Pharmacology Exam 2 PP

PHARM EXAM 2
Winter MSII
LOCAL ANESTHETICS
What are the acid- base properties of local anesthetics (LAs)?
Weak bases c pKas = 8-9 Mostly ionized at physiologic pH
Which form is more effective at the Na receptor?

Ionized form
How do LAs enter the nerve cell and act?

The non-ionized form diffuses across membrane In the cell the ionized form acts on the receptor from the inside
What effect does inflammation have on the effect of LAs?

pH ionized form less permeation and less effect
What is the role of co -injection c epinephrine?

Alpha 2 agonist that causes vasoconstriction to limit distribution of anesthetic and release of substance P that prolongs anesthetic effect
LOCAL ANESTHETICS
What property of LAs determine their distribution?
Amides: distribute rapidly, correlate c extent of perfusion (some fat sequestration) Esters: stay localized and are more rapidly metabolized
What are the esters?

Benzocaine, cocaine, procaine (all have one I in the name)
What are the amides?

Bupivacaine, lidocaine, prilocaine (all have two I in the name)
How are amides metabolized?

In liver via p450 system
How are esters metabolized?

Hydrolyzed in plasma by pseudocholinesterase
How are LAs excreted?

Via kidney
LOCAL ANESTHETICS
What Na channels do LAs prefer to bind to?
Higher affinity for active and inactivated than rested channels
What factors will binding?

Lower membrane potentials, more rapidly firing axons
What are the effects of Ca and K on the effects of LAs?

Ca : membrane potential more rested channels antagonizes effect K: depolarizes membrane more inactivated channels potentiates effect
How do nerves themselves affect LA actions?

Fiber diameter: greater diameter = less effect Firing frequency: greater frequency = greater effect Fiber position: outside fibers first
What is the purpose of adding sodium bicarb or CO 2 to LA?

intracellular pH and intracellular drug concentration
LOCAL ANESTHETICS
When should vasoconstrictors NOT be used c LA?
In the fingers or toes due to low perfusion
Where does LA instillation take place?

Epidural or subarachnoid space
What is regional anesthesia?

IV administration in limb c blockage of venous flow
Which Rx have a short duration of action?

Procaine and chloroprocaine
Which have intermediate duration?

Lidocaine, mepivacaine, prilocaine
Which are long-acting?

Tetracaine, bupivacaine, etidocaine, ropivacaine
LOCAL ANESTHETICS
What are the results of LA CNS toxicity?
Sleepiness, visual and auditory disturbance, tongue numbness, nystagmus, fasciculations, tonic-clonic convulsions
What is the result of cardiovascular toxicity?

Inhibition of Na and Ca channels arrhythmias, ( -) inotropic action, vasodilation
Which LA does not have ( -) inotropic effects and vasodilation?

Cocaine: SNS tone HTN and arrhythmias
Which is the most cardiotoxic?

Bupivacaine: binding to resting channels broadened QRS
Which LA may cause a blood toxicity and what is the Tx?

Prilocaine metabolite may cause methemoglobinemia Methylene blue is used for Tx
Which LAs may cause allergic rxns?

Esters (rare c amides)
LOCAL ANESTHETICS
How is procaine (Novocain) metabolized?
An ester that is metabolized by pseudocholinesterase
What is its duration of action?

Short
What is the metabolite of procaine and its action?

PABA inhibits action of sulfonamides
When is it used topically?

It is NOT
What is the relative time of onset and action of tetracaine?

Long-acting and slow onset of action (>10 mins)
When is it used?
Spinal anesthesia and ophthalmologic use
What is tetracaines potency relative to procaine?

10X more potent, but also more toxic
LOCAL ANESTHETICS
What type of tetracaine preparation is used for spinal anesthesia?
Combined c 10% dextrose to make it heavier than CSF
What type of preparation is used topically?

2% solution
What is benzocaine ( Americaine) used for?

OTC topically for sunburn, minor burns, and pruritis
When is cocaine used?

Topical anesthesia of mucous membranes
What ANS effect does cocaine have?

Blocks reuptake of catecholamines into nerve terminals (vasoconstriction)
When should cocaine be used cautiously?

Pts c HTN, CV disease, or thyrotoxicosis
What is the regulatory classification of cocaine?

Schedule II controlled substance
LOCAL ANESTHETICS
What is the prototype amide c intermediate duration of action?
Lidocaine
When is lidocaine preferred?

Infiltration blocks and epidural anesthesia
What are its pharmacokinetic properties?

Rapidly absorbed and is metabolized in liver by microsomal mixed-function oxidases (p450)
What is another use of lidocaine?

Antiarrhythmic (given systemically)
When is prilocaine used?

By injection, but NOT topically or for subarachnoid anesthesia
When should prilocaine be avoided?

Cardiac or respiratory disease or methemoglobinemia
Prilocaine causes methemoglbinemia
LOCAL ANESTHETICS
How is methemoglobinemia reversed?
Methylene blue
What is the duration of action of bupivacaine?

Long
When is it used?
Infiltration blocks and epidural anesthesia
What makes it stand out from other amides?

Greater cardiotoxicity
What Rx resembles bupivacaine, but is less arrhythmogenic?

Ropivacaine
How does its metabolism differ from bupivacaine?

Less lipid soluble and cleared via the liver more rapidly (less adverse events)
What are ropivacaines possible Rx interactions?

Alfentanil, theophylline, fluvoxamine, cimetidine
GENERAL ANESTHETICS
What is dissociative anesthesia?
Cataleptic state c profound analgesia, amnesia, unresponsiveness, but limbs and eyes may move
What Rx causes it?

Ketamine
How is depth of anesthesia assessed?

Observing reflex activity, reaction to stimuli, breathing, and BP
What IV general anesthetics are used?

Barbiturates, benzos, propofol, ketamine, and opioid analgesics
What is the mechanism of action of the 1 st 3 mentioned? What is the action of ketamine?
Blocks NMDA receptors
Act at the GABA A receptor
What is the effect of inhaled anesthetics?

Hyperpolarize neurons to depress activity of CNS
GENERAL ANESTHETICS
How do inhaled anesthetics act on excitatory and inhibitory synapses?
excitatory transmission (inhibit nicotinic receptors and activate K channels) inhibitory transmission (facilitation of GABA receptor)
What is the potency of inhaled anesthetics related to?

Their lipid solubility
What are the stages of anesthesia?

Inhibition of substantia gelatinosa in dorsal horn inhibition of sensory transmission Blockade of small inhibitory neurons causes excitation Loss of consciousness and reflexes (surgical anesthesia) Medullary respiratory and vasomotor center depression
What are the effects on BP?

due to vasodilation, cardiac depression, blunted baroreceptor reflex, SNS tone
What are the effects on respiration?

respiratory drive, gag/cough reflex, and LES tone
GENERAL ANESTHETICS
What are the CNS effects?
metabolism, but vasodilation causes cerebral blood flow and intracranial pressure
How do they affect body temp and why is it of concern?

Cause hypothermia that may post -anesthetic morbidity
What is a common postoperative Sx?

Nausea and vomiting
Which Rx is least likely to cause N/V?

Propofol
What Sx occur on emergence from anesthesia?

HTN and tachycardia (may result in myocardial ischemia) Excitement: tachy, restlessness, crying, moaning, thrashing, shivering
What is used to Tx the excitement?

Opioids (meperidine for shivering)
GENERAL ANESTHETICS
What determines the concentration of anesthetic in a tissue?
Partial pressure and degree of solubility
What factors determine the rate anesthetic gets into the brain?
Solubility of the anesthetic in blood and tissues Concentration in the inspired gas Pulmonary ventilation delivering the gas to the lungs Loss of agent from blood to tissues in the body
What is used to express solubility of a gas?

Blood/gas partition coefficient
What does this coefficient represent?

The ratio of anesthetic in the blood to the inhaled gas when blood and lung partial pressures are at equilibrium
How does blood solubility affect rate of delivery to the brain?

The faster the blood is saturated, the faster the delivery to the brain The less soluble the Rx in blood, the faster it becomes saturated (more rapid effect)
GENERAL ANESTHETICS
What are the relative solubilities of nitrous oxide and halothane?
Nitrous oxide (0.47): insoluble in blood = rapid onset Halothane (2.3): soluble in blood = slow onset
How can blood saturation and rate of induction be for a particular Rx?
the concentration ( for maintenance)
How does ventilation affect the partial pressure of the gas in the lungs?
ventilation [anesthetic] in blood
How can emphysema affect inhaled administration?

Less transfer to blood slow induction and recovery
How does pulmonary blood flow affect induction of anesthesia?

flow from CO means more blood is available to be saturated c anesthetics so it will rate of induction
What happens in shock?

CO is and ventilation quicker induction
GENERAL ANESTHETICS
How does perfusion rate affect delivery of Rx to tissue?
High perfusion means Rx will enter tissue quickly and diffuse away quickly when gas is turned off
What factors affect elimination of a Rx from tissue?

Blood flow: fast flow = fast elimination Solubility: low solubility = fast elimination
Why are combinations of inhaled Rx often used?

Decrease concentration of each Rx and minimize side effects
What is used to describe the potencies of general anesthetics?

Minimum alveolar concentration (MAC)
What is MAC?
How does age affect MAC?
in elderly pt [anesthetic] in % in an inhaled gas mix that results in immobility in 50% of pts when exposed to noxious stimulus (analogous to ED 50 )
GENERAL ANESTHETICS
How does MAC change as Rx are mixed?
It is additive (0.5 MAC of Rx -A and 0.5 of Rx-B = 1 MAC)
How is MAC affected by adjunct IV Rx?

Decreased (opioids, benzos)
How does MAC relate to potency?

Low MAC = more potent High MAC = less potent
What is diffusion hypoxia?
How is this avoided?
N 2 O is not very soluble in blood. When administration stops, large amount move into alveoli and expand lung volume to crowd out O 2 Give 100% O 2 after discontinuing anesthesia Addition of 2 nd gas (N 2 O) will partial pressure of the other gas in the blood and delivery and speed induction
What is the second gas effect?
GENERAL ANESTHETICS
What is the MAC and blood/gas of halothane?
MAC = 0.75, blood/gas = 2.54
What is its relative time of induction and activity?

SLOW induction, rapid awakening used for maintenance
How does halothane affect the heart?

Depresses myocardium and output Also sensitizes heart to catecholamines arrhythmias
What are other effects?

Relaxes uterus, laryngospasm, renal blood flow and urine output
What are serious complications c halothane use?

Hepatitis : more often seen c Hx of use and middle-age obese women Miscarriage (seen c repeated exposure)
What can happen c administration of halothane + succinylcholine?

Malignant hyperthermia (all inhaled do this, but halothane is the worst)
GENERAL ANESTHETICS
How is malignant hyperthermia treated?
Dantrolene
What is the MAC and blood/gas of enflurane?

MAC = 1.63, blood/gas = 1.9
How does its induction compare to halothane?

More rapid
What side effects may occur post -op c enflurane?

N/V, shivering
What can happen at high concentrations?

CNS stimulation and seizure
How can it affect the kidneys?

Production of fluoride during metabolism may cause reversible kidney damage
What is the MAC and blood/gas of isoflurane?

MAC = 1.17, blood/gas = 1.46
GENERAL ANESTHETICS
What is the most widely used inhaled anesthetic and why?
Isoflurane, due to its low toxicity
What is a drawback?
Pungent odor so not good for induction (also expensive)
What advantages does its low blood/gas coefficient confer?

Induction and emergence rapid c ability to adjust depth of anesthesia
What indicates depth of isoflurane anesthesia?

BP and respiration, HR
Why is it often used in neurosurgery? Which inhaled anesthetic has the least effect on the heart/BP?
Sevoflurane
Less dilation of cerebral vasculature than halothane and cerebral metabolic O 2 consumption
GENERAL ANESTHETICS
What is the MAC and blood/gas of sevoflurane?
MAC = 1.8; blood/gas = 0.69
What are its relative induction and recovery times?

Both are rapid
What patients often receive sevoflurane?

Those c CV disease and children (low airway irritation)
What is the MAC and blood/gas of desflurane?

MAC = 6.60; blood/gas = 0.42
What type of surgery is it used for and why?

Outpatient due to very rapid induction and emergence
What are its undesirable characteristics?

Very pungent (not for induction), BP, profound respiratory depression, intracranial pressure
GENERAL ANESTHETICS
How can halogenated hydrocarbons cause liver toxicity?
Chlorine and bromine are removed generating a toxic metabolite that may generate an immune response hepatitis Repeated exposure can lead to induction of hepatic enzymes and formation of more metabolites
Which can release fluoride ions that may cause renal toxicity?
Enflurane and sevoflurane
What is malignant hyperthermia?

Rapid rise in temp and O 2 consumption due to intracellular Ca causing prolonged muscle contraction
Although rare, which Rx are most likely to cause it?

Halothane combined c succinylcholine
What is the Tx?

IV dantrolene
GENERAL ANESTHETICS
What is the MAC and blood/gas of nitrous oxide?
MAC = 104; blood/gas = 0.46
What are its effects?

Analgesia (not anesthesia), relaxation, euphoria
When is it used?
Dental procedures and c other inhaled anesthetics to rate of induction
What must be done when nitrous oxide is terminated? How else can it act in combo c other anesthetics?
Reduces the amount of hypotension produced Give 100% O 2 at first to prevent diffusion hypoxia
What are its adverse effects?

Chronic exposure may cause peripheral neuropathy , and megaloblastic anemia
When is it contraindicated?
Do not use w/in 3 months of eye surgery where intraocular gas was used vision loss
GENERAL ANESTHETICS
What are IV anesthetics used for?
Induction of anesthesia
When is thiopental contraindicated?

Porphyrias
What are the characteristics of midazolam?

Ultrashort-acting benzo that causes sedation and anterograde amnesia
What is the most widely used anesthetic in the U.S.?

Propofol
What is its mechanism?

Facilitates GABA transmission
What makes it such a great anesthetic?

Rapid induction and recovery (recovery is 10X faster than thiopental)
In what form is it given and what is the result of this?

Given as an emulsion c albumin that may cause anaphylaxis
GENERAL ANESTHETICS
What are the drawbacks of propofol?
Allergic rxn Profound respiratory depression Reaction at site of injection (inject c lidocaine)
What is the mechanism of etomidate?

Facilitates GABA transmission
When is it used?
Induction of anesthesia in pt c risk of hypotension
What is the mechanisms of ketamine?

Blocks NMDA receptors
What are its effects in the patient?

Catatonic state, dissociative anesthesia, profound analgesia (not anesthesia)
What can happen on emergence from ketamine?

Emergence delirium bizarre dreams, hallucination, and psychosis
GENERAL ANESTHETICS
How does ketamine affect other body systems?
Sympathomimetic, bronchodilation, very little respiratory depression
What Rx can be given in a lollipop to children?

Fentanyl
What Rx class does it belong to?

Opioid
OPIOIDS AND ANTAGONISTS

What are the endogenous opioids and their function in the brain?
Enkephalins decrease pain Beta-endorphins pain and cause euphoria Dynorphin A may sensitivity to pain in spinal cord
What is the function of nociceptin?

Antagonizes analgesia @ receptors, but may be involved in reward system
What are the 3 opioid receptors and their roles?

Mu ( ) most important receptor for analgesia Kappa ( ) some anesthesia and dysphoria Delta ( ) may cause dysphoria
What are all opioid receptors coupled to?

G i/o proteins that close voltage-gated Ca channels on presynaptic nerve terminals
Results in NT release

In addition to closing Ca channels, what other channels do recepto rs act on?
Open K channels causing hyperpolarization
What are the relativ e affinities of the opioids for the 3 recepto rs?
: endorphins > enkephalins > dynorphins : enkaphalins > endorphins and dynorphins : dynorphins >> endorphins and enkephalins
How do opioids cause analgesia?

both sensation of pain and reaction to pain while maintaining proprioception, temp, and pressure sensations
Does toleran ce to analgesia develop?

Yes
How does morph in e act differen t from other opioids in overdose?

Morphine causes CNS depression , while others cause excitement and convulsion
Does toleran ce develop to the sedative effects of opioids?

Yes

How can opioids cause N/V in some patients?
Stimulate chemoreceptor trigger zone (CTZ) in brain
What non-analgesic effect do opioids cause that is useful?

Antitussive suppress cough
Which Rx are most effective at cough suppression and which has no antitussive effect?
Codeine and dextromethorphan are most commonly used Meperidine (Demerol) has NO effect on cough
How do opioids affect respiration? This makes them useful in Tx of what?

Pulmonary edema Cause respiratory depression (more common in overdose) by the brain stem response to CO 2
When should opioids not be used?

In pt c head trauma or intracranial pressure (causes intracranial pressure)

What happens to the eyes c opioid overdose?
Miosis pinpoint pupils are characteristic
What is the exception to this?

Meperidine does NOT cause miosis
How can the miosis be reversed?

It is a parasympathomimetic effect so it is blocked by atropine
Does tolerance develop to miosis?

NO
How do they affect muscles, when does it happen, and how is it prevented?
May cause truncal rigidity that can interfere c respiration Most common c highly lipid soluble Rx life fentanyl give IV Prevented using neuromuscular blockers
What is the CV effect?

May cause bradycardia (no direct effect), BP, and orthostatic hypotension

Which opioid may cause tachycardia?
Meperidine
What are the GI effects of opioids?

Constipation, gastric motility, biliary colic, constriction of sphincter of Oddi
What are the GU effects?

Antidiuretic effect as a result of renal blood flow sphincter tone = harder to urinate ureteral tone = harder to pass kidney stone
How does it affect the uterus?

May prolong labor (meperidine does not)
What are the endocrine effects?

ADH, prolactin, and somatotropin LH, FSH, cortisol, and testosterone

What may cause itching in some patients receiving opioids?
Causes release of histamine itching , flushing, sweating
More common if they are injected Treated or prevented c antihistamines
How can pain perception be changed c chronic use of opioids?

Hyperalgesia the sensation of pain is c chronic use
Tolerance develops to which effects?

Tolerance to analgesia, sedation, euphoria, N/V, respiratory depression Does NOT develop to miosis, constipation, seizures
When does addiction to opioids normally develop?

If they are underprescribed. The goal is to prevent pain and not treat it c opioids because this results in stimulation of the reward system
What opioid withdrawal Sx are seen?

Dysphoria, anxiety, insomnia, anorexia, vomiting, diarrhea
Not a life-threatening withdrawal

How can withdrawal Sx be reduced?
Use of clonidine or another opioid (methadone)
What opioid antagonist is used in overdose?

Naloxone
Use c what antidepressants should be avoided?

MAOIs cause hyperpyrexic coma
Which opioids are the worst for this?

Meperidine and dextromethorphan
How do opioids affect liver enzymes?

Inhibit CYP2D6
What are the consequences of this?

Those c to little CYP2D6 or those taking SSRIs (also inhibit) may not experience sufficient analgesia c codeine derivatives

Which SSRIs are the most potent CYP2D6 inhibitors?
Fluoxetine and paroxetine
When are opioids contraindicated?

Use of partial agonist c full agonist impairs analgesia or causes withdrawal Pt c head injury, pregnancy, impaired pulmonary function, hepatic or renal disease
What is the prototype opioid?

Morphine strong agonist of all opioid receptors
Although it can be give through many routes, what is the most effective?
Injection due to high first-pass metabolism
What is the standard therapeutic dose of morphine?

10mg SC or IM
How is it metabolized?
Metabolized by CYP2D6: conjugated to morphine -6-glucuronide (potent analgesic) morphine-3- glucuronid (major metabolite) eliminated in urine (90%) and feces

How does hydromorphone compare to morphine?
More potent Metabolites dont accumulate (good in renal dysfunction) Less likely to cause histamine release
What are the characteristics of methadone?

Long half life (15-60 hrs), stimulates receptors, blocks NMDA receptors and inhibits NE/5-HT reuptake
What are its uses?

Useful in long-term control of pain (neuropathic, cancer) Maintenance Tx of addicts used to withdrawal Sx
When is meperidine (demerol) used?

For very brief courses in patients
How does it differ from other opioids?

Anticholineric tachycardia, mydriasis ; no cough suppression

What are the Rx interaction of meperidine?
TCAs, SSRIs, MAOIs (phenelzine, selegiline, linezolid) serotonin syndrome
What toxicity can result from long term meperidine use?

Metabolized to normeperidine that may cause seizures
Caution in renal failure
What are the characteristics of fentanyl?

Very lipid soluble and highly potent (high abuse potential) Short duration of action and half -life
What are the moderate -to-strong agonists?

Hydrocodone and oxycodone
What are the moderate agonists?

Codeine and tramadol
What are the mixed agonist -antagonists?

Buprenorphine and pentazocine

What Rx is often combined c acetaminophen?
Hydrocodone (+ acetaminophen = Vicodin)
What is it often combined c to reduce abuse potential?

Homatropine (in antitussive products)
By CYP2D6 to a metabolite c some analgesic effects
What is the result of this metabolism?

Doesnt work well in pt on SSRIs (fluoxetine, paroxetine)
What is its scheduling classification?

Schedule II (alone) or schedule III (c acetaminophen)
What is oxycodone often combined with?

Acetaminophen (Percoset) or aspirin (Percodan)
CYP2D6

What is the schedule of oxycodone?
Schedule II
How is codeine often used?

As a cough suppressant
What is responsible for its analgesic effects?

Partial metabolism to morphine by CYP2D6
What is the schedule of codeine?

Schedule II (alone), III (when combined), IV (in antitussives)
What is the mechanism of pentazocine?

Kappa receptor agonist and receptor partial agonist
What is it used for?

Oral or IV administration for moderate pain
What advantage does it have?

Less sedating, less respiratory depression, fewer GI Sx, low abuse potential

What is the result of pentazocine being a receptor agonist?
May cause dysphoria
How might it act in a pt dependent on opioids?

May cause withdrawal due to partial agonist activity at receptors
What is the schedule?

IV
What is the mechanism of buprenorphine?

Partial agonist on and maybe
When is it normally used?

To reduce cravings in opioid addicts
Why is it often combined c naloxone?

Naloxone is not absorbed sublingually, which prevents pt from dissolving tablet in water and injecting solution

What is the mechanism of tramadol?
Weak agonist and inhibits reuptake of NE/5-HT
What are the Rx interactions?

With antidepressants seizures With MAOIs, SSRIs, TCAs serotonin syndrome
What is its schedule?

Not a scheduled Rx
What is the mechanism of dextromethorphan?

Blocks NMDA receptors and 5 -HT reuptake
What is the DOC in opioid overdose?

Naloxone
How is it administered?
Must be injected give until pupils dilate

What is the duration of action of naloxone?
Short duration (2 hrs) may require multiple doses in long-acting opioids
How does naltrexone differ?

It is effective orally and is long acting (24 hrs)
How is it used?
In recovering addicts to prevent them from getting high Also decreases cravings in recovering alcoholics
What is its adverse effect?

May cause liver toxicity c chronic use
How is nalmefene different?

Similar to naloxone c slightly longer duration and less liver toxicity
DRUG ABUSE
What is physical dependence?
Behavior and physical Sx occur if drug is withdrawn
DOES NOT indicate addiction
What is psychological dependence?

Dysphoria and intense craving occur following the withdrawal
What are pharmacokinetic and pharmacodynamic tolerance?

Pharmacokinetic tolerance due to metabolism of a drug Pharmacodynamic tolerance due to changes in receptor
What are the reward pathways in the brain?

DA is released from ventral tegmentum to different centers:
Nucleus accumbens: + reward and pleasure Frontal cortex: decision making, impulse control Amygdala: negative reward, fear
DRUG ABUSE
What is the mechanism of amphetamines?
Sympathomimetic promote release of newly synthesized catecholamines (NE, DA) presynaptically
What are the effects?

: alertness, energy, anxiety, irritability; appetite Psychosis may occur
How does smoking amphetamines affect the activity of the drug?

rapidity of action
What are the toxic effects?

Neurotoxic: persistent damage to dopaminergic and serotoninergic neurons Fatalities due to cardiac toxicity Dental problems meth mouth
What kind of tolerance and dependence occur c meth use?

Physical dependence occurs when brain creates a higher setpoint
Need more drug to feel normal
DRUG ABUSE
What are the signs of meth withdrawal?
appetite, need for sleep, energy. Intense craving c very slow recovery
Withdrawal is NOT life-threatening
What is the mechanism of cocaine?

Inhibits reuptake of DA and NE
What are the CNS effects of cocaine?

Alertness, euphoria, anxiety, hyperactivity
What are the peripheral effects?

Tachycardia, vasoconstriction, HTN, bronchodilation , temp, mydriasis
What are the chronic effects?

Nasal irritation, anxiety, paranoia, formication scratching skin into open sores
What are the lethal effects?

Ventricular tachy or fib, body temp, seizure Rapid rise in BP may lead to cerebral hemorrhage
DRUG ABUSE
What is the mechanism of nicotine?
Activates nicotinic receptors in CNS and periphery 5 -HT and DA release
What are the peripheral effects?

BP and HR, GI tone
What are the CNS effects?

DA and 5-HT release have antidepressant and reinforcing effects DA may activate endogenous opioid pathways Nicotinic activation memory, learning, and alertness
What type of dependence is seen?

Psychological and physical
What are the Sx of withdrawal?

Craving, irritability, anxiety, restlessness
How does opioid tolerance develop?

Receptor sensitization
DRUG ABUSE
What are the Sx of opioid withdrawal?
Restlessness, fever, chills, vomiting, piloerection, mydriasis
How does naltrexone work?

Blocks opioid receptors
What long -acting opioid is used for heroin and morphine addicts?
Methadone
What Rx can suppress opioid withdrawal Sx?

Clonidine
What is the mechanism of marijuana?

THC binds cannabinoid receptor and DA
What kind of dependence develops?

Psychological. Does NOT cause physical dependence
What are the adverse effects?

Paranoia, testosterone levels, sperm production and motility, bronchial irritation
DRUG ABUSE
What is the mechanism of LSD? What are the effects?
Binds to 5HT 2A or 5HT 1C receptors
Profound CNS effects c minimal peripheral actions:
Euphoria and visual hallucination Labile mood, bad trips c severe anxiety, or flashbacks may occur
What type of dependence does it produce?

NONE
What is the mechanism of MDMA?

Stimulates release/inhibits reuptake of 5HT; some in DA/NE release
What are the effects?

Peacefulness, empathy, feelings of closeness

Hyperthermia, dehydration , HR/BP, confusion, paranoia, panic
DRUG ABUSE
What happens c long -term MDMA use?
Degeneration of serotonin neurons leads to memory loss and depression
What is the mechanism of PCP/ketamine?

NMDA receptor antagonists
What are the effects of PCP?

Profound analgesia , aggression, hallucinations , slurred speech, mydriasis

Amnesia, coma, hyperthermia, rhabdomyolysis
What are the effects of ketamine?

Dissociative anesthesia floating, high doses cause delirium and amnesia

Tachycardia, hyperthermia, hallucinations, nystagmus
What are the effects seen c long term inhalant use?

Toxicity of liver, kidney, peripheral nerves, bone marrow depression, arrhythmias
DRUG ABUSE
What are the toxic effects of nitrous oxide?
Overdose results in unconsciousness and death Chronic use can cause peripheral neuropathy
What effect do amyl and butyl nitrite have in the body?

Smooth muscle relaxants
What changes are seen?

Hypotension c reflex tachycardia Euphoria, dilation of genital vessels for enhanced sexual pleasure
ANALGESICS AND ANTIINFLAMMATORIES

How are the eicosanoids made?
Long chain FAs are cleaved by phospholipase A 2 arachidonic acid Arachidonic acid (AA) cleaved by multiple enzymes:
Cyclooxygenases (COX-1 and COX- 2) thromboxane (TXA) and prostacyclin Lipoxygenases leukotrienes Other 2 routes not important for this lecture
How do COX-1 and COX-2 differ?

COX-1 is constitutively expressed , COX-2 is inducible COX-2 is an immediate early response gene whose expression is stimulated by growth factors, tumor promoters, and cytokines
Which is mainly responsible for prostacyclin synthesis in endothelial cells?

COX-2
What type of receptor do the eicosanoids bind to?

G-protein 2 nd messenger

What 2 G-protein receptors do they act on?
Gs: cAMP protein kinase phosphorylate Ca pumps intracellular Ca Gq : IP 3 free intracellular Ca
Vascular
TXA 2 mitogenic, vasoconstrictor PGE/PGI vasodilation by intracellular Ca
What are the effects of TXA and PGE/PGI on smooth muscle of vasculature, bronchial muscle, and GI?
Bronchial
TXA and PGF contract PGE/PGI relax
GI
Both cause cramps (longitudinal muscle contracted, circular muscle relaxed)

What is the source of PGs in semen?
Seminal vesicle function unknown but PG levels are high in fertile men
What is the function of PGE 1 on male genitalia?

Relaxes smooth muscles in corpus cavernosum to enhance erection
What are the roles of PG in females?

PGE 2 and PGF 2 have potent oxytocic actions that promote uterine contractions Soften the cervix by proteoglycan content and properties of collagen
How is it used pharmacologically?

For 1 st and 2 nd trimester abortion and priming cervix for abortion
How do PGs affect platelets?

May enhance or inhibit aggregation
What effect do they have in the kidneys?

GFR by vasodilation

What Rx will stimulate COX activity in the kidneys?
Loop diuretics
What Rx can diminish this effect?

COX inhibitors (like ASA)
What role doe PGs play in the ANS and CNS?

Produce fever Inhibit the release of NTs Facilitate release of TSH, ACTH, FSH, and LH
What effect do they have on bones

Facilitate bone resorption
What are the clinical uses of PGE 2 ?

Used for abortion, facilitating labor, and Tx of dysmenorrhea

What are the clinical uses of alprostadil (PGE 1 )?
Given intracavernosal or as urethral suppository for Tx of ED Used in pediatrics to keep PDA open before surgery
Penile pain and priapism
What are the side effects caused by PGE 1 used for ED Tx?
Trazodone also causes priapism
What are the uses of prostacyclin in the lungs?

Produce vasodilation in primary pulmonary HTN
Sildenafil and Bosentan also used
What is latanoprost and its action?

Analog of PGF 2 uveoscleral resorption of aqueous humor Topically in combo c timolol to produce complete additive synergism

What are the side effects of latanoprost?
Blurred vision, conjunctival hyperemia, foreign body sensation, iridial discoloration, irritation
What is the mechanism and use of zileuton?

Lipoxygenase inhibitor effective in asthma
How is montelukast different?

It is a leukotriene receptor inhibitor
What is the mechanism and use of misoprostol? Where does ASA act centrally to reduce fever and malaise?
Hypothalamus
PGE 1 analog reduces gastric acid secretion in ulcers
When is ASA not very effective?

As an analgesic in non-inflamed painful conditions
How does ASA affect body temp?

Lowers temp ONLY in febrile patients, but not normal patients

What is the ASA mechanism of action?
Irreversible inhibition of COX-1 and COX-2
How well does ASA cross placenta and the BBB?

Readily crosses placenta and slowly crosses BBB
What is the plasma concentration of ASA?

Low due to rapid hydrolysis
What Rx does it compete c for plasma binding sites?

T3, PCN-G, thiopental, bilirubin, phenytoin, naproxen
Low dose = 1 st order kinetics; high doses = zero order kinetics Excreted mostly by the kidney
How can renal excretion be promoted?

Alkalinization of the urine

What are all the pharmacodynamic effects of ASA?
Antiinflammatory, analgesic, antipyretic, inhibit platelet aggregation
How long do the effects on platelets last?

8-10 days (should be stopped 1 week prior to surgery)
What are its adverse effects on respiration?

Initial stimulation respiratory alkalosis, followed by depression acidosis
Due to the bleeding time, what pts should avoid ASA?

Hypothrombinemia, vit K deficiency, hemophilia, severe hepatic damage
What are the effects of ASA on uric acid excretion?

Low doses (1-2gm/day) uric acid excretion and plasma urate High doses (>5gm/day) uric acid excretion and plasma urate
What are adverse effects in the lungs?

Aspirin asthma due to synthesis of leukotrienes

What are the GI effects of ASA?
GI upset, gastritis, ulcers, bleeding, inhibit secretion of mucus, acid production
What can be used to protect the stomach in long term ASA therapy?
Misoprostol PG analogue
What are the adverse effects on the kidneys?

Renal damage, acute renal failure, interstitial nephritis, nephrotic syndrome
How can ASA affect male fertility?

PGs in semen that are necessary for sperm motility. Subfertile males may be adversely affected by ASA
What is a fatal dose that could cause acute salicylate poisoning?

20 grams
What are the signs of salicylism?

H/A, dizziness, tinnitus, thirst, hyperventilation, skin eruption, CNS problems Salicylate jag mental disturbance resembling EtOH inebriation s euphoria and elation

What are the ASA hypersensitivity rxns?
Skin rash, asthma, and anaphylactic rxns
What is Reyes syndrome?

Cerebral edema in children c viral infection caused by ASA
What is the DOC in children?

Acetaminophen
How do nonacetylated salicylates differ?

Effective anti-inflammatories c less analgesic effects than ASA and no irreversible COX inhibition
How does diflunisal differ?

Salicylic acid derivative that is NOT metabolized to salicylic acid
What is the prototype COX -2 specific inhibitor?

Celcoxib (Celebrex)
How does COX-2 inhibition differ?

It is reversible

What are the adverse rxns of celecoxib?
GI upset and ulceration (although less risk), hypersenstivity, risk of CV disease
What are the contraindications?

GI disease, asthma, breast feeding, pregnancy, renal failure, sulfonamide hypersensitivity
What is the non -specific NSAID c the best side effect profile?
Ibuprofen
What is the worst?

Indomethacin
What effect does indomethacin have on WBCs?

Reduces PMN migration

Inhibits phospholipase A
What is it often used for?

To maintain PDA

What is the advantage of sulindac?
Less nephrotoxic than other NSAIDs (but severe GI effects including pancreatitis)
What is the mechanism of diclofenac?

Potent COX inhibitor; AA bioavailability
What Rx is often combined c it?

Misoprostol to GI effects
What is ketorolac often used for?

As an analgesic in postsurgical pain
How is it administered and what is its 1/2 life?

Given orally, IV, or IM c a 1/2 life of 4 -8 hrs Often combined c opiates
What is its typical time frame of use?

After 5 days causes frequent GI upset

What happens when ibuprofen is combined c ASA?
Decreases the effect of ibuprofen
What is the mean plasma 1/2 life of naproxen?

13 hrs
How is it excreted?
Largely in the urine , but some in the feces
Who should not take it?

Pregnant women readily crosses placenta
What accounts for its adverse Rx rxns?

Extensively binds plasma protein, displacement causes adverse rxns
What effects does piroxicam have on WBCs?

Inhibits PMN migration and lymphocyte function Decreases oxygen radical production

What characterizes the pharmacokinetics of piroxicam?
Long half life, high incidence of GI side effects
What is unique about nabumetone?

Requires conversion to active metabolite Half life long enough for once daily administration Fewer adverse GI effects than others
What characterizes phenylbutazone?

Very potent c serious side effects, not marketed in U.S.
Why is acetaminophen preferred to aspirin?

Tolerated better, lacks ulcerogenics, blood clotting defects, ototoxicity, etc.
What happens c acetaminophen overdose?

Fatal hepatic necrosis

What is the plasma binding capacity of acetaminophen?
Low (20-50%)
How is it metabolized and secreted?

Metabolized in liver, conjugated, and excreted renally
What enzyme eliminates free radicals produced by acetaminphen?

GSH
How do its pharmacodynamics differ from the NSAIDs?

NO anti-inflammatory effects not effective as an antirheumatic
What is its antipyretic mechanism?

Inhibits the action of endogenous pyrogen @ the hypothalamus by inhibiting PG production
What dose is required for hepatotoxicity in adults?

10-15 grams (25 grams may be fatal)
When does the toxicity become serious?

When the metabolites exceed the available reduced glutathione in the body

What can increase the toxicity of acetaminophen?
Chronic EtOH consumption
What is the Tx of acetaminophen intoxication?

Gastric lavage, diuresis, hemodialysis N-acetylcysteine give parenterally w/in 10-12 hrs after intoxication
What is aurothioglucose (a gold salt) used for?

Inhibit phagocytosis, uncouple oxidative phsophorylation Stabilize lysosomal membranes and inhibit lysosomal enzymes React c proteins, inhibit proteolytic enzymes of leukocytes Prevent PG synthesis Suppress cellular immunity
What is its toxicity?

Bone marrow damage , dermatitis, enterocolitis , jaundice, neuropathy

What is penicillamine and its uses?
A chelating agent effective if RA and Wilsons disease
What may contribute to its antirheumatic effects?

Inhibits formation of collagen and circulating IgM rheumatoid factor
How does it differ from cytotoxic immunosuppressants?

Does not levels of absolute serum immunoglobulins
How does penicillamine affect lymphocytes?

Depresses T-cell activity but not B-cells
What are the adverse rxns?

Pruritis, rash, alteration in taste Pancytopenia, proteinuria, hypoalbuminemia Lupus like disease, Goodpastures , myasthenia gravis

What are the effects of hydroxychloroquine?
Antihistamine, anticholinesterase, antiprotease Inhibits PG synthesis, inhibits response to chemotactic stimuli and phagocytosis
Where is it concentrated in the body?

High affinity for melanin epidermis and retina
What is the half -life?

50 days
What is its toxicity?

Pruritis, hemolyis (G6PD deficiency), ototoxicity, retinopathy, neuropathy
How does sulfasalazine compare to penicillamine for Tx of RA?

As effective and less toxic
What should be monitored c sulfasalazine administration?

Hepatitis and marrow suppression

What is infliximab used for?
Crohns and RA when combined c methotrexate

Monoclonal Ab against TNF-
IV

Pregnancy, breast feeding, children, infections
What is the mechanism of rituximab?

IgG that binds to CD20 B-cells of non-Hodgkin lymphoma
What is the mechanism of adalimumab?

IgG for TNF- Approved for monotherapy of RA (unlike infliximab)

What is the structure of adalimumab?
100% human derived
Subcutaneously
What is the structure of etanercept (Enbrel)?

NOT a monoclonal Ab Made of extracellular binding portion of human TNF - receptor linked to human Fc portion of Ig
What is its action?

Binds TNF- but does not affect its production or serum levels
What are the pharmacokinetics?

Given subQ c 1/2 life of 102 hrs
What is the structure of abatacept?

Fully human recombinant fusion protein

Competes c CD28 (on T cell) for CD80/86 on APCs Disturbs inflammation and progressive joint destruction in RA May affect host defenses against infections and malignancies
What are its pharmacokinetics?

Given IV c a 1/2 life of 13 days
What is the mechanism of leflunomide?

Inhibits DHODH, an enzyme that catalyzes a step in de novo synthesis of pyrimidines Inhibition of cytokine and growth factor receptor tyrosine kinases Inhibits induction of COX-2
What is the mechanism of mycophenolate mofetil?

Prodrug for MPA that inhibits lymphocyte purine synthesis by inhibiting IMPDH
How is it given?
Orally or IV

What is the structure/action of anakinra?
Recombinant IL-1 receptor antagonist
GOUT
What Rx are used for acute gout attacks?
Colchicine and NSAIDs
What are primary causes of gout?

Over production of uric acid Underexcretion or uric acid
What are secondary causes of gout?

Accumulation of uric acid due to another disease (leukemia, polycythemia)
What is the pathogenesis of gout?

Deposition of uric acid tophi in peripheral joints are phagocytosed by synoviocytes that initiate an inflammatory rxn mediated by PGs and immune cells
What are the analgesic effects of colchicine?

NONE!
How does it urate?

It DOES NOT
GOUT
What is the mechanism of colchicine?
Binds to tubulin and inhibits the assembly of microtubules Inhibits leukocyte migration, phagocytosis, and formation of leukotriene B4
When is it used?
To reduce pain and inflammation in an acute attack Prophylactically at initiation of Tx c uricosuric agents
What are the pharmacokinetic properties?

Oral administration (IV: toxicity), effective in 12 -24 hrs

Diarrhea, N/V, abd pain
What is the primary NSAID used in gout?

Indomethacin
What others are also used?

Naproxen and sulindac
GOUT
What NSAIDs are contraind icated in gout and why?
ASA, salicylates decrease urate excretion
What is the mech an ism of uricosuric agents?

urinary excretion of uric acid by blocking active reabsorption in the proximal tubule
What are the uricosu ric agents?

Probenacid and sulfinpyrazone
How must the urine be modif ied c admin istr ation of uricosuric agents?
Maintain a pH >6.0 (alkalinize) and maintain large amounts to minimize the possibility of kidney stone formation
Why arent they used for acute attacks?

They can aggravate or trigger an attack
How is this avoided?

Give c prophylactic colchicine
What are the side effects?

GI irritation
GOUT
How is probenacid administered?
Orally, but not until 2-3 weeks after an acute attack
What are the Rx interactions?

Decrease excretion of many acidic compounds
PCN , methotrexate, glucuronides of NSAIDs
What are the additional interactions and adverse effects of sulfinpyrazone compared to probenacid?
Inhibits platelet aggregation and inhibits liver metabolism of warfarin
What are the xanthine oxidase inhibitors?

Allopurinol and febuxostat

Vasculitis, agranulocytosis, and hypersensitivity
What Rx are they often administered with?

Colchicine to prevent an acute gouty attack
GOUT
What are the Rx interactio n of allopurino l/ f ebux ostat?
Aluminum hydroxide the absorption of allopurinol effect of chemotherapeutic mercaptopurines the effect of cyclophosphamide Inhibits elimination of chlorpropamide Inhibits metabolism of warfarin and probenacid Inhibits activation of fluorouracil
What is rasburicase and its mech an ism

Recombinant form of urate oxidase (not found in humans) Catalyzes oxidation of uric acid to allantoin , a readily secreted metabolite
When is it often used?

To prevent tumor lysis syndrome after initiation of chemotherapy
How is it given?
IV infusion

Severe hypersensitivity rxns (anaphylaxis), N/V/D/C, fever, H/A
MIGRAINES
What is the mechanism of migraines?
First phase of vasoconstriction of intracranial arteries causing ischemic changes Second phase is vasodilation of extracranial arteries causing the H/A due to release of vasoactive materials
What is the prototype -triptan ?

Sumatriptan
What is its mechanism of action?

Selective 5-HT 1D agonist of intracranial vessels causing vasoconstriction and release of sensory neuropeptides
What are the pharmacokinetics?

Give PO or SC 1/2 life is 2 hrs; H/A recurs w/in 24-48 hrs
What are the toxicities?

Coronary artery vasospasm, arrhythmias, cerebral vasospasm intracranial bleed Peripheral or bowel ischemia, GI upset
MIGRAINES
What is the mechanism of ergotamine tartrate?
Vasoconstriction:
Partial agonist on 5-HT receptors Partial agonist on 1 receptors
How are the ergot alkaloids administered?

Orally, inhalation, sublingual, or parenteral routes

More potent vasoconstrictor than the -triptans :
Acute: N/V/D, CV toxicity Chronic: ergotism + CNS Sx

Thromboangiitis obliterans, atherosclerosis, severe HTN, ischemic heart disease, etc. Allergy, renal or hepatic disease, malnutrition, peptic ulcers. pregnancy
MIGRAINES
What are the characteristics of dihydroergotamine?
Similar to ergotamine, given IV
When is methylsergide used?

In migraine prophylaxis

It is an ergot alkaloid (5-HT partial agonist) but a weak vasoconstrictor
What are its pharmacokinetic properties?

High first pass metabolism 13% bioavailability
What are other Rx used for prophylaxis?

Beta blockers (propranolol), Ca channel blockers (verapamil), antidepressants (amitriptyline), clonidine, anticonvulsants ( valproic acid, topiramate), botox, ARBs

Pharmacology Exam 2 PP

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Pharmacology Exam 2 PP

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PHARM EXAM 2

Which form is more effective at the Na receptor?

How do LAs enter the nerve cell and act?

What effect does inflammation have on the effect of LAs?

What is the role of co -injection c epinephrine?

What are the esters?

What are the amides?

How are amides metabolized?

How are esters metabolized?

How are LAs excreted?

What factors will binding?

What are the effects of Ca and K on the effects of LAs?

How do nerves themselves affect LA actions?

What is the purpose of adding sodium bicarb or CO 2 to LA?

Where does LA instillation take place?

What is regional anesthesia?

Which Rx have a short duration of action?

Which have intermediate duration?

Which are long-acting?

What is the result of cardiovascular toxicity?

Which LA does not have ( -) inotropic effects and vasodilation?

Which is the most cardiotoxic?

Which LA may cause a blood toxicity and what is the Tx?

Which LAs may cause allergic rxns?

What is its duration of action?

What is the metabolite of procaine and its action?

When is it used topically?

What is the relative time of onset and action of tetracaine?

What is tetracaines potency relative to procaine?

What type of preparation is used topically?

What is benzocaine ( Americaine) used for?

When is cocaine used?

What ANS effect does cocaine have?

When should cocaine be used cautiously?

What is the regulatory classification of cocaine?

When is lidocaine preferred?

What are its pharmacokinetic properties?

What is another use of lidocaine?

When is prilocaine used?

When should prilocaine be avoided?

What is the duration of action of bupivacaine?

What makes it stand out from other amides?

What Rx resembles bupivacaine, but is less arrhythmogenic?

How does its metabolism differ from bupivacaine?

What are ropivacaines possible Rx interactions?

What Rx causes it?

How is depth of anesthesia assessed?

What IV general anesthetics are used?

Act at the GABA A receptor

What is the effect of inhaled anesthetics?

What is the potency of inhaled anesthetics related to?

What are the stages of anesthesia?

What are the effects on BP?

What are the effects on respiration?

How do they affect body temp and why is it of concern?

What is a common postoperative Sx?

Which Rx is least likely to cause N/V?

What Sx occur on emergence from anesthesia?

What is used to Tx the excitement?

What is used to express solubility of a gas?

What does this coefficient represent?

How does blood solubility affect rate of delivery to the brain?

How can emphysema affect inhaled administration?

How does pulmonary blood flow affect induction of anesthesia?