradient reverses
- drug re-enters the plasma
- beta phase describes drug elimination from the plasma by the clearing organ
Half-times, % eliminated and % remaining
- 0 half-time: 0% eliminated, 100% remaining
- 1 half-time: 50% eliminated. 50% remaining
- 2 half-time: 75% eliminated, 25% remaining
- 3 half-time: 87.5% eliminated, 12.5% remaining
- 4 half-time: 93.75% eliminated, 6.25% remaining
- 5 half-life: 96.875% eliminated, 3.125% remaining
Context sensitive half-time
- time required for the plasma concentration to decline by 50% after discontinuing the drug
- normal half-times do NOT consider time
Context sensitive half-times for narcotics
- context sensitive half-time for a fentanyl got increases the longer it was infused
- longer infusion = more time to fill peripheral compartments = more fentanyl to be eliminated = longer elimination half-time
- same thing with alfentanil and sufentanil
Remifentanil context sensitive half-time
- remi is highly lipophilic BUT it is quickly metabolized by plasma esterase’s
- has a similar context-sensitive half-time regardless of how long it was infused
What is the difference between a strong and weak acid or base?
- difference is the degree of ionization
- strong acid or strong base in water = will completely ionize
- weak acid or weak base in water = fraction will be ionized and fraction will be unionized
- acid donates H+
- base donates OH-
What is ionization? What factors determine how much a molecule will ionize?
- the process where a molecule gains a positive or negative charge
- amount of ionization depends on the pH of the solution and the pKa of the drug
When the pKa and the pH are the same, _________________.
50% of the drug will be ionized and 50% of the drug will be unionized.
Ionization affect on solubility
IONIZED
- water = hydrophilic and lipophobic
UNIONIZED
- lipid = hydrophobic and lipophilic
Ionization and pharmacologic effects
- ionized = not active
- unionized = active
Ionization and hepatic biotransformation
- ionized = less likely
- unionized = more likely
Ionization and renal elimination
- ionized = more likely
- unionized = less likely
Ionization and diffusion across lipid bilayer
- ionized does NOT diffuse across the BBB, GI tract or placenta
- unionized diffuses across the BBB, GI tract and placenta
Adding an acid in a basic solution
- the acidic drug will be highly ionized in a basic pH
- the acidic drug wants to donate protons and the basic solution wants to accept
- acidic drug donates the protons and becomes ionized
Adding an acid to an acidic solution
- the acidic drug will be highly unionized in an acidic solution (like dissolves like)
- both the acidic drug and solution want to donate protons
- there are no proton acceptors so the acidic drug retains them and remains unionized
Are most drugs acids or bases? Weak or strong?
- most drugs are weak acids OR weak bases
- usually are prepared and a salt that dissociates in solution
Examples of weak acids
- is usually paired with a positive ion like sodium, calcium or magnesium
ex: sodium thiopental
Examples of weak bases
- is usually paired with a negative ion like chloride or sulfate
ex: lidocaine hydrochloride, morphine sulfate
Three key plasma proteins. and what kind of drugs do they bind?
- albumin: primarily binds acidic drugs
- alpha1- acid glycoprotein: binds basic drugs
- beta-globulin: binds to basic drugs
What conditions reduce albumin concentrations?
- liver disease
- renal disease
- old age
- malnutrition
- pregnancy
What conditions cause increased alpha1-acid glycoprotein concentration?
- surgical stress
- MI
- chronic pain
- Rheumatoid arthritis
- advanced age
What conditions cause decreased alpha1-acid glycoprotein concentration?
- neonates
- pregnancy
How do changes in plasma protein binding affect plasma drug concentrations?
- decreased PP binding = increased Cp
- increased PP binding = decreased Cp
How do you calculate changes in plasma protein binding?
[free drug] + [unbound drug] = [bound drug]
- if a drug is 98% bound and the bound fraction is reduced to 96% = the unbound/free fraction has increased by 100%
- if the free fraction is 2% and it increases to 4%, then the free fraction has increased by 100%
First-order kinetics
- a constant FRACTION of a drug is eliminated per unit time
- most drugs follow this model
ex: a drug is cleared from the body at a rate proportional to its plasma concentration
Zero-order kinetics
- a constant AMOUNT of drug is eliminated per unit time
- rate of elimination is independent of the plasma drug concentration
ex: aspirin, phenytoin, warfarin, heparin, theophylline, alcohol
Function of a phase 1 reaction and list the three examples.
- small molecular changes that make a molecule more water soluble to prepare it for phase 2 reaction
- hydrolysis: adds water to a compound to split it up (usually an ester)
- reduction: adds electrons to a compound
- oxidation adds an oxygen molecule to a compound
How are most phase 1 biotransformations carried out?
P450 system
What is the function of phase 2 reactions? List the 5 common substrates.
- adds a highly polar/water soluble substrate to the molecule making it inactive and ready for excretion
- acetic acid
- glucuronic acid
- glycine
- sulfate
- methyl group
Enterohepatic circulation and a drug example
- some conjugated compounds are excreted in the bile, reactivated in the intestine, and then reabsorbed into the systemic circulation
ex: diazepam
What is the extraction ratio?
- a measure of how much drug is delivered to a clearing organ vs. how much drug is removed by that organ
- ER of 1.0 = 100% of drug delivered to clearing organ is removed
- ER of 0.5 = 50% of drug delivered to clearing organ is removed
Flow limited elimination
- for a drug with HIGH hepatic extraction ratio (>0.7), clearance depends on liver blood flow
- hepatic blood flow greatly exceeds enzyme activity, so changes in liver enzyme activity has little effect
- increased liver blood flow = increased clearance
- decreased liver blood flow = decreased clearance
Capacity limited elimination
- for a drug with a LOW hepatic extraction ratio (<0.3), clearance is dependent upon the ability of the liver to extract the drug from the blood
- changes in enzyme activity or protein binding have 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 clearance
- enzyme inhibition = decreased clearance
** if a drug has a low hepatic extraction ratio, CYP inhibition will have a greater effect on its metabolism
Drugs with Low Hepatic ER
- rocuronium
- diazepam
- methadone
- thiopental
- theophylline
- phenytoin
Drugs with intermediate hepatic ER
- midazolam
- vecuronium
- alfentanil
- methohexital
Drugs with high hepatic ER
- fentanyl
- sufentanil
- morphine
- meperidine
- naloxone
- ketamine
- propofol
- lidocaine
- bupivacaine
- metoprolol
- propranolol
- alprenolol
- nifedipine
- diltiazem
- verapamil
Hepatic enzyme inducer
- increase clearance
- decrease drug plasma level
- drug dose increase may be required
ex: tobacco, barbs, ethanol, phenytoin, rifampin, carbamazepine
Hepatic enzyme inhibitors
- decrease clearance
- increase drug plasma levels
- drug dose decrease may be required
ex: grapefruit juice, cimetidine, omeprazole, isoniazid, SSRIs, erythromycin, ketoconazole
Drug classes(2) and drugs (7) that are metabolized by pseudocholinesterase
NEUROMUSCULAR BLOCKERS
- succinylcholine
- mivacurium
ESTER LOCAL ANESTHETICS
- chloroprocaine
- tetracaine
- procaine
- benzocaine
- cocaine (also metab by liver)
Six drugs that are metabolized by non-specific plasma esterases
- esmolol
- remifentanil
- aspirin
- clevidipine
- atracurium (and Hoffman)
- etomidate (and hepatic)
One drug that is biotransformed by alkaline phosphatase hydrolysis
- fospropofol (propofol prodrug under trade name Lusedra)
Pharmacokinetics
- what the body does to the drug
- explains the relationship between the dose that you administer and the drug’s plasma concentration over time
- absorption, distribution, metabolizm, excretion
Pharmacobiophysics
- considers the drug’s concentration in the plasma and the effect site (bio phase)
Pharmacodynamics
- what the drug does to the body
- explains the relationship between the effect site concentration and the clinical effect
What is potency and how is it measured?
- dose required to achieve a given clinical effect (x-axis on dose response curve)
- ED50 and ED90 are measures of potency: dose required to achieve a given effect in 50% and 90% of the population
How is potency measured on the dose-response curve?
- left shift = increased affinity for receptor = higher potency = lower dose required
- right shift = decreased affinity for receptor = lower potency = higher dose required
What is efficacy and how is it measured on the dose-response curve?
- a measure of the intrinsic ability of a drug to produce a clinical effect
- height of plateau on y-axis measures efficacy
- higher plateau = greater efficacy
- once the plateau is reached, additional drug does NOT produce additional effect
What does the slope of the dose-response curve mean<
- the slope depicts how many receptors must be occupied to elicit a clinical effect
- steeper slope = small increase in dose can have a profound clinical effect
- flatter slope = higher doses are required to increase the clinical effect
Full agonist
- binds to a receptor and turns on a specific cellular response
Partial agonist
- binds to a receptor
- only capable to partially turning on a cellular response
- less efficacious than a full agonist
Antagonist
- occupies the receptor and prevents and agonist from binding to it
- does not tell the cell to do anything
- does not have efficacy
Inverse agonist
- binds to the receptor and causes an opposite effect to that of a full agonist
- has a negative efficacy
Competitive antagonism and an example
- is REVERSIBLE
- giving more of the agonist can overcome the competitive antagonism
ex: atropine, vec, roc
Noncompetitive antagonism and an example
- is IRREVERSIBLE
- drug binds to receptor via covalent bonds and its effect cannot be overcome by increasing agonist
- effect of noncompetitive agonist can only be overcome by producing new receptors
ex: aspirin and phenoxybenzamine
ED50
- dose that produces the expected clinical response in 50% of population
- is a measure of potency
LD50
- dose that will produce death in 50% of the population
Therapeutic Index
- helps determine the safety margin for a desired clinical effect
TI = LD50/ED50
- drug with a narrow TI has a narrow margin of safety
- drug with a wide TI has a wide margin of safety
Chirality
- division of stereochemistry that deals with molecules that have a center of 3D asymmetry
- stems from carbon bonding
- carbon binds to 4 different atoms
- a molecule with one chiral carbon will have 2 enantiomer
- the more chiral carbons in a molecule = more enantiomers created
Enantiomers and their clinical relevance
- chiral molecules that are non-superimposable mirror images of one another
- different enantiomers can produce different clinical effects
- 1/3 of drugs we administer are enantiomers
ex: side effects of one enantiomer of a drug can be different from another enantiomer of the same drug
What is a racemic mixture? Examples?
- racemic mixture Fontaine’s two enantiomers in equal amounts
- 1/3 of the drugs we administer are enantiomers and almost all are prepared as racemic mixtures
ex: bupivacaine, ketamine, iso, and des (NOT sevo)
Propofol MOA
- direct GABA-A agonist = increased Cl- conductance = neuronal hyperpolarization
Propofol dose
- induction: 1.5-2.5 mg/kg
- infusion: 25-200 mcg/kg/min
Propofol onset
30-60 seconds
Propofol duration
5-10 mins
Propofol clearance
- liver (P450) and extrahepatic (lungs)
Cardiovascular effects of propofol
- decrease BP (decrease SNS tone and vasodilation)
- decreased SVR
- decreased venous tone = decreased preload
- decrease contractility
Respiratory effects of propofol
- shifts CO2 response curve down and to the right = less sensitive to CO2 = respiratory depression/apnea
- inhibits hypoxic ventilatory drive
CNS effects of propofol
- decreased cerebral oxygen consumption (CMRO2)
- decreased cerebral blood flow
- decreased ICP
- decreased intraocular pressure
- no analgesia
- anticonvulsant properties
What is propofol made from?
- a 1% solution in an emulsion of egg lecithin, soybean oil and glycerol
- most people with egg allergies are allergic to the whites. and lecithin is made from the yolk
- no cross sensitivity b/w propofol and soy or peanuts
Propofol infusion syndrome
- propofol contains long chain triglycerides (LCT)
- increased LCT impairs oxidative phosphorylation and fatty acid metabolism
- cells (cardiac and skeletal muscle) get starved of oxygen
Risk factors for propofol infusion syndrome
- propofol dose > 4 mg/kg/hr (67 mcg/kg/min)
- propofol infusion duration > 48 hours
- children > adults
- inadequate oxygen delivery
- sepsis
- significant cerebral injury
Clinical presentation of propofol infusion syndrome
- metabolic acidosis (base deficit > 10 mmol/L)
- rhabdo
- enlarged or fatty liver
- renal failure
- hyperlipidemia
- lipemia (cloudy plasma or blood) may be an early sign
How long is propofol good for in a syringe and as an infusion?
- syringe: 6 hrs
- infusion/tubing: 12 hrs
What preservatives are used in branded propofol?
- Diprivan contains EDTA (disodium ethylenediamine tetraacetic acid) as a preservative
- doesn’t cause issues for any specific patient population
What preservatives are used in generic propofol?
- metabisulfite: can cause bronchospasm in asthmatic patients
- benzyl alcohol: avoid in infants
How can propofol injection pain be minimized?
- inject into a larger and more proximal vein
- lidocaine
- give an opioid prior to the propofol
Antipruritic effects of propofol
- 10mg of propofol can reduce itching caused by spinal opioids and cholestasis
Antiemetic effects of propofol
- 10-20 mg can be used to treat PONV
- or infusion at 10 mcg/kg/min
How does fospropofol become active?
- alkaline phosphatase converts fospropofol to propofol
Ketamine MOA
- NMDA antagonist (antagonizes glutamate)
- ketamine dissociates the thalamus (sensory) from the limbic system (awareness)
What are the secondary receptor targets for ketamine?
- opioid
- MAO
- serotonin
- NE
- muscarinic
- Na+ channels
Ketamine IV dose
- induction: 1-2 mg/kg
- analgesia: 0.1 - 0.5 mg/kg
Ketamine IM dose
4-8 mg/kg
Ketamine PO dose
10 mg/kg
Ketamine onset time
- IV = 30-60 sec
- IM = 2-4 mins
- PO = variable
Ketamine duration
10-20 mins
Ketamine clearance
- liver P450 enzymes
- produces an active metabolite = norketamine (1/3-1/5 the potency of ketamine)
- chronic ketamine use induces liver enzymes (ex: burn patients)
Cardiovascular effects of ketamine
- increased SNS tone
- increased CO
- increased HR
- increased SVR
- increased PVR
- doses < 0.5 mg/kg don’t activate SNS
- ketamine is actually a myocardial depressant. depressant effects will go unmasked in pt with depleted catecholamines (sepsis) or sympathectomy
Respiratory effects of ketamine
- bronchodilation
- preserves upper airway muscle tone and reflexes
- maintains respiratory drive
- doesn’t significantly shift the CO2 response curve
- increases oral and pulmonary secretions (increases risk of laryngospasm)
CNS effects of ketamine
- increased cerebral oxygen consumption (CMRO2)
- increased cerebral blood flow
- increased ICP
- increased intraocular pressure
- increased EEG activity
- nystagmus
- emergence delirium
Ketamine emergence delirium (symptoms, treatment, risk factors)
- s/s: nightmares and hallucinations
- treat: Benzos (midaz > diazepam)
- r/f: age > 15, female, dose > 2mg/kg, personality disorder
Analgesic properties of ketamine
- only induction agent that provides analgesia and opioid-sparing effect
- relieves somatic pain > visceral pain
- blocks central sensitization and wind-up in the dorsal horn of the spinal cord
- prevents hyperalgesia after remi infusion
- good for burn pt and chronic pain
Etomidate MOA
- binds to GABA and enhances receptors affinity for GABA neurotransmitter
Dose of etomidate
0.2-0.4 mg/kg IV
Onset of etomidate
30-60 sec
Duration of etomidate
5-15 mins
Clearance of etomidate
Hepatic P450 enzymes and plasma esterases
Cardiovascular effects of etomidate
- HD stability: minimal change in HR, SV or CO
- SVR is decreased causing a small decrease in BP
- does NOT block SNS response to intubation (esmolol or opioid will help)
Respiratory effects of etomidste
- mild respiratory depression
CNS effects of etomidate
- decreased CMRO2
- decreased cerebral blood flow
- decreased ICP
- stable cerebral perfusion pressure
- no analgesic effects
Etomidate and myoclonus
- involuntary skeletal muscle contraction, dystonia or tremor
- etomidate causes an imbalance between excitatory and inhibitory paths in the thalamus = myoclonus
Etomidate and seizure activity
- in the patient with no seizure history, etomidate doesn’t increase the risk
- if seizure hx: etomidate can increase seizure like activity and possibly seizures
Etomidate and adrenal suppression
- etomidate inhibits 11-beta-hydroxylase and 17-alpha-hydroxylase
- cortisol and aldosterone synthesis are dependent on those enzymes
- single dose of etomidate can suppress adrenal function for 5-8 hrs
- avoid in septic or acute adrenal failure patients who need lots of cortisol
What induction agent is most likely to cause PONV
- etomidate
What are the two sub-classes of barbiturates?
THIOBARBITURATES
- sulfur in the second position that increases lipid solubility and potency
- ex: thiopental, thiamylal
OXYBARBITURATES
- oxygen in the second molecule
- ex: methohexital, phenobarbital
Thiopental MOA
- GABA-A agonist: depresses the reticular activating system in the brainstem
- low/normal dose: increases the affinity of GABA for its binding site
- high dose: directly stimulates GABA-A receptor
Thiopental dose
- adult = 2.5-5 mg/kg
- child = 5-6 mg/kg
Onset of thiopental
30-60 sec
Duration of thiopental
5-10 mins
Clearance of thiopental
- liver (P450)
- awakening is determined by redistribution (NOT metabolism)
- repeat doses = tissue accumulation = prolonged wake up + hangover effect
CV effects of thiopental
- hypotension d/t ventilation and decreased preload
- non-immunologic histamine release = hypotension (short lived)
- baroreceptor reflex is preserved: reflex tachy helps to restore CO
Respiratory effects of thiopental
- repertory depression (shifts CO2 response curve to the right)
- histamine release can cause bronchoconstriction
CNS effects of thiopental
- decreased CMRO2
- decreased cerebral blood flow
- decreased ICP
- decreased EEG activity ( can cause burst suppression and/or isoelectric EEG = neuroprotection)
- no analgesia
When can thiopental be used for neuroprotection?
- for focal ischemia (carotid endarterectomy or temporary occlusion of cerebral arteries)
- NOT for global ischemia (cardiac arrest)
Pathophysiology of acute intermittent porphyria
- defect in heme synthesis where heme precursors build up (precursors can’t convert to heme)
- heme is important in hemoglobin, myoglobin and P450 enzymes
succinylcholine-CoA + glycine = ALA synthase = precursors = heme
Drugs to avoid in acute intermittent porphyria
Barbs, etomidate, glucocorticoids and hydralazine
*conditions to avoid: emotional stress, prolonged NPO
Acute intermittent porphyria treatment
- liberal hydration
- glucose supplementation (reduces ALA synthase activity)
- heme arginate (reduces ALA synthase activity)
- prevention of hypothermia
Risk of intra-arterial injection of thiopental and the treatment
- causes intense vasoconstriction and crystal formation
- leads to inflammation and tissue necrosis
TREATMENT
- vasodilator (phentolamine or phenoxybenzamine)
- sympathectomy: stellate ganglion or brachial plexus block
Gold standard durch for electroconvulsive therapy and dose.
- methohexital: decreases the seizure threshold producing a better quality seizure
- dose: 1-1.5 mg/kg
Dexmedetomidine MOA
Alpha2 agonist = decreases cAMP = inhibits locus coeruleus in the pons
Demedetomidine dose
- loading: 1 mcg/kg over 10 mins
- infusion: 0.4-0.7 mcg/kg/hr
Demedetomidine onset
10-20 mins
Demedetomidine duration
10-30 mins (after infusion stopped)
Demedetomidine clearance
liver (P450)
