Pharmacology Flashcards
Applications of benzodiazepines in critically ill
Sedation
Anxiolysis
Anticonvulsant
Muscle relaxant
Appetite stimulant
Minor cardiovascular and respiratory effects
Used as part of an anesthetic induction protocol for balanced anesthesia
They do NOT provide analgesia
Are benzodiazepines scheduled substances?
Yes, class IV
MOA of benzodiazepines
- Act primarily via the inhibitory neutrotransmitter GABA - bind to stereospecific receptors that facilitate the inhibitory actions of GABA
- May also involve antagonism of serotonin and diminished release or turnover of Ach in the CNS
- They act at the limbic, thalamic and hypothalamic levels of the CNS
- Metabolized in the liver to active metabolites, then after conjugation, excreted in urine
Diazepam vs midazolam - differences
Diazepam:
- Not water soluble - formulated in 40% propylene glycol and 10% alcohol vehicle.
- Propylene glycol - irritant to blood vessels -> causes phlebitis and thrombosis after repeated administration through peripheral vein -> give as CRI or through central line.
- Prolonged admin of diazepam -> propylene glycol toxicity -> metabolic acidosis, hyperosmolality, neurologic abnormalities and organ dysfunction. Important in CATS.
- Absorbs to plastic - infusion lines require pre-coating.
- Both midazolam and diazepam should be protected from light
Midazolam:
- Water soluble
- Well absorbed after IM injection.
- Poorly available when given IR.
- Can be given as CRI through peripheral vein.
- JVIM 2018 - intranasal midazolam terminated status epilepticus in 70% of cases compared to rectal diazepam, 20% of cases. All dogs showed sedation and ataxia.
Does benzodiazepines have always sedative effects?
No.
Some animals might demonstrate excitation, irritability and depression.
Patients already obtunded most likely will be sedated, especially if combined with an opioid.
Healthier dogs and cats may demonstrate dysphoria, especially if given as solo agent.
Complication of oral diazepam in cats
Idiosyncratic reaction - fulminant hepatic failure - acute hepatic necrosis.
Not reported with other routes of administration.
Which one is shorter acting, diazepam or midazolam
Midazolam - short elimination Half-life and duration of action - more suitable for CRI than diazepam
Half-life of diazepam - 3 to 6 h
Half-life of midazolam - 1h
How can we reverse benzodiazepines?
Flumazenil - antagonist
Sarmazenil - inverse agonist
Marked excitement and dysphoria can be precipitated by either drug.
Significant adverse effects like seizures and acute benzodiazepine withdrawal have been reported
Indications for flumazenil
Doses
- Due to the severe adverse effects, even in cases of benzodiazepines overdose, toxic effects can be managed with supportive care.
- Rarely indicated in stable patients.
- Used in critically ill patients with cardiovascular or pulmonary instability.
- 0.01 to 0.02 mg/kg IV.
- If requiring frequent dosing - CRI at 0.005 to 0.02 mg/kg/h
Benzos as anticonvulsant therapy
Doses for sedation / anticonvulsant
- Diazepam IM not recommended - IR route preferred
- Intranasal midazolam preferred over IR diazepam (JVIM 2018)
Benzodiazepines and appetite stimulant
- Low doses benzodiazepines can stimulate appetite, specially in cats
- MOA - involves binding to benzodiazepine receptors and appears to increase attraction to tastes.
- Increases both amount of food and rate of consumption.
- Diazepam at 0.005 to 0.4mg/kg IV q24h or 1mg orally q24h (risk of hepatic toxicity in cats)
- Food should be readily available - they might begin to eat within a few seconds of administration.
Hepatic encephalopathy and benzos
- Human patients with HE show arousal after flumazenil - suspected increased endogenous benzodiazepines agonist activity.
- Lack of arousal in other species including dogs and cats.
- Administration of inverse agonist sarmazenil in research models of acute and chronic HE - improvement of encephalopathies signs - consistent with an increased GABAergic constitutive activity in HE rather than an increase in endogenous benzodiazepine agonist ligands.
- Sarmanezil should not be considered part of the therapy of HE.
Percentage of cases reporting to veterinary referral centers involving epilepsy
0.6% to 2.3%
Age of idiopathic epilepsy
1 to 5 years old, but onset has been reported in both older and younger dogs.
Idiopathic epilepsy incidence
Higher in dogs, whereas in cats reactive (metabolic or toxic disturbance) and symptomatic (underlying intracranial dz) are more common than idiopathic epilepsy.
Most common anticonvulsants
Phenobarbital
Bromide (potassium bromide, sodium bromide)
Zonisamide
Levetiracetam
Felbamate - not used very commonly
Benzodiazepines (diazepam, midazolam, lorazepam, clorazepate) - short life and development of tolerance - used only in emergency treatment.
Phenobarbital MOA and metabolism
- Facilitates GABA-ergic activity - prolongs opening of Cl- channels
- Believed to inhibit glutamate receptors and voltage-gated calcium channels
- High bioavailability after PO admin - 86% - 96% - absorbed in 2h, maximal concentration in 4-8h when given PO
- Protein bound - 45%
- Metabolized in the liver primary by CYP450 - potent inducer of CYP450 → induces its own metabolism and that of other drugs (benzos, levetiracetam, zonisamide)
- Medications that inhibit CYP450 → may inhibit phenobarbital metabolism, increasing plasma concentrations and the risk of toxicity.
- 25% - 33% excreted unchanged in the kidneys
How long does it takes to achieve therapeutic levels of phenobarbital
15 to 20 minutes with phenobarbital IV
Clinical response to phenobarbital
>50% reduction in seizure frequency in 60% to 80% of dogs with idiopathic epilepsy
Phenobarbital doses in cats
Starting dose of 1.5 - 2.5mg/kg PO / IV q12h suggested
Loading doses of phenobarbital
- If a patient comes with cluster seizures or SE, 16-20mg/kg loading dose can be given
- Divide in 4-6 equal doses over a 24h period.
- Intent to achieve serum phenobarbital concentrations of 15-35mcg/mL
- Monitor closely for extreme sedation (loss of gag reflex), hypoventilation and/or hypotension → delay next dose if that happens.
Serum phenobarbital levels that has risk of hepatotoxicity?
>40mcg/mL
Half-life of phenobarbital
- Varies over time - suspected due to autoinduction
- Dogs - from 37 to 89 hours
- Cats - from 34 to 43 hours
- Serum steady-state levels reached in 97% of patients after 5 half-lives
Phenobarbital monitoring
- 2 and 6 weeks after starting phenobarbital
- 2 weeks after a dose change
- Due to auto induction of hepatic enzymes - monitor serum levels q6-12 months.
Phenobarbital adverse effects
- Sedation, ataxia / CP deficits → tend to be transient and resolve within 2-3 weeks.
- PU/PD
- Polyphagia
- Hyperactivity / aggression
Less commonly observed - suspected idiosyncratic:
- Bone marrow suppression (anemia, thrombocytopenia, neutropenia)
- Hepatotoxicity
- Superficial necrolytic dermatitis
- Pancreatitis
- Hypoalbuminemia
- Diskinesis and anxiety
Bloodwork changes with phenobarbital
- Increases in ALP - does not mean hepatotoxicity
- Increases in ALT - less frequent, may be more specific indicator of hepatotoxicity
- Decreases T4 levels
Anticonvulsant drugs and recommended dosages for dogs
Bromide MOA
- Mimics chloride ions in GABA receptors chloride channels → causes hyperpolarization of the neurons, increasing seizures threshold.
Bromide metabolism
- Not metabolized by liver - first line AED in dogs with hepatic dysfunction.
- Excreted unchanged by the kidneys - renal dz. will increase KBr levels
- Reabsorbed through Cl channels in renal tubules - amount of Cl in diet can affect KBr clearance - recommended to be on steady diet (regarding Cl intake).
- Peak absorption - 1.5h after PO admin
- Oral bioavailability - 46%
- Unbound to plasma proteins - diffuses freely across cellular membrane
- Half-life: approximately 25 days in dogs, 12 in cats
Clinical efficacy of KBr
Decreases seizure frequency in 72% to 74% of epileptic dogs
Why is not KBr recommended in cats
Causes fatal eosinophilic bronchitis - reported in 35% to 42% of cats
KBr doses
- Loading doses of 400 - 600 mg/kg PO/IR over 1-5 days if needed
- Maintenance - 20-40mg/kg q24h
KBr therapeutic range
- Time to steady state - 2.5-3 months after PO initiation
- Therapeutic range of 1000-3000mcg/mL when used as mono therapy, or 800-2500mcg/mL when used as add-on therapy.
KBr adverse effects
- Neuro deficits (sedation, agitation or excitability, ataxia, decreased pelvic limb withdrawals, paraparesis)
- Polyphagia
- PU/PD
- Vomiting
- Pancreatitis
What is bromism / clinical signs / treatment
- Toxic serum concentrations of KBr
- Clinical signs: altered mentation, ataxia, upper or lower motor neuron paresis.
- Cut off value for toxicity not established
- Treatment: dosage reduction or IV 0.9% NaCl
Zonisamide class and MOA
- Sulfonamide - structurally unrelated to all other AED
- Inhibits voltage-gated Na+ channels
- Inhibits voltage - gated Ca2+ channels
- Neuromodulation:
- Enhancement of GABA function
- Inhibition of glutamate release
- Facilitation of dopamine / serotoninergic transmission
- Increases Ach turnover
- Neuroprotection - free radical scavenger
- Inhibitory effect on carbonic anhydrase - does not contribute to antiepileptic effects
Zonisamide metabolism
- Peak serum 2.5-6h post PO dose
- Oral bioavailability approximately 68%
- Half-life 17h
- Protein bound - 40%
- 10% excreted unchanged in urine
- 90% liver metabolism by CYP450 - coadministration with PHB increases ZNS clearance by 50% and decreases half-life
- Time to steady state 4 days in dogs, 7 days in cats
Zonisamide clinical efficacy
- Reported seizure reduction in frequency by 50% in dogs with idiopathic epilepsy
- 58% to 80% when used as adjunctive therapy
- 60% when used as monotherapy
Zonisamide doses and therapeutic range
- Monotherapy - 5mg/kg PO q12h
- Add-on with PHB - 10mg/kg PO q12h
- Therapeutic range (from human medicine) - 10-40mcg/mL
Zonisamide adverse effects
- Prevalence in dogs (10%-55%)
- Sedation, ataxia, vomiting, innapetence, KCS
- Idiosyncratic adverse reactions: acute hepatopathy, renal tubular acidosis, neutropenia with or without concurrent regenerative anemia
Zonisamide monitoring
- 1-2 weeks after treatment initiation, dose adjustment or increases in seizure frequency
- Collect sample within 1h before the next dose is due
Levetiracetam MOA
- Binds to synapticvesicle protein A (SVA2) → modulates synapticle vesicle fusion and NT release
- Inhibits Na dependent Cl/HCO3 exchange
- Antagonizes neuronal hyper synchronization
Levetiracetam metabolism
- 100% bioavailability after PO administration
- <10% protein binding
- Readily crosses BBB
- Half-life time 4-8h
- Time to steady state - 15-20h
- 90% excreted in urine via glomerular filtration - 45% unchanged
- Small portion metabolized by liver (not CYP450) → no autoinduction
- Long term PHB in epileptic dogs can decrease levetiracetam half-life
- Does not cause bloodwork changes
- Does not alter PHB / KBr serum concentrations
- Recommended in patients with hepatic disease
Levetiracetam doses and therapeutic range
- Starting dose of 20mg/kg PO q8 - if ER → 30mg/kg PO q12h
- Recommended decrease in dose in patients with renal disease (concerns for decreased clearance)
- Therapeutic range (humans) - 12-46mcg/mL
Levetiracetam adverse effects
- Sedation, ataxia
- Aggression
- Hyporexia
- Vomiting
- Transient mild lethargy and hyperemia in cats
- Honeymoon effect
Levetiracetam monitoring
- Has a high therapeutic index, plasma concentrations not measured.
- Relationship between serum concentrations of levetiracetam, treatment response and adverse effects has not been established yet.
Gabapentin and pregabalin MOA
- Add-on anticonvulsants, not first line AED
- Similar mechanism for both
- Binding on the alpha2-delta subunit of the voltage gated calcium channels, leading to inhibition of release of excitatory NT into the synapse.
Gaba and pregabalin metabolism
- Bioavailability approximately of 80% with a 50mg/kg/day dose
- About 34% of GABA is metabolized by the liver, and suspected similar for pregabalin.
- GABA half-life: in dogs, 3-4 hours. Pregabalin - 7 hours.
Gaba and pregabalin clinical efficacy
- Gaba: effective as add-on, with a 55% response rate.
- Pregabalin - response rate of 64%
Gaba and pregabalin doses and therapeutic range
- Gabapentin - 10 mg/kg q8h
- Pregabalin - 2-4mg/kg
- No therapeutic range established.
Gabapentin and pregabalin adverse effects
- Sedation, ataxia - typically mild and may respond to dosage adjustments.
- As both undergo hepatic metabolism (unlike in humans) - abnormalities in biochemistry might be noted
Is Felbamate used commonly in veterinary medicine?
No, it has fallen out of favor
Felbamate MOA
- Inhibition of aspartate receptor-mediated excitation
- Potentiation of GABAergic activity
Felbamate metabolism
- Bioavailability of near 100%
- 22-25% protein bound.
- Liver metabolism
- 30% excreted unchanged in urine.
- Half-life in dogs 4-6 hours.
Felbamate doses and therapeutic range
- Dose - 15mg/kg q8h with a maximum dose of 300mg/kg/day (toxic dose)
- Therapeutic dose (humans) - 60-80mg/L.
Felbamate adverse effects
- Not reported on doses under 300mg/kg/day
- Ataxia, limb rigidity, tremors, salivation, emesis, weight loss, increased serum liver enzymes, hepatopathy and blood dyscrasias
What’s the mechanism of action of azathioprine
Drug class: purine analogue (immunosupressor)
acts on proliferating lymphocytes and induces both B-cell and T-cell lymphopenia.
Azathioprine gets converted to 6-mercaptopurine in the liver.
What’s the mechanism of action of cyclosporine
Drug class: Calcineurin inhibitor
Cyclosporine inhibits T-cell activation and prevents synthesis of several cytokines in particular, interleukin 2. It blocks calcineurin-mediated cytokine signaling. Cyclospoine binds to a cyclophilin, immunophilin in the cytoplasm, binding and blocking the function of calcineurin, an enzyme necessary for T-cell activation.
What’s the mechanism of action of Mycophenolate Mofetil
Drug class: inhibitor of purine synthesis in both T and B lymphocytes.
acts on DNA metabolism by noncompetitive, reversible inhibition of inosine monophosphate dehydrogenase, which is needed for synthesis of guanosine triphosphate. MMF blocks the synthesis of guanosine, thereby enhancing the synthesis of adenosine. Both result in inhibition of purine synthesis in the lymphocytes.
Other effects of MMF in- clude limiting production of nitric oxide, reducing secretion of tumor necrosis factor a, and reducing pro- liferation of T and B lymphocytes
What’s the mechanism of action of Leflunomide
Drug class:Antimetabolite Isoxazol derivative
Leflunomide’s immunomodulatory activity is credited to its primary metabolite, A77 1726, that inhibits T- and B-cell proliferation, suppresses immunoglobulin production, and interferes with cell adhesion.
What’s the mechanism of action of IVIG
Human intravenous immunoglobulin (hIVIG) involves interaction with inhibitory Fc receptors on phagocytic and antigen-presenting cells by enhancing expression of the inhibitory IgG Fc receptors
hIVIG impedes stimulatory molecules and suppresses antibody production; it interferes with activating complement and formation of membrane attack complex. hIVIG interrupts the complement activation pathway at the C3 stage
Actions of anticholinergics
- Blocks the action of the neurotransmitter acetylcholine at synapses in the central and the peripheral nervous system.
- Inhibit parasympathetic nerve impulses by selectively blocking the binding of the neurotransmitter acetylcholine to its receptor in nerve cells.
- Anticholinergics are divided into three categories in accordance with their specific targets in the central and peripheral nervous system: antimuscarinic agents, ganglionic blockers and neuromuscular blockers
- Antimuscarinic agents: atropine and glycopyrrolate
Pharmacokinetics - what is and stages
It is how the drug moves through the body
Absorption
Distribution
Metabolism
Excretion
Name routes of medication administration
- PO
- Rectal
- Topical
- Intradermal
- SQ
- IM
- IV
- Inhaled
- Buccal
- Sublingual
Name mechanisms of drug absorption
- Passive diffusion. From high to low concentration, no need of transporters.
- Very small
- Hydrophobic
- Facilitated diffusion → require transport proteins. From high to low concentration.
- Larger
- Hydrophilic molecules
- Active transport → From low to high concentration, against concentration gradient. Requires ATP.
- Larger
- Hydrophilic molecules
- Endocytosis
- Very large molecules like B12
- Will bind to receptors, then trigger endocytosis.
- Then exocytosis to be released in the blood.
How does pH affect weak acid drugs absorption?
- Drugs that are weak acids are better absorbed in the nonpolar form (HA) than in the dissociated state (H+ proton + A- polar acid), as in the dissociated state, the acid is negatively charged and will be repelled.
- To increase the drug being as a weak acid state (HA) we have to increase the amount of protons → acidic environment → reaction will shift towards nonpolar form.
- Stomach is acid but not much absorption happens in the stomach
- Proximal duodenum would be the place where most weak acids would be absorbed as there is still some acid from the stomach.
How does pH affect weak base drugs absorption?
- For weak bases, the dissociated state (B + H+) will be the nonpolar as the Base will not have a charge, whereas the BH+ state will be polar, more difficult to be absorbed.
- We want to decrease the amount of protons to shift the reaction towards the dissociated state → we make the environment more alkaline.
- Therefore they will be better absorbed in the alkaline parts of the GI → distal ileum.
How can blood flow affect drug absorption
- Less blood flow, less absorption
- In shock states, there is decreased blood flow to GI tract / skin - less will be absorbed
- In shock - better IV route
How does total surface area and contact time affect drug absorption?
- If there is diarrhea → increased motility, decreased time → decreased absorption.
- If there is constipation → increased contact time → increased absorption.
- Total surface area of intestines is very large - with IBD, gastroenteritis… the microvilli, villi are destroyed, therefore total surface area decreases.
- If TSA decreases → decreases absorption.
How can p-glycoprotein affect drug absorption?
- People can develop multidrug resistance
- Imagine a drug taken orally → moves into enterocytes
- In some situations, on the apical surface of the enterocytes there is a p-glycoprotein, that will spit the drug back into the GI lumen instead of moving it into the blood → decreased absorption.
- Seen in a lot of multidrug resistant situations.
What is bioavailability?
- Fraction of drug that enters the systemic circulation
- 100% on IV medications.
How do we calculate bioavailability (F)?
F = AUC oral / AUC IV
What factors affect bioavailability?
- Solubility
- Instability
- First pass effect
How can solubility affect bioavailability?
- Small molecules, hydrophobic, will be absorbed easily → increased absorption → increased bioavailability
- Larger molecules, hydrophilic → absorption will be decreased → decreased bioavailability.
How can instability affect bioavailability
- Some medications will be affected by the acid in the stomach, will not be stable in acidic environments, like penicillin g → decreased bioavailability.
- Some drugs might be affected by enzymes that are excreted in the GIT (proteases) → insulin never given orally because proteases will break it down.
How can the first pass effect can affect bioavailability?
- Drug taken orally → bloodstream → hepatic portal circulation (from GI to liver).
- Liver will metabolize part of the drug → most of the times inactivates them
- Then what really gets into the circulation is much less → decreased bioavailability
- Rectal → very small amount goes to liver.
- Other routes than oral do not go to liver.
- Nitroglycerin given PO - only remaining 10%, that’s why it is given sublingual.
What is the pKa of a drug?
- The degree of ionization (pKa) of a drug is a unique physicochemical property that controls its ionization state when in solution.
- If the drug’s pKa is the same as the pH of the solution it is dissolved in, then 50% of the drug exists ionized and 50% exists nonionized.
- As the pH of the solution changes, the state of ionization changes as well.
- We want the pKa to be closer to the pH of the solution where the drug will be absorbed.
- The pH of extracellular fluid is always going to be within some decimal fractions of 7.4 → drugs with a pKa under 7 (weak acids) will usually be water-soluble.
- Weakly basic drugs with a pKa closer to 8 will usually be lipid-soluble and will therefore find it easier to negotiate the barrier membranes on their way to their target.
What is the distribution process and what factors affect it?
- Movement of the drug from the systemic circulation to the tissues/organs
- Blood flow, capillary permeability, protein binding, solubility and volume of distribution
How does blood flow affects drug distribution?
- Organs with more blood flow, like brain and liver and kidneys might get more drug.
- Organs with less blood flow, less drug (skin, adipose tissue).
- A patient in shock → decreased blood flow → drug will not be delivered as good → decreased distribution
How does capillary permeability affect drug distribution?
- Organs like liver, bone marrow, spleen → sinusoidal capillaries → very leaky, large fenestrations → drugs can easily leak out
- Fenestrated capillaries → kidneys, glands → also easy to leak from systemic circulation to tissues.
- In these organs, distribution is increased as there is an increased capillary permeability.
- In other organs like brain and muscles → tight junctions, not easy to deliver drugs → decreased distribution. Depends on transporters to facilitate movement of the drug out of the blood, or a very hydrophobic drug, very lipid soluble and very small to be able to pass through the capillaries and into the tissues. Best example is brain.
- Patients in septic shock → extreme increase in capillary permeability → concentration of drug inside the blood will decrease → increase distribution, decrease serum concentration of drug → high doses of antibiotics as distribution changes.
How does protein binging affects drug distribution?
- Plasma or tissue protein binding → most common plasma proteins.
- Liver makes albumin and kidneys keep it in the blood.
- Patients with normal liver and kidney function: should be able to make albumin and keep it in the blood.
- Albumin → binds to drugs in the circulation.
- Drug that highly bound to albumin → not much free drug, that is the part that is distributed → decreases distribution of drug. Those drugs will concentrate in plasma.
- As the free drug moves out of the circulation → concentration decreases, and the drug bounded to albumin acts as a reservoir → releases small amounts into the blood, increasing the free concentration.
- Opposite → drug that barely binds to proteins → a lot of free drug → concentrate the drug in the interstitial / intracellular fluid.
- If a patient has kidney disease → albumin is lost in urine → less albumin in blood → increases amount of free drug.
- If a patient has liver disease → produces less albumin → increases amount of free drug.
How will solubility affect drug distribution?
- Small, nonpolar, hydrophobic molecules → increased distribution → concentrate in tissue spaces.
- Larger, polar, hydrophilic molecules → lower distribution → concentrate in the blood.
What is the volume of distribution (Vd)?
- The theoretical space / volume that a drug would be distributed
- Intravascular - interstitial - intracellular
- If a drug occupies all 3 - large Vd
- If a drug only stays in the IV compartment - low Vd
- All factors affecting distribution, they play a role in the Vd of a drug.
Low volume distribution drug example
- Large, polar, hydrophilic molecule, highly protein bound…
- Imagine plasma 4L, interstitial fluid 8L, and intracellular 12L (total of 24L).
- Out of those 24L, the drug will stay IV - in 4L → that will be the Vd, very concentrated in the plasma.
- Example: warfarin, Vd=8L → small. It concentrates in the plasma → supposed to interact with clotting proteins, is what we want.
Intermediate volume distribution drug example
- Mild protein binding, low molecular weight, still hydrophilic (has some charge)
- Will move out of the vascular space into the interstitial space.
- IV 4L, interstitial 8L, intracellular 12L → this drug would occupy 2 compartments → Vd - 8 + 4L = 12L.
- Maybe a small amount in the cells but primarily IV and interstitial
High volume distribution drug example
- Hydrophobic, small molecule, not protein bounded, not polar
- Drug will distribute in all 3 compartments → large Vd = 24L (following others examples).
- Example: chloroquine - Vd = 150,000L → higher than the total volume → barely stays in the plasma, distributes everywhere.
How can we calculate Vd?
Vd = F x dose / C = Liters
Where:
F: bioavailability (intravenous would be 1 => 100%)
Dose given (total mg)
C: peak plasma concentration (mg/L)
Vd is in L / Kg => divide result by weight to have L/kg.
What can the liver do to drugs / toxins?
- Can convert toxins into non toxic metabolites
- Can convert a prodrug and convert it in active drug
- Can convert an active drug and convert it in an inactive drug - to be excreted in urine / feces
How many phases are necessary to convert an active metabolite in a inactive one?
Phase I and phase II.
Not all drugs do all phases in same order.
Some drugs will only do phase I, some only phase II, some will do phase II then phase I.
Phase I of biotransformation
- In hepatocytes → smooth endoplasmic reticulum and mitochondria → inside them → heme containing enzymes → CYP450 system (cytochrome family)
- 2 different types of enzymes in the CYP450 that metabolize 70% of drugs → CYP3A4 and CYP2D6
- CYP450 → can oxidate, reduce or hydrolyze. The goal is to take a drug that is nonpolar and converted into something polar. Something lipid soluble into something water soluble → so it is easily excreted and not reabsorbed.
- It does that adding an oxygen or OH group.
What factors can affect phase I of biotransformation?
- Polymorphism → different genes that will make CYP450 more or less effective. That will decrease the concentration of active drug → decreased therapeutic effect, will need more drug. Opposite → slow metabolism → more active drug remaining in blood → toxic side effects.
- CYP450 inducers → when someone takes more than one medication → a patient on warfarin → if we give a CYP450 inducer → warfarin will be metabolized faster, decreasing the amount of effective warfarin → higher risk of clotting. Other inducers - phenobarbital, rifampin, phenytoin.
- CYP450 inhibitors → will do the opposite, decrease the activity of CYP450 → example of warfarin → if we give an inhibitor, the concentration of active warfarin in plasma will increase → risk of bleeding, toxic effects. CYP450 inhibitors: erythromycin, omeprazole…
- Liver disease - main place where metabolism happens (minimal in kidneys, lungs and intestinal cells). If the liver is diseased / failing → not able to metabolize correctly as the CYP450 will decrease in number / efficacy → develop toxicity. Age: babies and older individuals, CYP450 activity is decreased.
- To consider → if instead of deactivating a drug, the metabolism is to convert a prodrug into its active form, the CYP450 inhibitors and inducers would have the opposite effect → inducers would increase the amount of active drug, increasing risk of toxicity, and inhibitors would decrease the amount of active drug, decreasing its effectivity.
Phase II biotransformation
- Take the drug that maybe is not polar enough, not water soluble enough, and we make it more polar and more water soluble.
- Enzyme transferases → can add different groups (methyl, acetyl, sulfa, gluthatione, glucoronate) into the inactive molecule → CONJUGATION REACTIONS.
- Gives more polarity to the drug → easily to excrete into feces with bile or in the urine.
Factors that affect drug distribution
What factors affect oral bioavailability?
How can sepsis affect Vd?
What is clearance of a drug?
What comes in vs what comes out of a drug
What is the extraction ratio (E)?
Fraction of a drug / molecule that is eliminated by an organ
How can sepsis alter clearance?
What is the elimination of a drug?
- Moving the drug out of the body
- Rate of elimination influences duration of action
- Mainly through kidneys and biliary tract - enterohepatic circulation, renal dz will affect drug clearance.
- Less significant through saliva, lungs
How can sepsis affect the pharmacokinetics of medications?
Define drug absorption
Absorption is the process of drug movement from the site of drug administration to the systemic circulation. Various processes underlie the successful absorption of drugs. They include passive diffusion, facilitated diffusion, active transport, and endocytosis. Drug absorption is quantified in terms of bioavailability
Define bioavailability (F%)
Bioavailability is the extent to which absorption occurs. In other words, is the fraction of the administered drug that reaches the systemic circulation in the unchanged form. Compares extravascular administration with IV administration, using AUC.
Ex. Buprenorphine given transmucosal in cats have 40 to 50% bioavailability
F = AUC po / AUC iv
The ___________ tells us about drug exposure. Is most usefl to calculate bioavailability and for some PK/PD modeling of antibiotics
AUC
Define drug distribution
movement of drug from blood to sites in the body (site of action)
T/F Most of the anesthetic drugs are hydrophilic and have a low volume of distribution
FALSE - most are lipophilic with a large Vd
If the volume of distribution is similar to the plasma volume, the medication _______ (does/does not) distribute significantly out of the plasma compartment
does not
How can you calculate the volume of distribution of a drug?
Vd = dose given/Cp (plasma concentration of the drug)
List hydrophilic antibiotics
Aminoglycosides (gentamicin, tobramycin, amikacin, neomycin)
Beta lactams (penicilins, cefalosporins and carbapenems)
Glycopeptides (vancomycin)
If a septic patient with vasculitis and hypoalbuminemia is receiving Amoxicillin and clavulanic acid, you would expect that the volume of distribution of this medication would _____________(increase/decrease). Based on that, plasma concentrations would _____________ and you’ll need to administer a ________ (higher/lower) dose to achieve a target dose.
Vd = increase
Plasma concentration = decreases
Dose needs to be increased
* Remember this is a hydrophilic antibiotic (so this applies for hydrophilic drugs, lipophilic drugs are less affected by this)
* Fluid overload can cause the same changes
List lipophilic antibiotics
Macrolides
fluoroquinolones
Lincosamides
If you have a drug that is 30% protein bound and another drugs that is 70% protein bound, which one has a higher volume of distribution?
the drug that is 30% protein bound
Low protein binding = increased vD
T/F - The volume of distribution of a drug can be calculated only if the drug was given IV
TRUE - if drug is given via an extravascular route, the absorption of the medication will be unknown
Dose/AUC = ????
Clearance
Which drugs have a high extraction ratio in the liver? Why is this important?
Opioids
Lidocaine
Beta blockers
Benzodiazepines
Alpha-2 agonists
It matter because the blood flow to that organ would be the main limiting factor for drug extraction.
Then, hypotension, vascoconstriction, hyperdinamic shock –> will alter the clearance of these medications
A drug takes ____ half lifes to reach steady state
3 to 5
Inhibitors of CYP450
Ketoconazole
Omeprazole
Cimetidine
Fluoxetine
Fluoroquinolones
Inducers of CYP450
Phenobarbital
Rifampin
Glucocorticoids
Omeprazole
What is the usefulness of half life
can be used to design dose regimens
Can be used to determine time of a medication to reach steady state
Tells us how long before a drug is eliminated
The majority of drugs, it takes ___ half lifes to be eliminated
3-5 half lives for 87 to 97% to be eliminated
What is the steady state of a drug?
The rate going in equals the rate going out
What is the first pass metabolism?
Phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemic circulation. It is the fraction of drug lost during the process of absorption which is generally related to the liver and gut wall.
After a drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system. It is carried through the portal vein into the liver before it reaches the rest of the body. The liver metabolizes many drugs, sometimes to such an extent that only a small amount of active drug emerges from the liver to the rest of the circulatory system. This first pass through the liver thus may greatly reduce the bioavailability of the drug.
What are the 2 principal factors that affect pK?
Volume of distribution
Drug clearance
T/F Antimicrobials need to reach effective concentrations in the interstitial fluid of tissues, as this is the site of most infections
TRUE
T/F An increased Vd may result in a greater loss of antimicrobial from the intravascular space, therefore actually increasing the concentration in the interstitial space.
TRUE
Is Vd increased or decreased in critically ill?
Increased
Why is Vd increased in critical illness?
o Is a result of critical illness-related pathophysiology (eg, vascular dysfunction, microvascular failure, fluid extravasation) and medical interventions, including fluid resuscitation.
o The effect on changes to Vd is predominantly restricted to hydrophilic drugs.
o It has been recommended to administer loading doses of hydrophilic antimicrobials in critically ill human patients to ensure that therapeutic concentrations are achieved.
o It has also been recommended to administer hydrophilic antimicrobials as extended infusions.
o The Vd for lipophilic drugs is usually high and often unchanged in critically ill patients, and a loading dose is not recommended.
For all antimicrobial classes, including concentration-dependent antimicrobials, an ________ Vd can prolong the time needed to reach therapeutic concentrations.
Increased
What happens when the patient starts recovering with the Vd?
With recovery from infection (and correction of the changes associated with critical illness), the Vd will return to normal resulting in the need for dose modifications throughout treatment during longer courses of antimicrobials.
How is the clearance of hydrophilic antibiotics? and the lipophilic ones?
The clearance of hydrophilic agents is predominantly via renal mechanisms while hepatic clearance is more common for lipophilic agents.