9.1 Which class of drug is more clinically useful: GABA agonists or antagonists? NMDA agonists or antagonists? Why?

GABA receptors are the major inhibitory neurotransmitter in the CNS. Therefore when you stimulate them, they cause sedation and anxiolysis by allowing Chloride (anion) into the cells causing hyperpolarization.

GABA agonists are more useful clinically for sedation, to provide anxiolysis, and some drugs even have anticonvulsant activity. (Ex. Benzodiazepines, barbiturates)

GABA antagonist are not clinically useful. They are used in the lab to mimic seizures for research.

NMDA-glutamine receptor stimulation in the CNS appears to be critical for the formation of certain memories; however, overstimulation of these receptors has an excitotoxic effect (by allowing too much Na and Ca ions to enter the neuron) and is suggested to be a mechanism for neurodegenerative or apoptopic processes.

NMDA receptor antagonists are more important clinically because they are considered to be neuroprotective. They block the NMDA receptors which prevents overstimulation. Ex. Memantine (used for Alzheimer’s disease), Riluzole (ALS treatment), Ketamine (anesthetic), Nitrous oxide, PCP, Methadone, Tramadol, among many others.

NMDA agonists are not clinically useful. They are mainly used in research.

9.2 What are the mechanism of action and therapeutic uses of benzodiazepines?

The mechanism of action of Benzodiazepines is that of a GABA agonist. They cause their effects binding to a specific high-affinity site located at the interface of the alpha and gamma-2 subunit on the GABA receptor. This binding to GABA leads to an increase in chloride (anion) conductance, which causes hyperpolarization of the cell and therefore, a decrease in excitability.

Therapeutic uses include: Anxiety disorders: (panic disorder, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, anxiety/depression of schizophrenia, and extreme anxieties with specific phobias.)

Muscular disorders: skeletal muscle spasms, such as occur in a muscle strain (diazepam), and treating spasticity from degenerative disorders, such as in multiple sclerosis and cerebral palsy.

Amnesia: premedication for procedures and also for use during conscious sedation.

Seizures: Epilepsy maintenance treatment (clonazepam), diazepam and lorazepam are the drugs of choice for terminating grand mal epileptic seizures and status epilepticus. Also useful in preventing alcohol withdrawal seizures.

Sleep disorders: flurazepam (Dalmane), temazepam (Restoril), and triazolam(Trilam). (Not the preferred drugs.)

9.3 Briefly outline the pharmacology of flumazenil? How does flumazenil compare to physostigmine? Flumazenil (Romazicon) is a GABA-receptor antagonist. It causes reversal of the benzodiazepines effect by competitive inhibition at the GABA receptor. Therefore, it is used as an antidote and reversal drug. It is only available as an IV drug with a rapid effect and short half-life.

These are very good answers.

Flumazenil may precipitate an acute abstinence (withdrawal) reaction in patients addicted to benzodiazepines, and, it may also induce seizures. Because it has a short duration of action, repetitive dosing may be required when administered for reversal of long-acting benzodiazepines.

Physostigmine (Antilirium) is an indirect acting cholinergic agonist. It causes these effects by inhibiting acetylcholinesterase. It is a tertiary amine so it can cross the blood brain barrier with ease. Physostigmine may be used to antagonize the delirium and CNS depressant effects of benzodiazepines; therefore, it could be useful to manage undesired effect of benzodiazepines. Little is known about how these actions occur but studies suggests that it may cause an additive effect of the two neurotransmitter systems rather than a direct interaction at the central receptor sites. Physostigmine should not be used in the instance of a benzodiazepine overdose because of it is nonspecific and has a potential toxicity. Flumazenil is the drug of choice for benzodiazepine reversal.

Note: If you administer physostigmine to patients confused or comatose from high doses of benzodiazepines or anticholinergics (this includes TCAs, atropine and scopolamine), the confusion will improve and often they will wake up from a drug-induced coma (this is where the name Antilirium comes from). It makes sense that physostigmine will counteract CNS side-effects of anticholinergics. What is not intuitive, but interesting, is that if you increase ACh levels with physostigmine, you can also counteract symptoms of benzodiazepines (which do not work on ACh receptors) and that increasing CNS ACh levels helps patients with Alzheimer's Disease.

9.4 What is GHB? Name two receptor classes that may mediate the actions of GHB.GHB (gamma-hydroxybutyrate) is a naturally occuring substance found within the body. Used as a general anesthetic as well as to treat insomnia, clinical depression, narcolepsy, and alcoholism. It is also used as an intoxicant and is otherwise known as "the date rape drug"

GHB is an agonist at the GHB receptor, which is excitatory and it is a weak agonist at the GABA-B receptor, which is inhibitory.

9.5 Why is the half-life of midazolam less than that of diazepam (hint: volume of distribution or clearance)?Midazolam and diazepam have similar volumes of distribution but midazolam (Versed) has a high clearance and diazepam (Valium) has a low clearance comparatively. Midazolam (Versed) also has a significantly higher hepatic clearance when compared to diazepam (Valium).

These last two sentences are stating the same thing. Total body clearance = sum of all individual organ clearances (hepatic + renal + ...). Since these drugs are primarily cleared by the liver, the fact that midazolam has a higher hepatic clearance implies that it will also have a higher total body clearance.

9.6 Compare the mechanisms of action and side-effects of benzodiazepines, barbiturates, buspirone, and hydroxyzine? Benzodiazepines: *Mechanism of Action: Bind to the gamma sub-unit of the GABA-A receptor. Their binding causes a structural modification of the receptor that results in an increase in GABA-A receptor activity.*Side effects: Confusion, Hallucinations, Difficulty swallowing or breathing

Barbiturates: *Mechanism of Action: Bind to the GABA-A receptor at the alpha subunit. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor as well as block the AMPA receptor, a subtype of glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the CNS.*Side effects: depression, confusion, or unusual excitement

This is correct. - JM

(The following is an answer submitted last year that explains this a bit differently). GABA is a neurotransmitter that when bound to its receptor allows for an influx of Cl- ions into the cell. This leads to hyperpolarization of the cell. Benzodiazepines bind to GABA receptors and enhance the effect of the GABA stimulation. Greater influx of Cl- makes it even more difficult for the cell to depolarize. SE include: drowsiness, confusion, ataxia (at high doses). Barbiturates also potentiate the effects of GABA stimulation, but the mechanism is different from benzodiazepines. Barbiturates increase the duration of the opening of the Cl- channel which also leads to difficulty in depolarization. Additionally, barbiturates can block excitatory glutamate receptors. This leads to decreased neuronal activity. SE include: drowsiness, impaired concentration, mental /physical sluggishness (synergistic with the effects of ethanol).

Buspirone: *Mechanism of Action: Buspirone binds to 5-HT type 1A receptors thus inhibiting the firing rate of 5-HT-containing neurons. Buspirone also binds at dopamine type 2 (DA2) receptors, blocking presynaptic dopamine receptors*Side effects: headaches, dizziness, nervousness, light-headedness

Buspirone is an antianxiety medication that is useful because it is not sedating and there is no cross-tolerance with other sedatives. It does not have muscle relaxant or anticonvulsant effects.

Hydroxyzine: *Mechanism of Action: Hydroxyzine blocks histamine H1-receptors. Hydroxyzine competes with histamine for binding at H1-receptor sites on the effector cell surface, resulting in suppression of histaminic receptors*Side effects: dizziness, hallucinations, decreased breathing, fatigue, drowsiness, nausea, vomiting, dry mouth and diarrhea

Hydroxyzine is a drug that is good for anxiety in patients with a history of substance abuse. It is also useful because it has anti-emetic properties.

9.7 A patient with a brain tumor has a grand mal seizure as he is entering the operating room. What drugs could you use to treat this seizure?

Diazpeam and lorazepam

Other drugs that you will have available include midazolam, thiopental (a barbiturate) and inhalational agents like isoflurane. You could stop the symptoms of a seizure with a muscle relaxant but NDMRs will have no effect on seizure activity in the brain. Of all these drugs, isoflurane is the most powerful anti-seizure medication you have available. Other traditional antiseizure medications like phenytoin are also available in the OR.

9.8 Very briefly discuss the mechanism of action and indications for zolpidem, zaleplon, ramelteon and chloral hydrate.

Zolpidem: GABAa receptor agonist; used for short-term treatment of insomnia; onset of action 15 minutes and has half-life of 2-3 hours

Zaleplon: GABAa receptor agonist; used in the short-term treatment of insomnia; rapid onset of action and very short half-life of 1 hour

Ramelteon: selective MT1 and MT2 agonist in the suprachiasmatic nucleus, produces a melanin effect of inducing sleep; indicated for long-term treatment of insomnia when the primary complaint is falling asleep. Note, MT receptors are melatonin receptors. - JM

Chloral hydrate: trichlorinated derivative of acetaldehyde that is converted to the active metabolite trichloroethanol, which enhances the GABA receptor complex; it is used for short-term treatment of insomnia and for sedation before minor medical or dental procedures

9.9 Briefly summarize the pharmacology of ethanol.

Binds to acetylcholine, GABA, serontonin, and NMDA receptors. Metabolism is limited in the body, so ethanol leaves the body at a constant rate, rather than by following an elimination half-life. It is metabolized in the liver and excreted mainly in the kidneys.

Ethanol is metabolized by zero-order kinetics and not first order kinetics. Other notable drugs that are metabolized by zero-order processes are aspirin and phenytoin.

Ethanol has anxiolytic and sedative effects, but has high toxic potential. It's effects are seen at a range of doses and volume of distribution is almost the same as that of total body water. When combined with other sedative/hypnotics, CNS depression can be severe.

Chronic ethanol consumption can lead to liver disease and nutritional deficiencies. Ingestion of too much can lead to cardiomyopathy ("holiday heart"). Withdrawl symptoms can be severe.

In general, body water composition is greater in men than women, greater in younger people than older people, and greater in lean patients than in obese patients. When administered according to weight, peak blood alcohol levels will be lower in those people with larger body water compartments. This is also true of other water soluble drugs like succinylcholine.

Be able to discuss questions 9.1 - 9.4 on page 116.

The pharmacology of alpha-2 agonists and antagonists was presented in chapter 6. You are responsible for knowing the mechanism of action of clonidine (Catapres) and dexmedetomidine (Precedex) and 2 important indications of these drugs - sedation and treatment of hypertension.

Know that barbiturates are weak acids, are highly protein bound, inhibit GABAa receptors, they are highly lipid soluble, they are metabolized by Phase 1 microsomal oxidative enzymes in liver, they may induce hepatic microsomal enzymes, and that like benzodiazepines their effects wear off by redistribution, they reduce ICP, and they may cause hypotension (vasodilation greater effect than negative inotropism).

ANESTHESTHETICS

Be prepared to discuss questions at the end of chapter 11 and all figures in this chapter. There may be one graph on this test - a graph of Fa/Fi versus time that will be very similar to Figure 11.6. This will be discussed in class. You will be expected to know the difference in the Fa/Fi curves for the commonly used inhalational anesthetic agents. Figure 11.10 is a bit misleading - note that thiopental, opioids, propofol and etomidate all lower ICP.

11.1 What is Malignant Hyperthermia (MH)? Describe the presenting symptoms and progression of MH. Who is at risk for MH and what is the treatment of an acute episode of MH?

MH is primarily thought to be an autosomal dominant genetic disorder that causes a hypermetabolic state after administration of volatile anesthetics (i.e. halothane, sevoflurane, isoflurane, desflurane, enflurane) and succinylcholine. The reported incidence ranges from 1:3000 to 1:65000. Conditions such as Duchenne dystrophy, Central Core Disease, Osteogenesis Imperfecta, and burns may also cause MH. Interestingly, an increase incidence has been reported in Wisconsin, Nebraska, West Virginia, and Michigan. Those at risk are patients who have had previous problems with anesthesia, or patients with an immediate family member who has had anesthesia problems.

MH is caused by an abnormal release of calcium in the sarcoplasmic reticulum, usually caused by a defect of the ryanodine receptor. The increased intracellular calcium causes sustained muscle contraction, hypermetabolism, ATP depletion, heat production, and eventually cell death.

The early signs of MH include: unexplained increased ETCO2 and decreased SpO2, hypoxemia, tachycardia, hypertension, and muscular rigidity (specific sign). As MH progresses, acidosis, elevated body temperature, hyperkalemia, rhabdomylosis, myoglobinuria, and dysrhythmias are common. Symptoms usually occur within one hour of administration of triggering substance, although in rare cases, several hours have elapsed.

Treatment of MH includes: call for help, stop volatile agents, hyperventilate with 100% O2, give Dantrolene which blocks the release of calcium from the SR, finish or abort surgical procedure, cool the patient, change to a clean anesthesia circuit, treat hyperkalemia, treat acidosis, increase urinary output.

Know: (1) the ryanodine receptor is located within sarcoplasmic reticulum, (2) dantrolene blocks release of calcium from sarcoplasmic reticulum and (3) dantrolene is first line therapy for MH. - JM

11.2 For each of the following inhalational anesthetics, describe MAC, blood-gas solubility, and the clinical pros and cons of the agent: Nitrous Oxide, Ether, Cyclopropane, Halothane, Isoflurane, Sevoflurane, Desflurane, Xenon

MAC is the minimum concentration necessary to cause unresponsiveness in 50% of the general population (variable age, co-morbidities, metabolism). The higher the MAC, the less potent the anesthetic. Blood-Gas Solubility refers to how soluble the agent is in the blood. The lower the solubility, the faster the onset and recoveryNitrous Oxide: MAC 105, BGS 0.47Clinical Pros: moves very rapidly in/out, provides “second gas effect” for other agents, good analgesia, minimal CV effects, least hepatotoxic, does not trigger MHClinical Cons: Increases ICP and CBF (according to Morgan & Mikhail, not Lippincott), weak general anestheticEther: MAC 2.0%, BGS 12Clinical Pros: rarely used in the U.S. (still used in 3rd world countries), little respiratory depression or CV effects, bronchodilitationClinical Cons: flammable, slow onset/recovery, secretions, PONVCyclopropane: MAC 0.77, BGS unavailableClinical Pros: very low blood solubility, favorable pharmacokineticsClinical Cons: No longer available, highly explosive

Halothane: MAC 0.75, BGS 2.3Clinical Pros: no chronotropic effect (SA node), no dromotropic effect (AV node), potent, non-flammableClinical Cons: highly arrhythmogenic, increases CBF and ICP, hypotension, hepatotoxic

Isoflurane: MAC 1.2, BGS 1.4Clinical Pros: dilates coronary vessels, not tissue toxic, not arrhythmogenicClinical Cons: positive chronotrope (SA node), hypotension, increase CBF and ICP

Sevoflurane: MAC 2.0, BGS 0.65Clinical Pros: non-irritating to airways (useful for children), fast onset/recovery (recovery is not fast, similar to isoflurane - JM)Clinical Cons: positive chronotropy (SA node), increases CBF and ICP, nephrotoxicity (nephrotoxic effects are debatable - JM)

Desflurane: MAC 6.0, BGS 0.42Clinical Pros: fast onset/recovery (fastest of all available volatile anesthetics - JM)Clinical Cons: positive chronotropy, increases CBF and ICP, pungent/airway irritant

Xenon: MAC 70, BGS 0.115Clinical Pros: lowest BGS, rapid induction/recovery, no MH, little CV effects, non-toxic, produces unconsciousness with analgesia, some muscle relaxation, neuroprotection, environmentally friendly (only agent on this list that is not a major greenhouse gas)Clinical Cons: High cost, complex delivery systems necessary for administration

*Note: All of these agents decrease blood pressure (except Nitrous and Xenon) and decrease SVR (exception Halothane, Nitrous, Xenon). All increase CBF and ICP (according to Morgan & Mikhail). All increase respiratory rate and decrease tidal volume. All decrease renal and hepatic blood flow.

Very good answer. Know which agents may be used in patients with MH. – JM

11.3 How can you speed inhalational induction of anesthesia?

During induction of anesthesia, a gradient of anesthetic partial pressure develops such that the partial pressure of the anesthetic in the lungs exceeds the partial pressure of the anesthetic in arterial blood, which in turn exceeds the partial pressure of anesthetic in the brain. A key concept to grasp is that anesthetic induction will be increased as more anesthetic is delivered to the lung or as less anesthetic is removed from the lung. The partial pressure of the anesthetic in the lung is the principle force driving the anesthetic into the body.

So, factors that increase the rise in anesthetic partial pressure in the lung will speed this process. Important factors include increasing minute ventilation, delivering unusually high concentrations of anesthetic agents (i.e., overpressure), using high gas flows or non-rebreathing anesthetic systems, and having a reduced FRC (functional residual capacity). Coadministering high concentrations of nitrous oxide may also speed induction through the concentrating effect and/or second-gas effect.

Also, factors that decrease the rate at which anesthetics are removed from the lung will speed this process. There are two important factors to consider - cardiac output and the lipid solubility of the anesthetic agent. High cardiac output and high lipid solubility of the anesthetic will slow induction (because anesthetic partial pressure in the lung will rise more slowly), while avoiding high cardiac output and selecting agents with a low blood:gas solubility will increase the rate of induction.

11.4 Describe the concentrating effect and second-gas effect?1) Only occur on induction of anesthesia2) Describes processes whereby the delivery of an inhalational anesthetic can be enhanced by the presence of a large amount of nitrous oxide.3) Second-gas effect: when a volatile inhalational anesthetic is given with a large concentration of nitrous oxide (for example, this could be 76% N2O, 20% O2 + 4% Sevoflurane), the rapid uptake of nitrous oxide from the alveoli creates a negative pressure that draws more gas into the lung.4) Concentrating Effect: during induction, much more nitrous oxide is absorbed from the alveoli than O2 or volatile anesthetic (eg, sevoflurane). If you measure the concentration of various gases in the alveoli after much of the nitrous has been absorbed you will find that the % O2 and % volatile agent are increased.

The second gas effect brings more anesthetic into the alveoli, the concentrating effect increases the alveolar concentration of O2 and volatile anesthetic.

11.5 What are the Induction, Maintenance and Emergence (or Recovery) phases of anesthesia?Induction - the administration of a drug or combination of drugs at the beginning of an anesthetic that results in a state of general anesthesia.

Maintenance – the drugs used to initiate the anesthetic are beginning to wear off, and the patient must be kept anesthetized with a maintenance agent. In this stage the patient must be kept anesthetized enough so the surgeon may perform the operation.

Emergence – Reversing the NMB’s if used, and allowing the patient to wake up. The process of emergence starts several minutes before the surgical team is done. Good communication should be kept with the surgeon to know when to turn off gasses/NMB’s/and so the anesthesia provider can dose narcotics appropriately.

11.6 In 1937 Arthur Guedel published a Depth of Anesthesia Classification System. This original system was described for ether anesthesia following morphine and atropine premedication. It is important to realize that muscle relaxants were not commonly employed in 1937. Describe Guedel's classification system and other limitations of this system.

There are basically four stages of anesthesia. A patient should be kept in stage 3 or less for reasons shown below. A limitation to this scale is it does not take into account that NMB's can be given, thus all muscle movement will stop. This does NOT mean that the patient is anesthetized or their pain is at an appropriate level. Administration of NMB's simply means the patient can not move.

Stage I (Stage of Analgesia or the stage of Disorientation): from beginning of induction of anesthesia to loss of consciousness. Note - late in stage 1 there is usually amnesia. - JM

Stage II (Stage of Excitement or the stage of Delirium): from loss of consciousness to onset of automatic breathing. Eyelash reflex disappear but other reflexes remain intact and coughing, vomiting and struggling may occur; respiration can be irregular with breath-holding.

Stage III (Stage of Surgical anesthesia): from onset of automatic respiration to respiratory paralysis. It is divided into four planes:Plane I - from onset of automatic respiration to cessation of eyeball movements. Eyelid reflex is lost, swallowing reflex disappears, marked eyeball movement may occur but conjunctival reflex is lost at the bottom of the planePlane II - from cessation of eyeball movements to beginning of paralysis of intercostal muscles. Laryngeal reflex is lost although inflammation of the upper respiratory tract increases reflex irritability, corneal reflex disappears, secretion of tears increases (a useful sign of light anesthesia), respiration is automatic and regular, movement and deep breathing as a response to skin stimulation disappears.

Plane III - from beginning to completion of intercostal muscle paralysis. Diaphragmatic respiration persists but there is progressive intercostal paralysis, pupils dilated and light reflex is abolished. The laryngeal reflex lost in plane II can still be initiated by painful stimuli arising from the dilatation of anus or cervix. This was the desired plane for surgery when muscle relaxants were not used.Plane IV - from complete intercostal paralysis to diaphragmatic paralysis.

Stage IV: from stoppage of respiration till death. Anesthetic overdose cause medullary paralysis with respiratory arrest and vasomotor collapse. Pupils are widely dilated and muscles are relaxed.

Very Good answer. All this info will not be on the test but anyone administering anesthesia should be aware of the stages and planes of ether anesthesia. Note that these stages and planes only really apply to ether anesthesia. For example, 5 stages were described for chloroform anesthesia. You will hear people commonly talk about Stage II for modern anesthetics but this is not technically correct. It is more correct to refer to "excitement stage" than "Stage II" when talking about modern agents. For almost all anesthetics you will have similar stages: first is analgesia (nitrous oxide is given in dental offices for analgesia, not for anesthesia), then a drunken/confused/delirious/excited stage, then surgical anesthesia, and finally medullary paralysis (body does not regulate breathing, bloodpressure, etc). – JM

11.7 What are common features of modern inhalational anesthetics?Non-flammable and non-explosiveDecrease cerebrovascular resistance resulting in increased perfusion of the brainCause bronchodilationDecrease minute ventilationDecrease hypoxic pulmonary vasoconstrictionMovement throughout the body depends on their solubility in blood & tissues as well as blood flow

11.8 Describe the pharmacology and indications for ketamine. Ketamine is a short acting, non-barbituate anesthetic that induces a dissociated state in which the patient is unconscious but appears to be awake and does not feel pain. It provides sedation, amnesia, and immobility. It works by interacting with the N-methyl-D-asparate receptor. It is Lipophilic and enters brain circulation very quickly. It is metabolized by the liver; in small amounts it can be excreted unchanged.

It is not widely used because it increases cerebral blood flow and induces postoperative hallucinations

Ketamine stimulates sympathetic outflow-->stimulates the heart-->increases blood pressure and cardiac output. Therefore it is used when circulatory depression is undesireable; i.e. hypovolemic/cardiogenic shock as well as patients with asthma.

Know that "the interaction with NMDA receptor" = ketamine is an NMDA antagonist.

Ketamine is a short-acting, lipophilic, non-barbiturate anesthetic. It acts as an uncompetitive NMDA receptor antagonist thus causing anesthesia. Ketamine also binds to opioid receptors giving it an analgesic effect. Indications for Ketamine are based on its capacity to stimulate sympathetic outflow which causes increase heart rate, blood pressure and cardiac output. This property is of value for patients with hypovolemic or cardiogenic shock as well as patients with asthma..

11.9 Local anesthetics:a) How are local anesthetics classified? Local anesthetics are classified in two ways: 1. Chemical structure and 2. Duration of ActionChemically there are divided into two groups determined by the molecule attached to the intermediate chain of the molecule: they are either amides or esters. The ester type local anesthetics go through rapid hydrolysis by plasma cholinsterases, thus making it less toxic due to its rapid metabolism. However, ester type local anesthetics have a short duration due to their rapid metabolism. The amides types of local anesthetics are broken down in the liver. Amide types of local anesthetics require hepatic extraction therefore can lead to higher blood concentration causing toxicity. Ester-type local anesthetics contain para-amino benzoic acid (PABA) (cocaine is only exception: it contains benzoic acid, not para-amino benzoic acid).

Duration of action include three subtypes:1. Short duration: lasting 30 to 60 minutes2. Intermediate duration: lasting 60-120 min3. Long acting duration: lasting 2-6 hours

Clinical duration can be dependent on dosage, site of injection, and use of vasopressors.

b) What is the mechanism of action of local anesthetics? Local anesthetics bind to voltage gated sodium channels from the INSIDE of the cell, leading to inactivation of the voltage gated sodium channel. This prevents subsequent channel activation leading to influx of sodium intracellularly causing depolarization.

In order of LA’s to be stable in a solution, it is a placed with a hydrochloride salt. When the drug is injected, it is water soluble (ionized), and therefore unable to penetrate the lipid bilayer of the neuron. A drug’s time of onset is dependent on its’ pKa, which is the measurement of pH when which the drug is 50% ionized and 50% non-ionized. The non-ionized fraction, which is the lipid soluble, diffuses intracellularly thru the neuronal lipid membrane, and equilibrated back into its ionized form. As the non-ionized fraction move intracellularly, the concentration of non-ionized fractions increases within the neuronal cell. In attempts to maintain balance inside the neuron, the non-ionized fraction converts back to its ionized state. It is the ionized state which attaches to the gated sodium channel, thus preventing the nerve to reach an action potential by inhibiting sodium influx.

Local anesthetics are weak bases with ranging pH’s approximately from 7.8-9.0. Therefore a drug’s pKa that is closer to normal physiological pH (7.35-7.45) will have faster onset because they will have a higher concentration of non-ionized fractions that can pass the lipid membrane upon LA injection. It is important to note that although a pKa of a LA may be more basic than other LAs, it does not mean that the more basic LA cannot eventually be absorbed. Since the concentration of non-ionized fractions are depleting extracellularly, the ionized fractions will create more non-ionized fractions to maintain a dynamic balance.The pH only delays the process. Thus if the pH is more acidic, it provides more time for LA to be taken up by the circulation causing adverse systemic effects.

Very important!LAs with a low pKa have a faster onset of action.LAs with high protein binding have a longer duration of action.LAs with high lipid solubility are more potent and have a longer duration of action.Fast onset of action then low pKa.High potency then high lipid solubilityLong duration of action then high lipid solubility + high protein binding.There is only one set of doses you must memorize:The dose of lidocaine when given iv = 1 - 1.5 mg/kgThe maximum lidocaine dose when administered s.q. = 5 mg/kgThe maximum lidocaine dose when administered s.q. with EPI = 7 mg/kg

c) Do these actions involve ligand-gated channels?No, they act on voltage gated sodium channels.

d) Which nerve fibers are more resistant to local anesthetics? All nerve fibers are sensitive to LA, but nerve fibers that are larger in diameter and are myelinated tend to be more resistant to LA. From high sensitization to low sensitization: small myelinated axons, nonmyelinated axons, large myelinated axons.

e) How are local anesthetics metabolized?The mechanism of local anesthetics differ depending on their structure: Ester or Amide

Ester type local anesthetics are metabolized via hydrolysis rapidly by pseudo cholinesterase. Hydrolysis is very rapid, and the water soluble metabolite is excreted thru urine.

Amide type local anesthetics are metabolized by P-450 enzymes in the liver. The rate of amide metabolism is dependent on the drug, but overall metabolism is much slower than those of the ester LA. Since metabolism is slower than ester LA, amide LA are can lead to toxicity, esp. in patients with hepatic insufficiency.

Actually not entirely true. The amount of metabolism of lidocaine and some other amides is limited by liver blood flow. If there is more liver blood flow, clearance is increased (and vice versa).

Note, oxidative metabolism is Phase 1 reaction; conjugation and hydrolysis reactions are Phase 2. Phase 1 more complex than Phase 2 -- patients with liver disease (eg, cirrhosis) are more likely to have problems metabolizing an amide like lidocaine than an ester like tetracaine.f) What are the toxic effects of local anesthetics. What is the role of intralipid in the treatment of local anesthetic toxicity? LA toxicity involves the CNS and Cardiovascular system:

CNS: As plasma concentration continues to increase, symptoms of restlessness, vertigo, and tinnitus occur. Further increases in the CNS result in slurred speech and skeletal muscle twitching, which are signals of the imminence of tonic-clonic seizures.

CV: Toxic levels can lead to hypotension due to relaxation of arteriolar vascular smooth muscle and direct myocardial depression. When plasma LA concentrations are excessive, sufficient cardiac sodium channels become blocked so that conduction and automaticity become adversely depressed.

Intralipid (fat emulsion) has been used to treat cardiovascular collapse in LA toxicity. Mechanism of action is unclear, but hypothesized to increase fatty acid delivery to the heart for energy metabolism. Mechanism is that the lipid soluble local anesthetic drugs partition out of plasma and into lipid after intralipid is administered. As plasma levels of the drug fall, toxic symptoms improve.

Prilocaine is a local anesthetic that is metabolised to o-toluidine. This metabolite may cause methemoglobinema. The treatment of methemoglobinemia is i.v. methylene blue.

g) How does adding bicarbonate solution or epinephrine affect the pharmacokinetics of local anesthetics? Explain.LA are commercially prepared as water-soluble hydrochloride salt with a pH of 6-7. Since epinephrine is unstable in alkaline environments, epinephrine containing LA solutions are made even more acidic to a pH of 4-5. As a consequence, these concentrations have a lower concentration of free base (non-ionized fractions) therefore slower onset in comparison to when a clinician adds epinephrine at the time of use. Adding epinephrine produces vasoconstriction at the site of administration. This allows increase of neuronal uptake, enhances quality of analgesia, prolongs duration of action, and limits toxic side effects.

The addition of sodium bicarbonate to epinephrine containing LAs have been known to cause alkalinization of the LA solution therefore speeding onset, improving quality of the block, and prolonging blockage by increasing the amount of free base available in the solution.

Bicarb causes local anesthetics to begin working faster, EPI increases duration of action.

11.10 If patient is highly allergic to sunscreen, which of these local anesthetics would you not administer: procaine (Novacaine), tetracaine, lidocaine, bupivacaine (Marcaine), mepivacaine, prilocaine, ropivacaine, 2-chloro-procaine (Nesacaine), piperocaine? Procaine (Novocaine) is metabolized to p-aminobenzoic acid (PABA). PABA is a common ingredient in sunscreen.

If the generic name has one "i" in it the drug is an ester. If it has two "i's" it is an amide. The exception to this rule is piperocaine (which is an ester). Therefore procaine and tetracaine are both esters (that are metabolized to PABA) and should not be administered to someone with a PABA allergy.

NEUROLEPTICS

Be prepared to discuss study questions 13.1 - 13.4 at the end of chapter 13 and Figure 13.8.

13.1 What are the three main classes of typical (or first-generation) antipsychotic medications? Give examples of each class.

1. Butyrophenones: Example Haloperidol, and droperidol 2. Phenothiazines: Example Chlorpromazine 3. Thioxanthenes: Example Chlorprothixene

13.2 What percentage of D2-receptors are blocked by typical antipsychotic medications? What other receptors may be blocked by these medications? Typicals block ~ 80% D2 receptors.Atypicals block about 40 - 60% of D2 receptors + 5HT receptors.Make sure you understand how this accounts for their actions and side effects.

13.3 What are the main side-effects of first-generation antipsychotics?

Side effects with first generation antipsychotics include sedation, anticholinergic effects, extrapyramidal symptoms (EPS), orthostatic hypotension, weight gain, photosensitivity, and elevated prolactin levels.

EPS: Include muscle stiffness, rigidity, tremor, drooling, “masklike” face. These symptoms may be treated with antiparkinson agents. Akathisia is not treated with antiparkinson agents however a beta-blocker maybe beneficial. Dystonia is an EPS common with acute onset (sudden spasm of muscle in tongue, jaw, and neck) the patient needs to seek immediate medical attention as this can be rapidly reversed with an anticholinergic.

The low-potency first-generation antipsychotics have more anticholinergic activity than the high-potency agents. When antipsychotics are combined with other medications with significant anticholinergic activity, such as tricyclic antidepressants and antiparkinson agents, the anticholinergic action of the medications are additive.

Adverse reactions include: Neuroleptic Malignant Syndrome, heatstroke, Tardive Dyskinesia, seizures, and arrhythmia (QTc prolongation).

13.4 What effect do these medications have on prolactin levels? Explain.First generation antipsychotics increase prolactin levels by blocking the inhibitory actions of dopamine on lactrophic cells in the anterior pituitary.

Know: Dopamine receptor stimulation of anterior pituitary inhibits prolactin secretion. DA agonists like DA, bromocryptine and apomorphine will inhibit prolactin secretion. Neuroleptics and other DA antagonists increase prolactin levels.

13.5 Three of the more important side-effects of antipsychotic medications are neuroleptic malignant syndrome , acute extrapyramidal symptoms , and serotonin syndrome . Explain the manifestation and treatment of these three side effects. How often is NMS fatal? Who is more likely to get NMS? Serotonin syndrome is potentially life threatening and may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreation use of certain drugs. It is a predictable consequence of excess serotonergic activity at CNS and peripheral serotonin receptors. Symptoms range from barely perceptible to fatal. Treatment consists of discontinuing medication and in moderate to severe cases administering a serotonin antagonist. Another important adjunct treatment is controlling agitation with benzodiazepine sedation. Symptoms include cognitive effects (headache, hypomania, mental confusion, hallucinations, coma), autonomic effects (shivering, sweating, hyperthermia, hypertension, tachycardia, nausea, diarrhea), and somatic effects (myoclonus, hyperreflexia, tremor).

Acute extrapyramidal symptoms include akinesia (inability to initiate movement) and akathisia (inability to remain motionless). They are various movement disorders such as acute dystonic reactions (torticollis, occulogyric crisis, muscular spasms of tongue or jaw), pseudoparkinsonism (drug induced parkinsonism), tardive dyskinesia (involuntary, irregular muscle movements, usually in the face). Anticholinergic drugs are used to control symptoms but akathisia may require beta blockers or benzodiazepines. Switching to an atypical antipsychotic may relieve symptoms. Other commonly used medications for EPS are benztropine (Cogentin), diphenhydramine (Benadryl), and trihexyphenidyl (Artane).

NMS is a life-threatening neurological disorder that presents with muscle rigidity, fever, autonomic instability and cognitive changes such as delirium, and is associated with elevated CPK. It is very unpredictable so there is no one set course of action to treat the syndrome but usually removal of the antipsychotic drug treatment along with medical management leads to a positive outcome. Some say there is a genetic risk factor for NMS. Males under 40 are at greatest risk and so are postpartum women. Another very important risk factor is dementia; neuroleptics should be used very cautiously. Ten percent of cases are fatal.

Good answer.

Note: NMS is triggered by D2 blockers. More powerful D2 blockers like typical (or first generation) antipsychotics are much more likely to cause this than weaker D2 blockers like atypical (or second generation) antipsychotics. Treatment of NMS is to discontinue meds and may use either dantrolene or bromocrytpine.

13.6 Name some early atypical (second-generation) antipsychotic medications (list generic and trade names)?Aripiprazole (Abilify), Clozapine (Clozaril), Ziprasidone (Geodon), Paliperidone (Invega), Risperidone (Risperdal), Quetiapine (Saroquel), Olanzapine (Symbax), Olanzapine (Zyprexa)The positive symptoms of neuroleptics: reduce the hallucinations and delusions associated with schizophrenia by blocking dopamine receptors in the mesolimbic system of the brain.

The negative symptoms of atypical and typical neuroleptics: anhedonia (not getting pleasure from normally pleasurable stimuli), apathy, blood dyscrasisas, extrapyramidal effects (Parkinson like symptoms,of bradykinesia, rigidity, tremor, tardive dyskinesia), postural hypotension, constipation, sexual dysfuntion, fever, weight gain, seizures, nocturnal salivation and myocarditis.

Cognitive impairments of atypical and typical neuoleptics: confusion, sedation, altered mental status, stupor, and drowsiness

Typicals and atypicals block positive symptoms of schizophrenia (via DA receptor blockade).Atypicals (but not typicals) block negative symptoms of schizophrenia (via 5HT receptor blockade).

13.7 What effects do typical and atypical antipsychotics have on: postive symptoms of schizophrenia, negative symptoms of schizophrenia, and cognitive impairment associated with schizophrenia? Describe these symptoms.

13.8 What is the mechanism of action of atypical antipsychotic medications and how does this compare to the mechanism of action of typical antipsychotic medications?

Typical neuroleptics block dopamine receptors (D1-D5) in the brain and the periphery.Atypical neuroleptics inhibit serotonin receptors (5-HT), particularily 5-HT2A.

Atypical antipsychotic medications block ~ 40 to 60% D2 receptors.Typical (or first generation) antipsychotics: block D2 receptors very effectively, do not block serotonin receptors.Atypical (or second generation) antipsychotics: block D2 receptors, but not as effectively as typicals + also block serotonin receptors.

13.9 What are the main side-effects of second-generation antipsychotics?Also known as atypical antipsychotics, they block both serotonin & dopamine receptors (clozapine, risperidone).

They have lower potential of causing extrapyramidal effects and have lower risk of tardive dyskinesia, attributed to their blockade of 5HT receptors. This is not exactly correct. DA antagonists produce parkinsonian symptoms. Second-generation (atypical) antipsychotics are less likely to produce these effects (extrapyramidal effects/tardive dyskinesia) because they are less effective at blocking D2 receptors than first-generation antipsychotics.

Main side effects: Bone marrow suppression, seizures, cardiovascular side effects especially clozapine. There’s high incidence of agranulocytosis with clozapine. All atypical antipsychotics carry increased risk of mortality in elderly patients with dementia-related behavioral disturbances and pyschosis.

13.10 Metaclopramide (Reglan) has central antidopaminergic and peripheral cholinergic properties. What are the side effects of metoclopramide (reglan) and how would you treat them?

Serious side effects caused by metaclopramide are: EPS - Parkinsonism, akathisia, neuroleptic malignant syndrome, tardive dyskinesia. These are caused by DA receptor blockade and may be treated with diphenhydramine, benztopine (Cogentin), or trihexyphenidyl (Artane).

Other side effects are: seizures, diarrhea, loss of bladder control, depression/suicidal thoughts, hallucination. Many of these side effects are due to the peripheral cholinergic effects of metaclopramide and may be treated with anticholinergic agents.

Study note: Neuroleptic agents may be used to treat nausea and vertigo. Drugs you might give during the perioperative period include droperidol (a butyrophenone) and prochlorperazine (Compazine, a phenothiazine).

OPIODS

14.1 What is the source of opium (provide the common and scientific name)?Opium is not a single compound but an extract of the immature seeds of the opium poppy, Papaver somniferum. This extract contains up to 10% morphine, the opiate alkaloid, which is processed to produce diamorphine (better known as heroin). The resin also includes codeine and non-narcotic alkaloids, such as papaverine and noscapine. The source of opium is the poppy. Common name: white poppy, opium poppy. The opium alkaloids are sometimes called “phenanthrenes”.

14.2 What is an alkaloid? Which alkaloid was the first to be isolated (or purified)? The names of many alkaloids end in what 3 letters? An alkaloid is, strictly speaking, an amine that is produced by a plant. However, the term has been extended to amines produced by animals and fungi as well. The name derives from the word alkaline originally- the term was used to describe any nitrogen containing base.

Alkaloids are usually derivatives of amino acids, and many have a bitter taste. They are found as secondary metabolites in plants (such as potatoes and tomatoes), animals (such as shellfish), and fungi. In many cases, they can be purified from crude extracts by acid-base extraction.The first individual alkaloid, morphine, was isolated in 1804 from poppy (Papaver somniferum).Good answer. The names of many alkaloids end in “ine” (eg, atropine, meperidine, neostigmine, codeine, morphine, etc.) - JM

14.3 Where do the names opium, morphine and papaverine come from?The name opium comes from the Greek opion. Morphine is named morphium after Morpheus, the Greek god of dreams.Papaverine is derived from Latin “poppy” and added “ine” from which the Greek paparouna originated.

14.4 During cardiac bypass surgery, the surgeon may inject papaverine around the mammary artery. Why is this done? Describe the cardiovascular effects may this produce and briefly describe the mechanism for these effects.Papaverine is a nonxanthine phosphodiesterase inhibitor used for for the relief of cerebral and peripheral ischemia associated with arterial spasm and myocardial ischemia complicated by arrhythmias. The main actions of papverine are exerted on cardiac and smooth muscle. Papaverine acts directly on the heart muscle to depress conduction and prolong the refractory period. The muscle cell is not paralyzed by papverine and still responds to drugs and other stimuli causing contraction. The antispasmodic effect is a direct one, and unrelated to muscle innervation. Papaverine is mainly devoid of effects on the central nervous system. It relaxes the smooth musculature of the larger blood vessels, especially coronary, systemic peripheral, and pulmonary arteries. In the above scenario, Papaverine is used as a smooth muscle spasmolytic to assist in maintaining graft patency (from spasm). Muscle relaxation may occur due to inhibition of cyclic nucleotide phosphodiesterase, increasing cyclic AMP. Papaverine is naturally occuring alkaloid in opium. It gets its name from the name of the opium poppy = papaver somniferum. Note that papaverine is a PDE inhibitor and these vasodilating properties are similar to those of other PDE inhibitors (eg, milrinone = primacor). – JM

14.5 What is the difference between an opioid and a narcotic?An opioid is a natural or synthetic compounds that acts by binding to specific opioid receptors in the CNS to produce effects that mimic the action of endogenous peptide neurotransmitters. The term Narcotic refers to any substance that induces sleep, insensibility, or stupor and refers more to a side effect than an action of a drug.

14.6 What are the differences between naturally occurring narcotic analgesics, semi-synthetic narcotic analgesics and synthetic narcotic analgesics? How would you classify these agents: morphine, codeine, diacetylmorphine (heroin), fentanyl, remifentanil, sufentanil, alfentanil, meperidine, buprenorphine, methadone, dihydromorphone (dilaudid)?Naturally occurring narcotic analgesics are natural compounds that bind to specific sites on the opioid receptors of the CNS to produce effects that mimic the action of endogenous peptide neurotransmitters. An example of this is codeine which is an opiate derived from opium. Opiates are naturally occurring narcotic analgesic drugs that are alkaloids and contain opium.

Semi synthetic narcotics are derived by altering chemicals contained in opium and are produced by chemically treating the natural alkaloid. Two examples are diacetylmorphine (heroin) and dihydromorphone (dilaudid).

Synthetic narcotics are produced entirely within the laboratory and are not derived from opium but have a similar chemical structure. Examples of synthetic narcotic analgesics are: Fentanyl, Remifentanil, Sufentanil, Alfentanil, Meperidine, and Methadone. (edit note: spelling mistakes corrected - note fentanyl is only opioid listed here that contains a "y". Synthetic narcotics are man-made and do not have a similar structure. They are structurally different from naturally occuring narcotic analgesics. - JM)

14.7 What are the differences between opioid-receptor agonists, antagonists, and partial-agonists? How would you classify these agents: morphine, codeine, diacetylmorphine (heroin), fentanyl, remifentanil, sufentanil, alfentanil, meperidine, buprenorphine, methadone, dihydromorphone (dilaudid), butorphanol (stadol), nalbuphine (nubain), pentazocine (talwin)?

An opioid agonist activate mu and kappa receptors. By activating these receptors, the agonist can produce analgesia, euphoria, sedation, respiratory depression, physical dependence, constipation, and other effects. Examples of agonists are: Codeine, Fentanyl, Sufentanil, Alfentanil, Meperidine, Methadone, Diacetylmorphine (Heroin), and Dihydormorphine.

An opioid agonist-antagonist when administered alone produces analgesia, however if given to a patient who is taking a pure opioid agonist these drugs can antagonize analgesia. Examples of agonist-antagonist include: Pentazocine (Talwin), buprenorphine, butorphanol (Stadol), and nalbuphine (Nubain). Agonists/antagonists may be agonists at one set of receptors (eg, kappa) and antagonists at other receptors (eg, mu). These drugs may precipitate an acute abstinence (withdrawal) reaction if administered to a narcotic addict. - JM

An opioid antagonist acts as a antagonist at mu and kappa receptors. These drugs do not produce analgesia or any of the other effects caused by opioid agonists, their principle use is for reversal of respiratory and CNS depression caused by overdose with opioid agonists. Examples of a opioid antagonist is naloxone (Narcan) and naltrexone. These agents may also precipitate an acute abstinence (withdrawal) reaction if administered to a narcotic addict. - JM

14.8 Describe the enkephalins, endorphins, and dynorphins.The body has three families of peptides that have opioid-like properties. These families are named enkephalins, endorphins, and dynorphins. The enkephalin is a pentapeptide that interacts more selectively with the δ receptors in the periphery and regulates norciception. The endorphins are produced by the pituitary gland and the hypothalamus during exercise, excitement, pain, consumption of spicy food, love and orgasm, and they resemble the opiates in their abilities to produce analgesia and a feeling of well-being. Dynorphins exert their effects primarily through the κ-opioid receptor (KOR), a G-protein-coupled receptor. Dynorphin has been shown to be a modulator of pain response.

14.9 Describes mu- kappa- and delta receptors. Where are these receptors located, what are their endogenous ligands, and list drugs that stimulate these receptors.Mu and Delta receptors are opioid receptors. All opioid receptors are protein receptors found on the membrane of certain CNS cells, on nerve terminals in the peripheral nervous system and on cells in the GI tract. In the brain they are found in the brainstem and thalamus. They are also found in the spinal cord, hypothalmus and limbic system.

14.10 Where is codeine naturally found? How is it structurally similar to morphine?Codeine is made from the milky juice of unripe seeds of the opium poppy plant. (Poppies).

Codeine is structurally similar to morphine in that Codeine adds a methyl group on the 3 position hydroxyl group of morphine. Codeine is morphine with a methyl group (-CH3) attached to the 3 position carbon.

14.11 True or false? Codeine is not effective until it is converted to morphine in the liver.TRUE

14.12 How does the activity of the cytochrome P450 enzyme CYP2D6 affect the way individuals respond to codeine? Why is this clinically important.CYP2D6 is a member of the cytochrome P450 family (a mixed-function oxidase system). The function of most CYP enzymes is to catalyze the oxidation of organic substances. This enzyme, CYP2D6, shows the largest phenotypical variability among the CYPs which means that depending on the genetic make-up of the person, this enzyme can have different observable characteristics or traits. The CYP2D6 function in any particular person can vary between being a poor metabolizer to an ultra metabolizer of certain drugs. CYP2D6 has a role in the metabolism of codeine. Approximately 0 – 15% of codeine is O-demethylated to morphine, the most active metabolite, which has an approximate 200-fold greater affinity for the mu opoid receptor when compared to codeine. People who are poor metabolizers are unable to convert codeine to morphine efficiently so they may not experience pain relief. Ultrametabolizers may metabolize codeine too efficiently which could lead to morphine intoxication.Here is a list of drugs metabolized by CYP2D6: Amiodarone (Cordarone), Bupropion (Wellbutrin), Chlorpheniramine (Chlor-Trimeton), Chloroquine (Aralen), Chlorpromazine (Thorazine), Cinacalcet (Sensipar), Diphenhydramine (Benadryl), Duloxetine (Cymbalta), Fluoxetine (Prozac), Halofantrine (Halfan), Haloperidol (Haldol), Imatinib (Gleevec), Paroxetine (Paxil), Perphenazine (Trilafon), Propafenone (Rythmol), Propoxyphene (Darvon), Quinacrine (Atabrine), Quinidine (Quinidex, etc), Quinine, Terbinafine (Lamisil).

Note: for active drugs, patients with absent CYP2D6 will have prolonged drug effect (decreased clearance). Most of these drugs are already active so they will last longer. In the case of codeine, codeine is not as potent as its metabolite (morphine) so these patients will have a diminished response to codeine.

14.13 How is meperidine different in its actions and toxicity from other narcotics?

Some of the different actions of meperidine:1. Structurally similar to atropine so it possesses a mild atropine-like antispasmodic effects2. Can be effective in suppressing postoperative shivering most likely due to stimulation of kappa receptors and a drug induced decrease in the shivering threshold3. Not useful for the treatment of diarrhea or as an antitussive4. Can cause increases in heart rate 5. Large doses can result in decreases in myocardial contractility6. Delirium and seizures can reflect the accumulation of normeperidine which has stimulating effects on CNS7. Does not cause miosis but rather tends to cause mydriasis

Toxicity:Meperidine is metabolized to normeperidine, an active metabolite and a compound capable of inducing seizures at high concentrations. Normeperidine is only about half as effective as the parent compound meperidine as an analgesic, however, it can be neurotoxic and can cause significant CNS adverse effects. Some of the CNS toxicity secondary to normeperidine is nervousness, hallucinations, tremors, myoclonus and generalized seizures. Normeperidine is primarily eliminated renally and its half-life is about 5 – 10 times longer than that of meperidine depending on renal function. Patients with impaired renal function can accumulate normeperidine in their system.Meperidine is one of the most toxic narcotic analgesics. It increases myocardial work and should not be used in patients with CAD. It has a very toxic metabolite (normeperidine) that can cause seizures with repetitive dosing (eg, PCA administration) or else in patients with renal failure. – JM

14.14 What are the clinical effects of morphine?1. Analgesia, euphoria, sedation, diminished ability to concentrate2. Nausea, vomiting (partially due to stimulation of the chemoreceptor trigger zone in the floor of the fourth ventricle delayed gastric emptying), feeling of body warmth, heaviness of the extremities3. Dryness of mouth4. Pruritus5. Increased pain threshold and modify the perception of noxious stimulation6. Decreased sympathetic nervous system tone to peripheral veins, decreasing venous return, cardiac output and bloodpressure7. Coronary artery dilatation 8. Bradycardia from possible increased activity over the vagal nerves and depressant effect on the SA node 9. Histamine release10. Dose dependent respiratory depression through agonist effect at mu2 receptors11. In absence of hypoventilation, decrease cerebral blood flow and possibly ICP12. Miosis13. Decreases propulsive peristaltic contractions of small and large intestines which can result in constipation14. Can have delayed or prolonged effects due to its active metabolite M6G

14.15 What are the main metabolites of morphine?1. Morphine – 3 – glucuronide (M3G)2. Morphine – 6 - glucuronide (M6G)**M6G is an active metabolite and an opioid agonist believed to be approximately 2 – 4 times more potent than morphine.

(You are not responsible for knowing the trade names of any drugs in this course.)

The synthetic narcotics are meperidine, methadone, fentanyl, remifentanil, alfentanil and sufentanil. These are all potent mu-receptor, kappa-receptor and delta-receptor agonists. Meperidine was the first synthetic narcotic analgesic and has weak anticholinergic properties. It increases myocardial work and should not be administered to patients with coronary artery disease. Repetitive doses of meperidine may be associated with high levels of a metabolite (normeperidine) that may cause seizures. In general, meperidine should be avoided in patients with a seizure disorder. One usual feature about meperidine is that has strong membrane stabilizing properties (this is a local-anesthetic like effect). Alfentanil and remifentanil are short-acting agents: alfentanil has a relatively small volume of distribution; remifentanil, the shortest acting of these agents, has a very high clearance.

Methadone is a potent mu-agonist that has a slow clearance and large volume of distribution therefore it has a very ______ duration of action. Methadone is used for analgesia and to treat opiate addiction. The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with opiates.

Agonists-Antagonists: Buprenorphine (Buprenex) is a semisynthetic, mu-receptor partial agonist. Butorphanol (Stadol) and nalbuphine (Nubain) are kappa-agonists and very weak mu-agonists (practically speaking, these two agents are mu-antagonists). Pentazocine (Talwin) is a mu-antagonist, kappa-agonist, delta-agonist.

ANTI-INFLAMMATORY41.1 What is the mechanism of action of NSAIDs?NSAIDs are used for their analgesic, anti-inflammatory, and antipyretic properties. Their therapeutic actions are thought to stem primarily from their ability to block the formation of certain prostaglandins through inhibition of the cyclooxygenase (COX) enzymes. In general, COX-1 catalyzes the production of several cytoprotective prostaglandins that coat the stomach lining with mucus and aid platelet aggregation, among other functions. COX-2 catalyzes the conversion of arachidonic acid into the inflammatory prostaglandins that are involved in three key biological functions: sensitizing skin pain receptors, elevating body temperature through the hypothalamus, and recruiting inflammatory cells toward injured body parts.

41.2 Why are prostaglandins (PG) also known as eicosanoids?There are four families of eicosanoids- prostaglandins, protacyclins, thromboxanes and leukotrienes. Prostaglandins and leukotrienes are potent eicosanoid lipid mediators derived from phospholipase-released arachidonic acid that are involved in numerous homeostatic biological functions and inflammation. They are generated by cyclooxygenase isozymes and 5-lipoxygenase and their biosynthesis and actions are blocked by clinically relevant nonsteroidal anti-inflammatory drugs, the newer generation coxibs (selective inhibitors of cyclooxygenase-2), and leukotriene modifiers. The prime mode of prostaglandin and leukotriene action is through specific G protein–coupled receptors, many of which have been cloned recently, thus enabling specific receptor agonist and antagonist development. Important insights into the mechanisms of inflammatory responses, pain, and fever have been gleaned from our current understanding of eicosanoid biology.

Prostaglandins are made of unsatured fatty acid derivatives containing 20 carbons that include a cyclic ring structure. These compounds are referred to as eicosanoids where "eicosa" refers to the 20 carbons atoms.

41.3 Outline the role of arachadonic acid in PG biosynthesis.Arachidonic acid is freed from a phospolipid molecule by the enzyme phospholipase A2, which cleaves off the fatty acid, but can also be generated from DAG by Diacylglycerol lipase. Arachidonic acid generated for signaling purposes appears to be derived by the action of a phosphatidylcholine-specific cytosolic phospholipase A2, whereas inflammatory arachidonic acid is generated by the action of a low-molecular-weight secretory PLA2. Arachidonic acid is a precursor in the production of eicosanoids. The enzymes cyclooxygenase and peroxidase lead to Prostaglandin H2, which in turn is used to produce the prostaglandins, prostacyclin and thromboxanes. The enzyme 5-lipoxygenase leads to 5-HPETE, which in turn is used to produce the leukotrienes. Arachidonic acid is also used in the biosynthesis of anandamide. Some arachidonic acid is converted into hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids by epoxygenase. The production of these derivatives and their action in the body are collectively known as the arachidonic acid cascade.

Good answer.

Arachinoid acid, a 20 carbon fatty acid, is the primary precursor of the prostaglandins.It is present as a component of the phospholipids of cell membranes. It is released from tissue phospholipids by the action of phospholipase A2 and other acyl hydrolases via a process controlled by hormones and other stimuli. Two major pathways exist by which eicosanoids are synthetized from arachidonic acid: 1. cyclooxygenase pathway, 2. lipoxygenase pathway. -JM

41.4 Is it difficult to detect PG in blood? Why?It is difficult because prostaglandin D2 is excreted directly into the urine. The highest sites of prostaglandin D2 activity are the brain, spinal cord, intestines, and stomach. Prostaglandin D2 is the major Prostaglandin produced by uterine tissue. Prostaglandin D2 is a potent bronchoconstrictor, neuromodulator, and anti-antithrombin agent. It also stimulates the secretion of pancreatic glucagon. Prostaglandin D2 has been found to have an anti-metastatic effect on many malignant tumor cells. Prostaglandin D2 production and circulating levels are drastically suppressed by aspirin and Indomethacin.

Prostaglandins are produced in minute quantities by virtually all tissues and generally act locally on the tissues in which they are synthesized (that’s why they are called autacoids). They are rapidly metabolized to inactive products at their site of action. Therefore, PGs do not circulate in blood in significant quantities and are difficult to detect in blood.

41.5 Briefly compare cyclo-oxygenase and lipoxygenase pathways of PG synthesis.Arachidonic acid has a short half-life and can be metabolized by two major routes, the cyclo-oxygenase and lipoxygenase pathways. The cyclo-oxygenase pathway produces prostaglandins, prostacyclin, and thromboxanes; the lipoxygenase pathway produces in one branch leukotrienes and in the second branch lipoxins.

41.6 Summarize PG actions and functions.

Prostaglandins, are like hormones in that they act as chemical messengers, but do not move to other sites, but work right within the cells where they are synthesized. They are mediators and have a variety of strong physiological effects such as regulating the contraction and relaxation of smooth muscle tissue. Prostaglandins are mediated by their binding to a variety of distinct cell membrane receptors that operate via G proteins that activate or inhibit AC or stimulate phospholipase C. This causes an enhanced formation of diacylglycerol and inositol 1,4,5 –triphosphate. Prostaglandin F2a, the leukotrienes, and thromboxane A2 mediate certain actions by activating phosphatidly inositol metabolism, causing an increase of intracellular Ca. There are currently ten known prostaglandin receptors on various cell types. Prostaglandins ligate a sub-family of cell surface seven-transmembrane receptors, G-protein-coupled receptors. These receptors are termed DP1-2, EP1-4, FP, IP1-2, and TP, corresponding to the receptor that ligates the corresponding prostaglandin (e.g., DP1-2 receptors bind to PGD2).Prostaglandins act on an array of cells and have a wide variety of effects such as:• cause constriction or dilation in vascular smooth muscle cells• cause aggregation or disaggregation of platelets• sensitize spinal neurons to pain

• decrease intraocular pressure• regulate inflammatory mediation• regulate calcium movement• control hormone regulation• control cell growth• acts on thermoregulatory center of hypothalamus to produce fever• acts on mesangial cells in the glomerulus of the kidney to increase Glomerular filtration rate

There are a variety of physiological effects including:1. Activation of the inflammatory response, production of pain, and fever. When tissues are damaged, white blood cells flood to the site to try to minimize tissue destruction. Prostaglandins are produced as a result.2. Blood clots form when a blood vessel is damaged. A prostanoid called thromboxane stimulates constriction and clotting of platelets. Conversely, PGI2 (prostacyclin), is produced to have the opposite effect on the walls of blood vessels where clots should not be forming.3. Certain prostaglandins are involved with the induction of labor and other reproductive processes. PGE2 causes uterine contractions and has been used to induce labor. (PGFalpha also does this - JM)4. Prostaglandins are involved in several other organs such as the gastrointestinal tract (inhibit acid synthesis and increase secretion of protective mucus), increase blood flow in kidneys, and leukotrienes promote constriction of bronchi associated with asthma.

41.7 Explain the mechanism of nephrotoxicity of NSAIDs.NSAIDs inhibits cyclooxygenase and as a cyclooxygenase inhibitor, it prevents the synthesis of certain prostaglandins. The major prostanoids synthesized in the kidney include PGI2 (prostacyclin), PGE2, thromboxane A2 (TXA2), and PGF2-alpha (Table 1).

These prostaglandins are produced to preserve renal function when pathologic states supervene and compromise physiologic kidney processes such as:Decreased synthesis of prostaglandins can result in retention of sodium and water and may cause edema and hyperkalemia in some patients. Severe and potentially life-threatening hyperkalemia can develop following NSAID therapy. This most often occurs in patients with underlying renal insufficiency or in those who are concurrently receiving other medications that alter potassium balance. An NSAID-induced reduction in the synthesis of renin and aldosterone is the major cause of impaired renal potassium excretion and hyperkalemia. Decreased delivery of sodium chloride and water to the distal nephron, which is perpetuated by the effect of the NSAID, also contributes to the development of hyperkalemia. The diminished availability of intraluminal sodium for sodium-potassium exchange limits potassium excretion. Interstitial nephritis can also occur with all NSAIDs except aspirin.In marginally functioning kidneys and hypovolemia, prostaglandins derived from renal cortical COX-2 maintain renal blood flow and GFR through their local vasodilating effects. These prostanglandins also modulate systemic blood pressure through regulation of sodium and water excretion.

For a little more detail…I found this great article regarding this matter and wanted to post this information for everyone else to benefit from. Intravascular volume depletion--associated with vomiting, diarrhea, and diuretic therapy--stimulates COX enzyme activity and prostaglandin synthesis to optimize renal blood flow. Other causes of an effective decrease in renal blood flow include congestive heart failure (CHF), cirrhosis, and nephrotic syndrome. Prostaglandin production is also increased in chronic renal insufficiency to maintain perfusion of remnant nephrons.

Locally produced PGI1 and PGE2 antagonize the local effects of circulating angiotensin II, endothelin, vasopressin, and catecholamines that normally maintain systemic blood pressure at the expense of the renal circulation. Glomerular filtration rate (GFR) is preserved through the antagonism of arteriolar vasoconstriction and mesangial and podocyte contraction, both of which are induced by endogenous vasopressors.

Renal prostaglandins also have an important role in modulating salt and water homeostasis. In states of volume overload, both the inhibition of tubular sodium chloride reabsorption and the impairment of vasopressin's effect on water channels result in increased salt and water excretion. (5,8) Regulation of medullary blood flow by PGE2 also contributes to the kidney's ability to modify renal solute excretion. Ultimately, intravascular volume status is controlled, and hypotension and dehydration--as well as hypertension and edema formation--are avoided.

Patients with high-renin states (such as CHF, volume depletion, and cirrhosis) and chronic renal insufficiency rely on renal prostaglandin synthesis to ensure sufficient renal blood flow and to maintain an adequate GFR. In the absence of these prostaglandin effects, unopposed vasoconstriction leads to a decrease in renal blood flow and a decline in GFR.

This is why you should not give drugs like ketorolac (toradol) to these patients. - JM

Thus, NSAID therapy in patients with prostaglandin-dependent disease states often precipitates renal ischemia and acute renal failure. Fortunately, discontinuation of the NSAID leads to reversal of renal failure within 2 to 5 days. In some cases, short-term dialysis may be required for severe uremia or extreme metabolic perturbations.

Edema formation and volume overload may also complicate NSAID therapy. In elderly patients with underlying heart disease, NSAID use can double the risk of CHF.

Diuretic resistance can also develop during NSAID therapy, especially in patients with underlying salt-retentive states, such as CHF and cirrhosis. In addition, new-onset hypertension and exacerbation of previously well-controlled hypertension can occur with NSAIDs. Most of these adverse effects result predominantly from NSAID-induced sodium retention by the kidney. NSAIDs also potentiate the antidiuretic effects of vasopressin, which can lead to total body water excess and hyponatremia.

Note: loop diuretics, like furosemide, produce some of their effects by stimulating COX activity. This is one reason diuretic resistance may occur during NSAID therapy. - JM

41.8 Is aspirin metabolism zero-order, first-order or both? Explain.Aspirin, ethanol and phenytoin are metabolized by zero-order kinetics.

With zero-order kinetics, the metabolizing enzymes are operating at full capacity. They can not metabolize more drug. So for instance, if you increase or decrease liver blood flow then the same amount of drug is being metabolized. Zero-order drugs have erratic half-lifes and are dose dependent, as you point out. For first-order processes, the enzymes can metabolize all the drug they encounter. So if you double liver blood flow, then you will double the volume of plasma cleared of drug per unit time. Zero-order processes have units of mg/time, first order processes have units of volume of plasma cleared per time. – JM

41.9 Summarize the pharmacology of ASA.Aspirin inhibits cyclooxygenase and thus the prostaglandin synthesis. The drug has analgesic, anti-inflammatory and antipyretic effects. Through its effect on the thrombocyte-cyclooxygenase it inhibits the formation of a highly effective platelet (thrombocyte) aggregator and a vasoconstrictor (thromboxane A2). Since the platelets do not synthesize proteins, the effect remains demonstrable as long as the affected thrombocytes live (7-10 days).

ASA is a weak organic acid that irreversibly inactivates cyclooxygenase. ASA exhibits three major therapeutic functions: anti-inflammatory, analgesic, and antipyretic. All of these effects are related to the inhibition of prostaglandins. In the GI tract, ASA inhibition of prostaglandins results in increased gastric acid and decreased mucus production. This process can lead to irritation, ulceration, and potentially hemorrhage. ASA also inhibits thromboxane (TXA2) production and therefore decreases platelet aggregation. ASA is to be avoided in children and teenagers with concomitant viral infections such as varicella or influenza due to the risk of Reye’s syndrome (often fatal fulminating hepatitis with cerebral edema). Absorption does additionally occur through the BBB, placenta, and skin. ASA is 90-95% protein bound and can be displaced from the protein (increasing its concentration in the blood) or displace other protein bound drugs such as warfarin, phenytoin, or valproic acid which results in higher free concentrations of these drugs. Mild ASA toxicity is characterized by nausea, vomiting, marked hyperventilation, headache, mental confusion, dizziness, and tinnitus. Severe toxicity progresses to restlessness, delirium, hallucinations, convulsions, coma, respiratory and metabolic acidosis, and death from respiratory failure. ASA is not used in patients with gout because it is a weak organic acid that interferes with the kidneys' ability to eliminate uric acid.

41.10 Compare and contrast the pharmacology of proprionic acid, acetic acid, oxicam derivatives, and fenamates.Note that all these drugs are reversible nonselective COX inhibitors (ie, they inhibit COX-1 and COX-2). They all have anti-inflammatory, analgesic and antipyretic effects. They all inhibit platelet function and increase bleeding time (by inhibiting TXA2 production). They all are highly bound to albumin and may cause drug interactions. Like aspirin, high doses may cause headaches, dizziness and tinnitus. Unlike aspirin but not unlike COX-2 inhibitors, they all have risk of precipitating life-threatening thrombotic cardiovascular events.

Propionic acid (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiporfen, oxaprozin) posess anti-inflammatory, analgesic, and antipyretic activity and can alter platelet function and prolong bleeding time. Used in treatment of RA and osteoarthritis due to their less intense GI effects than aspirin. These are reversible inhibitors of cyclooxygenases and inhibit the synthesis of prostaglandins but not leukotrienes. Well absorbed on oral administration an dare almost totally bound to serum albumin. Hepatic metabolism and renal excretion.

Acetic acid (indomethacin, sulindac, etodolac) posess anti-inflammatory, analgesic, and antipyretic activity. Reversibly inhibit cyclooxygenase. Generally not used to lower fever. Toxicity of indomethacin limits its use to treat acute gouty arthritis, ankylosing spondylitis, and osteoarthritis of the hip; therefore, sulindac which is closely related to indomethacin although less potent is used instead. GI problems are less common than other NSAIDs.

Oxicam derivatives (piroxicam, meloxicam) are used to treat RA, ankylosing spondylitis, and osteoarthritis. They have long halflives, which permit once daily administration and metabolites are excreted in the urine.

Note: piroxicam = feldene, meloxicam = mobic - JM

Fenamates (mefenamic acid, meclofenamate) have no advantatges over other NSAIDs as anti-inflammatory agents. Side effects, such as diarrhea, can be severe, and are associated with inflammation of the bowel.

41.11 Describe COX-1 and COX-2 enzymes and summarize the pharmacology of celecoxib.COX-1 enzymes are responsible for the physiologic production of prostanoids, whereas COX-2 enzymes cause the elevated production of prostanoids that occurs in sites of disease and inflammation. COX-1 regulates normal cellular processes, such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney function.

COX-2 is normally expressed in tissues such as the brain, kidney, and bone. Its expression at other sites is increased during states of inflammation. COX-2 has a larger and more flexible substrate channel and a larger space at the site where inhibitors bind than COX-2. These structural differences allowed for the development of selective COX-2 inhibitors. COX-2 expression is inhibited by glucocorticoids, which may contribute to the significant anti-inflammatory effects of those drugs.

Note that glucocorticoids block inflammation by (1) inhibiting PLA2 and (2) by inhibiting COX-2 expression. - JM

Celecoxib inhibits prostaglandin synthesis through inhibition of COX-2. At therapeutic levels it does not inhibit COX-1. It may cause sodium and water retention through inhibition of Prostaglandin E2 synthesis. In comparison to aspirin and other NSAIDs, it does not inhibit platelet aggregation or increase bleeding time. It has a similar risk of negative cardiovascular events when compared with other NSAIDs.

Celecoxib is indicated for osteoarthritis, RA, acute pain, menstrual symptoms, and to prevent colon polyps in patients at risk of colon CA (eg, strong family history or familial polyposis). Celecoxib has lower risk of causing GI problems than nonselective COX inhibitors. It can inhibit cytochrome 2D6 (CYP2D6, the same enzyme that converts codeine to morphine) which can increase levels of some B-blockers, antidepressants, and antipsychotic drugs.

41.12 What are the pros and cons of acetaminaphen vs. NSAIDs?Pros:No effects on bleeding timeLess GI disturbancesSafe for use in children (when specifically compared with aspirin)Safer for use in renally impaired patientsNot a risk for negative cardiovascular eventsCheaper and does not require a prescription (when compaired with COX-2 inhibitors)

Cons:Lacks significant anti-inflammatory actionPotential for life threatening hepatic insult at higher than therapeutic levels

41.13 What is N-acetylcysteine and what are its indications and mechanism of action?N-acetylcysteine, perhaps more recognizable by one of its trade names, Mucomyst, is a mucolytic and antidote to acetaminophen overdose. It is indicated for management of excessive mucous production, prevention of contrast induced nephropathy, and treatment of acetaminophen overdose. The textbook focused on its use in acetaminophen overdoses. A portion of acetaminophen is hydroxylated to form N-acetylbenzoiminoquinone, a toxic metabolite that reacts with sulfhydryl groups. At normal doses, the N-acetylbenzoiminoquinone reacts with the sulfhydryl group on glutathione, forming a nontoxic substance. When acetaminophen is taken in excess, glutathione stores are depleted and excess N-acetylbenzoiminoquinone is free to react with sulfhydryl groups of hepatic proteins, leading to hepatic necrosis. N-acetylcysteine contains a sulfhydryl group that will directly bind to the excess N-acetylbenzoiminoquinone, protecting the liver from potential necrosis.

This is a very good answer. Note that mucus is a noun and mucous is an adjective. Mucus is produced by mucous glands. - JM

41.14 Briefly describe the pharmacology of methotrexate. If a patient taking methotrexate presents for surgery (eg, knee arthroscopy), what lab tests would you order and why?Methotrexate slows the appearance of new erosions within involved joints. It is unclear what the exact mechanism of action is. It is a immunosuppressant, and this is believed to account for its effectiveness against autoimmune disorders. When used in oncology patients, the drug acts by folic acid antagonist by inhibiting the enzyme that converts folic acid to its active form. Folic acid is essential for cell replication. Actively proliferating cells, such as malignant cancer cells, are more sensitive than non-proliferating cells to this action of methotrexate.

Cytopenias, liver cirrhosis, and acute pneumonia-like syndrome may occur with chronic methotrexate administration. Accordingly, labs for this patient should include a CBC, hepatic function panel, and pancultures if the patient presents with signs and symptoms of infection.

MTX is the disease modifying antirheumatic drug of choice for patients with rheumatoid arthritis. MTX doses in RA are much lower than those used in cancer chemotherapy. At high doses MTX inhibits folic acid synthesis as Matt mentioned. At low doses MTX works by inhibiting proliferation and stimulating apoptosis in immune-inflammatory cells (by inhibition of AICAR which is aminoimidazolecarboxamide ribonucleotide)

Study note: You must know that TXA2 causes vasoconstriction and platelet aggregation. You do not need to know anything specific about the actions of any of the other prostaglandins (E2, F-alpha, D2 or I2 which is prostacylcin). The general actions that you should know are that prostaglandins are pyrogenic (raise the temperature set point in the hypothalamus), mediate inflammation, produce hyperalgesia, protect the GI tract (decrease acid production and increase mucus production), cause uterine contraction, lower intra-ocular pressure, and may be used to treat pulmonary hypertension. Know that if you block COX-1 you will affect TXA2, prostacyclin (PGI2) and prostaglandin production. Know the difference between COX-1 and COX-2. Know that steroids (glucocorticoids) block PLA2 and the expression of COX-2. Know the difference between ASA and other NSAIADs. Know the pros and cons of COX-2 therapy. Know that COX-2 use is reserved for only a few indications, especially Rheumatoid Arthritis and prevention of colon polyps. Know what misoprostol is and that it may be used to protect the stomach in patients requiring NSAID therapy.

Don't worry about the lipoxygenase pathway or leukotrienes/lipoxins now. We will touch on a few things about these pathways when we discuss pulmonary medications.

AUTACOIDS AND AUTACOID ANTAGONISTS

42.1 What are autacoids?Autacoids are a group of compounds such as prostaglandins, histamine, and serotonin that are heterogeneous substances which have widely differing structures and pharmacologic activities. They are called autacoids meaning they are formed by the tissues on which they act, from Greek autos (self) and akos (remedy). Autacoids differ from other circulating hormones because they are produced by many tissues rather than specific endocrine glands.

42.2 Briefly describe the use of prostaglandins (PG) in the treatment of pulmonary hypertension, peptic ulcer disease and as abortifacients. Prostaglandins are unsaturated fatty acid derivatives that act on the tissues in which they are synthesized and are rapidly metabolized to inactive products at the site of action.

Pulmonary HTN: Iloprost and Epoprostenol are examples of prostaglandins used to treat pulmonary HTN. They can both be given IV, resulting in systemic effects, or Iloprost can be given via inhalation, resulting in a more focused effect on the lungs. They both cause Beta-2 receptor stimulation, causing broncho and vasodilation by increasing cAMP.

PUD: Misoprostol can be used to treat peptic ulcer disease by inhibiting secretion of HCL and pepsin, and enhancing mucosal resistance. Useful for patients with gastric ulcers who chronically take NSAIDs

Abortifacients: Mifepristone (RU-486) is a synthetic steroid given orally with antiprogestational effects, followed within 24 hours by Misoprostol, a synthetic prostaglandin, administered vaginally. The combination of these two drugs causes first trimester abortions with over 95% success rate.

42.3 Summarize the pharmacology of histamine. Include mechanism of action and role in allergy and anaphylaxis.

Histamine, an amine, is a chemical messenger located in all tissues, which is usually released in response to various stimuli. Histamine can bind to any of the 4 histamine receptors, H1, H2, H3, and H4. H1 and H2 are widely expressed and are the targets of clinically useful drugs, while H3 and H4 receptors are in only a few cell types and are clinically unclear. Stimulation of H1 receptors promote vasodilation and increase capillary permeability, cause an increased production of nasal and bronchial mucus, constrict bronchioles decreasing lung capacity, constrict intestinal smooth muscle causing cramps and diarrhea, and can cause itching and pain at sensory nerve endings. Stimulation of H2 receptors increases gastric HCL secretion, and also has an effect on vasodilation and increased capillary permeability. In response to an allergic reaction, histamine is released and can either cause a local response, producing reactions on the skin or respiratory system, or a full-blown anaphylactic response systemically. It is thought that the major determinant on type of reaction, local or anaphylactic, is dependent on the rate of release of histamine. For example, if it is released slow enough to permit inactivation before entering the bloodstream, only a local response will occur. Antihistamines are aimed at blocking the receptor sites.

H1 receptor stimulation causes vascular endothelium to release nitric oxide (NO) which in turn causes vasodilation.

42.4 True or False: H-2 receptors are located in the stomach and skin?True

Note: If you want to block a systemic histamine reaction (eg, allergic reaction), you would administer an H1 blocker (eg, diphenhydramine) plus an H2 blocker (eg, famotidine, ranitidine or cimetidine). The H2 blocker works in the stomach and to prevent skin flushing, the H1 blocker works everywhere else. The other histamine receptors (H3 and H4) are clinically unimportant. If on the other hand you wanted to block histamine receptors in the stomach to reduce acid production, then you would just administer and H2 blocker. If you are treating cold symptoms or chronic sinusitis, you would use an H1 blocker.- JM

42.5 Outline the pathophysiology and medical management of Migraine Headaches. Make sure to include the role of the triptans.There are two types of migraines;

1. Migraine without aura- a severe, unilateral pulsating headache that can last from 2-72 hours and is usually associated with nausea, vomiting, photophobia, and phonophobia.

2. Migraine with aura- is when the headache is preceded by neurologic symptoms called auras, which can be visual, sensory, or cause speech or motor disturbances that begin before onset of pain. These auras are caused by hypoperfused regions of the brain prior to hyperperfusion.

In both types of migraines, the pain is caused by extracranial and intracranial arterial dilation, which in response to the stretching, leads to release of neuroactive molecules.

Treatment of migraines can occur several ways. Some meds, such as Beta-blockers Propranolol and timolol, TCA Amitriptyline, Anticonvulsant Divalproex, and Calcium-channel blocker Verapamil, have been successful in reducing the frequency and severity of migraines prophylactically if the patient suffers from multiple monthly attacks. During an attack, symptomatic treatment may be used to reduce severity of symptoms. The triptans (sumatriptan, naratriptan, rizatriptan, eletriptan, almotriptan, frovatriptan, and zolmitriptan) have been shown to rapidly and effectively abort or markedly reduce the severity of migraine headaches. These drugs are serotonin agonists and act at 5-HT1D receptors.

Note: sumatriptan = Imitrex. Know which classes of drugs can prevent migraine and which class can treat an active migraine. - JM

It is easy to confuse whether drugs like ondansetron, sumatriptan and many other drugs acting on 5HT are agonists or antagonists. Here is how I remember the triptans: 5HT = 5-hydroxytryptamine which was named "serotonin" because it was found in serum = "sero" + "tonin" = it increases vascular tone (in other words, serotonin is a vasoconstrictor). Migraines are caused by arterial dilation, serotonin is a vasoconstrictor, so if a drug acting on serotonin receptors is useful in treating migraines then it must be a 5HT agonist. I find that if I just try to memorize this type of info I soon get confused about which drugs are agonists and which are antagonists. - JM