Pharm Exam 1

Lectures 1-3

Absorption

How the drug gets in

Route/bioavailability

IV, IM (slower), transcutaneous, subcutaneous (less reliable), oral/rectal, SL, intrathecal, epidural, perineurial, inhalationals

Distribution of CO

VRG Components

Brain, heart, kidneys, liver, endocrine glands

Lipophilic or hydrophilic rapidly equilibrate into CNS tissue

Lipophilic

Lipophilic redistribution single vs. multiple doses

Single: short duration because of redistribution to peripheral tissues

Multiple: Increase in peripheral tissue concentrations, longer duration of action

After multiple doses of a lipophilic drug depend on?

Elimination

Protein that binds to acidic/neutral drugs

Albumin + binds to benzos and SSRIs

Protein that binds to basic drugs

Alpha-1-acid glycoprotein

What causes low protein levels? What does this do?

Malnutrition/chronic illness

Increases level of free drugs

What is the central compartment composed of?

Plasma and VRG

Alpha phase of compartment model

Quick decline

Distribution phase

Beta phase of compartment model

Slower decline

Elimination phase

How do hydrophilic drugs get into the CNS

Active transport

Acid equation

H+ + A- (ionized) ←→ HA (nonionized)

Base equation

H+ + B (nonionized) ←→ HB+ (ionized)

Etomidate (base): pKa = 4.2 (pH blood = 7.4)

99% non-ionized in the blood

Propofol (acid): pKa = 11 (pH blood = 7.4)

99% non-ionized in the blood

Biotransformation

Alteration of the drug via a metabolic process (usually in liver)

Phase I of biotransformation

Oxidation, reduction, and hydrolysis

Increases polarity so the drug is water soluble and can be excreted in urine

What catalyzes most Phase I reactions?

Cytochrome P-450 (CYP) enzyme system

Induction of CYP

Increase in CYP activity with ongoing drug exposure

Can alter metabolism of other medications that are metabolized by the same CYP subtype

St. John’s Wort effect

Induces CYP3A4

Causes decreased drug effect due to greater Phase I activity

CYP inhibition

• Drugs compete for the same CYP subtype

• Cimetidine inhibits metabolism of meperidine, propranolol, diazepam

• Grapefruit juice inhibits CYP3A4 causing exaggerated drug effects because a lower percentage of the drug undergoes Phase I biotransformation

Phase II biotransformation

Conjugation with a polar substance to make it more water soluble

Glucuronate, acetate, glutthione group

What is unique about neonates-1y/o biotransformation?

Diminished Phase I and Phase II activities

Hepatic drug clearance (definition)

Volume of blood that the liver can cleanse of a drug in a given amount of time

Hepatic drug clearance (equation)

=hepatic blood flow x extraction ratio

Volume of blood that the liver can cleanse of a drug in a given amount of time

Hepatic drug clearance

What does hepatic blood flow depend on?

CO and BP

Hepatic extraction ratio

Fraction of drug that is removed from the blood as it passes through the liver

High extraction ratio

Flow limited

Ex. Propofol and etomidate

What causes diminished clearance in drugs with high extraction ratios?

Metabolic capacity (Vm) is severely compromised

Decreased blood flow

Low extraction ratio

Capacity limited

Ex. Rocuronium

What is low extraction ratio limited by?

The liver can only handle a fraction of drug it sees, even under ideal conditions

Changes in metabolic capacity (Vm) will produce a nearly proportional effect on clearance

Renal clearance is a small fraction of renal blood flow because of

Protein binding

Only unbound drugs will be filtered into the kidneys for excretion

Renal tubular active transporters

Allow renal clearance to approach RBF

Drugs with significant renal excretion (6)

Pancuronium

Penicillins

Digoxin

Rocuronium

Sugammadex

Neostigmine

Zero order kinetics - which drugs are they found in?

Phenytoin and alcohol

Saturation kinetics

Occur when excess amounts of drug saturate the capacity of metabolic enzymes or transport systems

ex. digoxin

Half-life

Time for serum concentration to change by a factor of 2

Volume of distribution (Vd)

Extent of drug distribution

Capacity of tissues for absorbing a drug

What determines Vd

Depends on tissue mass and affinity of drug for tissue

Do hydrophilic or lipophilic drugs have larger Vd?

Lipophilic

Vd (equation)

Vd = Amount of drug given/serum concentration

Loading dose (equation)

Loading dose = Vd x target concentration

Elimination clearance (Cl_E)

Theoretical volume of blood from which drug is completely and irreversibly removed in a unit of time

Clearance equation

Clearance = dose given/area under concentration vs. time curve

Elimination half life

Amount of time it takes for the amount of drug int he body to decrease by a factor of 2

= ln 2 x (Vd/Cl_e)

Why does midazolam have increased elimination half time in elderly?

Vd is increased

NOT due to metabolism

What does termination of effect depend on?

Serum concentration

Therapeutic Index

LD₅₀/ED₅₀

Low and high toxicities to avoid

Low - awareness

High - overdose

Partial agonists

Have lower efficacy

Competitively inhibits the response produced by a full agonist

Redundancy at the neuromuscular junction

Only needs 25% of receptors to be bound to ACh for clinical strength

Why we need more than 75% blocked for clinical weakness

Tolerance (and mechanisms)

Diminished response to a drug due to chronic exposure

Cellular tolerance (adaptation)

Enzyme induction (change in metabolism)

Depletion of neurotransmitters

Tachyphylaxis

Acute tolerance after only a few doses

Competitive antagonists

Decreases potency, efficacy is not changed

Non-competitive antagonists

Decreases potency and efficacy

Ideal IV anesthetic

• Water-soluble and stable

• Lack of pain on injection; no tissue damage with extravasation

• Low incidence of histamine release or hypersensitivity

• Rapid smooth onset

• Rapid metabolism to inactive metabolites

• Steep dose-response curve

• Minimal cardiac/respiratory depression

• Decreases ICP/CMRO2

• Rapid smooth recovery

• Minimal side effects: PONV, amnesia, HA, dizziness

Propofol - mechanism of action

Inhibitory transmission through GABA

Propofol - emulsion

Intralipid

Soybean oil, glycerol, egg lecithin

Why use aseptic technique for Propofol?

Supports bacterial and fungal growth

Discard after 12 (6?) hours

Fospropofol (Aquavan)

Prodrug, water soluble

Perineal burning

Propofol absorption

IV

Propofol distribution

Highly lipid soluble

Very fast redistribution (less than 8 minutes)

Propofol - biotransformation

Exceeds HBF - some degree of extra-hepatic metabolism (lungs)

Propofol excretion

Renal

Not effected by chronic renal failure

Propofol dosing

Induction - 1.5-2.5 mg/kg in adults

Sedation - 25-75 mcg/kg/min

General infusion - 100-200 mcg/kg/min

Target plasma concentration for propofol

4-6 mcg/mK

Propofol - CV effects

Decrease in SVR, contractility, preload

Hypotension

Potential for bradycardia but normally tachycardia with induction

What causes worsening CV effects from Propofol?

LV failure, old age, rapid injeciton

Propofol Resp effects

Resp depression, apnea, depress hypoxic/hypercapnic drive

Depression of upper airway reflexes

Propofol Neuro effects

Decrease CBF, ICP, CMRO2

Antiemetic

Anti-epileptic

Myoclonic twitches, hiccough

How to prevent burning on injection of Propofol

Bier block

Pretreat with IV opioid

Mixing propofol w/ lidocaine (acidifies emulsion)

Lidocaine bolus doesn’t do much to prevent burning

Acute Hypertriglyceridemia (cause and treatment)

Caused by high fat content and inhibition of fatty acid oxidation by propofol

Treatment - stop propofol infusion, give insulin/dextrose to promote lipoprotein lipase activity

Propofol infusion syndrome

Hyperlipidemia, rhabdomyolysis, metabolic acidosis, refractory bradycardia, circulatory collapse, death

Prolonged high dose infusions (>75 mcg/kg/min, <24 hours)

Seen in critically ill patients (esp. with vasopressors)

Barbiturates (drugs)

Phenobarbital, methohexital, thiopental, thiamylal, secobarbital

Barbiturates - mechanism of action

Depress reticular activating system

Suppress excitatory neurotransmitters (ACh), enhance inhibitory (GABA)

Barbiturates - acidity and solubility (including preparation)

Water soluble

Preparation is alkaline (pH>10) and unstable (2-6 wks in fridge)

Weak acid with pKa close to 7.4

Barbiturates - Extravasation

Pain

BUT painless on injection

Barbiturates - intra-arterial injection of thiobarbiturate (and treatment)

Crystals → thrombosis, necrosis

Treatment - papaverine, lidocaine, stellate ganglion block, heparin

Thiobarbiturate (thiopental, thioamylal) - lipid solubility, potency, onset, duration

High lipid solubility

Greater potency

Rapid onset

Shorter duration

thiopental no longer available due to objections from manufacturer due to lethal injection use

Oxybarbiturates (phenobarbital, methohexital) - lipid solubility, potency, onset, duration

Lower lipid solubility

Less potency

Slower onset

Longer duration

Except methohexital, more potent and shorter duration than thiopental

Barbiturates - absorption (GA and premedication)

IV for GA

Rectal/IM for premedication

Barbiturates - Distribution (solubility and redistribution)

Lipid soluble → fast onset (30 seconds) and rapid redistribution (10-20 minutes) after single dose

Higher plasma levels in hypovolemia, hypoalbuminemia, acidosis, elderly

Multiple doses: saturate peripheral compartments, slower redistribution - poor choice for maintenance

Barbiturates - Biotransformation

Almost completely hepatic oxidation

Methohexital extarction

High hepatic extraction

Shorter elimination half life

Thiopental extraction

Low hepatic extraction

Longer elimination half life

Liver disease unlikely to cause prolonged effect from a single dose

Barbiturates speed excretion and why

Protein bound, lipid soluble

Difficult renal clearance until biotransformation

Barbiturates - elimination half life

3-12 hours

Methohexital - 3.9 hours

Thiopental - 11.6 hours

Dose of thiopental and methohexital

Thiopental

• 3-5 mg/kg, 6-8 mg/kg for infants

• 2-4 mg/kg/hr for treatment of intracranial HTN or intractable seizures

Methohexital

• 1-1.5 mg/kg (half of thiopental)

Barbiturates - CV effects

Decrease BP, Increase HR (central vagolytic effect)

Venous pooling

CO maintained except in hypovolemia, CHF, beta blockade = decrease in CO and BP

Barbiturates - Respiratory effects

Decrease hypoxic/hypercapnic drive

Airway obstruction

Bronchospasm/laryngospasm

Barbiturates - Neuro effects

Decrease CBF, ICP

Mega decrease in CMRO₂ to burst suppression on EEG

Anti-epileptic

Methohexital - neuroexcitation (myoclonus, hiccups, seizures)

Common drug for electroconvulsive therapy (ECT)

methohexital

Barbiturates - renal

Decrease RBF (due to hypotension)

Barbiturates - hepatic effects (2)

Decrease HBF

Induction of enzymes (CYP);

Do barbiturates evoke histamine release?

Yes. Sulfur-containing (thio-) evoke histamine release

Etomidate - Mechanism of Action

Depress reticular activating system - mimics GABA