Pharmacology 8-10amSonia Patel

11/03/00Nehal Shah

Dr. Machu

LOCAL ANESTHETICS

General Properties

*block nerve conduction, affect both sensory and motor nerves, effects are reversible

Mechanism of Action

*blockade of voltage dependent Na channels

*normally neuron is at certain resting membrane potential, then Na leaks into cell reaching a threshold potential and a spontaneous action potential occurs

*local anesthetic: as Na channel opens, it enters through the cytoplasmic site and enters the channel to start blockade. Thus, subsequent action potentials become lower in amplitude until they are blocked completely

*final pathway: reduction in Na current

*pore blockers: their actions are frequency-dependent. Voltage dependent Na channel must open for anesthetic to gain access to site of action. If firing rate of a neuron is increased, that neuron is more susceptible to anesthetic because it is opening more frequently. In contrast, a neuron that fires slowly is less susceptible to anesthetic action.

*After Na channels are activated, they desensitize and are rapidly inactivated. In the inactive state, they are not available for reopening eve if membrane depolarization occurs.

*Local anesthetics also stabilize Na channel s in the inactive state, making it less likely to fire

*If you depolarize the membrane, you will increase the probability of Na channel opening and increase the susceptibility to local anesthetics

*In contrast, hyperpolarized neuron decreases the probability of firing and decreases susceptibility to the local anaesthetic

Effect on pH

*most local anesthetics are weak bases with pKa’s of 8-9, poorly water soluble as free base

*marketed in the salt form at slightly acid pH

*in the body primarily exist in cationic form

*Henderson-Hassalbach equation: pKa-pH=log (protinated/unprotinated), pH=7, pKa=9, thus 2=log (protinated/unprotinated), 100 fold ratio of protinated:unprotinated

*lipophilicity and conversion to the charged form are the rate-limiting steps for local anesthetic action

*local anesthetic comes from the extracellular site and must be uncharged to gain entry through the plasma membrane. It is then converted to charged from intracellularly. The charged form binds to the Na channel when it opens.

Features of nerve blockade

*all kinds of nerve sensitive to anesthetics

*features of nerve blockade: diameter of nerve, length of nerve, frequency of firing, location in a bundle (those on periphery will be affected before the central ones

*Type C(pain fibers) blocked quicker than Type B (preganglionic autonomic nerves), which are blocked quicker than type A (sensory and motor nerves). Motor nerves blocked last but motor function recovers first and pain function recovers last

Chemical Structures:

*two commonly used types of local anesthetics: esters and amides

*three components

lipophilic part (benzene ring)

ester/amide linkage

ionizable group

*Ester linkages are very susceptible to hydrolysis, so they have shorter duration of action. Plasma esterases rapidly hydrolyze ester linkage

Pharmacokinetics

*the ability to produce anesthetic action is limited by their systemic absorption

*Factors affecting systemic absorption

  1. properties of the drug itself: more lipophilic a drug, it will tend to be sequestered in fatty tissues and removed from the site of action. Amides taken up more rapidly than esters
  2. the site of injection: highly vascularized site will remove drug more quickly than a less vascularized site
  3. intrinsic vasodilator activity of the drug: cocaine does not have intrinsic vasodilator activity, more vasodilation, quicker removal from site of action
  4. drug-tissue binding
  5. presence of a vasoconstrictor agent: if you add a vasoconstrictor, it reduces the removal of drug from the site and increases duration of action by 50%. Drugs that are used as vasoconstrictors with local anesthetics are epinephrine, norepinephrine, phenylephrine, and vasopressin. In overdoses, local hypoxia can result. Cocaine, the only natural vasocontrictor due to its sympathomimetic activity, blocks DA and catecholamine reuptake.

Metabolism

*Esters are metabolized by butyrylcholinesterases that are present in the blood and secondarily by liver esterases. CSF has very little cholinesterases present, so esters will last for a long time if injected into the spinal column.

*Amides are metabolized by the hepatic microsomal oxidative system. Impaired liver function results in decreased amide metabolism

Esters

  1. Procaine: first synthetic local anesthetic to be marketed, low potency, slow onset, short half life
  2. Chloroprocaine: chlorinated analog of procaine, shorter half life that procaine

*Some individuals have hypersensitivity to these esters because after metabolism, para-aminobenzoic acid is formed resulting in an allergic rxn. These two drugs are made for injection and are used form infiltration, nerve block, and spinal anesthesia. They are inefficiently absorbed through the mucous membranes so they are not used on the skin.

  1. Tetracaine: longer duration of action, available in topical and injectable forms, also used in the eye and spinal anesthesia
  2. Cocaine: used topically as a respiratory tract anesthetic, used to “deaden” the ear, overdose: serious CNS side effects of extreme excitation, tonic-clonic seizures, pyrexia, cardiovascular side effects due to local anesthetic on the heart as well as sympathomimetic activity
  3. Benzocaine: topically used, available in ointments and creams

Amides

  1. Lidocaine: most widely used amid, advantages over esters include longer lasting, no hypersensitivity, sufficiently absorbed by mucous membranes, given by all routes except the eyes
  2. Bupivacaine: long duration of action, given by injection, not used topically because ineffective

Toxicology

  1. Immune system: hydrolysis of esters produces para-aminobenzoic acid
  2. Cardiovascular: due to excessive concentration being absorbed, direct inhibitory effects on the heart muscle, decreased conduction velocity and inotropic effects, arteriolar dilation leading to hypotension and shock
  3. CNS toxicity: due to accidental administration of the anesthetic intravascularly, generalized excitation due to suppression of inhibitory neuronal pathways, restlessness, convulsions, coma, cardiorespiratory arrest, with chloroprocaine=long term motor and sensory deficits

Different routes of Anesthesia

  1. surface anesthesia: aqueous salts or ointments, used over all body surfaces, including the eye, benzocaine is especially good for denuded areas (burn pts, poor absorption systemically)
  2. infiltration anesthesia: inject the drug into the region without worrying about the cutaneous route of the nerve, used for superficial tissues and intra-abdominal organs
  3. nerve block: injection of a local anesthetic into a peripheral nerve or nerve plexuses, both sensory and motor nerves are affected
  4. epidural anesthesia: used for labor in women, injected in the epidural space, which is bounded by ligamentum flavum, the dura, and the spinal periosteum. Also injected into the sacral hiatus, lumbar, thoracic or cervical regions, spinal nerve roots are mostly affected, a large amount is needed because diffusion is required.
  5. Spinal anesthesia: local anesthetic is injected into the subarachnoid space in the lumbar region, “deaden” the entire lower body, can use position of the patient and specific gravity of the drug to achieve the desired length or height of block

Adverse Effects

*autonomic nerves are particularly sensitive to local anesthetics so cardiovascular function can be depressed

*hypotension and poor venous return if the depression is severe enough

*headache is a common side effect, CSF leaking from the hole in the dura

***STUDY GUIDE***

*She will test from the learning objectives

MOA of local anesthetics

Differences between the amides and esters

Drug list: know if amide or ester and distinguishing properties

Utility of vasoconstrictors

HEADACHE

*A number of conditions can cause headaches including ruptured aneurysms, meningitis, brain tumors, TMJ syndrome, etc.

*Rule out organic causes before diagnosing a patient with migraines, cluster headaches, or tension headaches

What Kind of Headache? Diagnosis based on:

*severity, duration, location, frequency, other symptoms, pt. characteristics

Migraine Headaches

*more common in females, ratio is 4:1 of females:males

*heritable factors involved

*intense, unilateral pain. Pain is sever enough that some degree of disability occurs, does not always stay unilateral, pain often occurs in the temporal area, in the eye, but sometimes the forehead, back of the head or above the ear

*Duration: 1 hour->days

*Sensory components:

1. aura/predrome=30 min before headache occurs

2. twinkling lights, increased sensitivity to surroundings

3. visual disturbances=scintillating scotoma (in the middle of the visual field there is a bright light that breads apart and makes a zig zag pattern towards the periphery)

  1. digital-lingual syndrome-fingers start feeling numb and numbness moves up the arm to the face and tongue
  2. migranous strokes (rare): blindness can occur, paralysis of muscles

*Two types of migraines:

  1. common migraine: occurs more frequently, no aura
  2. classical migraine: aura is present

Cluster headaches

*most sever headaches

*pain is constant and usually felt in and around the eye. Some report pain in the face and neck region

*describe the pain as “pressing”

*pain is unilateral and tends to stay on one side

*autonomic effects: usually ipsilateral, runny nose, watery eyes, ptosis, miosis, and flushing

*cluster=frequency at which headaches occur, typically last 1-2 hrs in duration

*types of clusters

  1. episodic: 1-3 headaches/day for 1 week to several months
  2. chronic: 2 headaches/week for a minimum of one year

*more common in males (6:1 ratio)

*heritable factors involved

*male: has an interesting personality profile, looks bulky and big, but quiet personality, more likely to drink and smoke

Tension Headaches

*two different types

  1. everyday type: common every-day headache, responds to OTC meds like aspirin and tylenol
  2. chronic recurrent: recurrent, daily headache that lasts for hrs to days in duration, much less responsive to OTC meds, usually have an underlying emotional problem

*tension headaches more common in females

*mild to moderate pain, not as severe as migraine or cluster headaches

*pain is bilateral-pulsatile, tightening type pain

Mechanisms of Headache pain

*pain sensitive structures of the head

  1. extracranial structures: skin, subcutaneous tissues, ears, eyes, sinus cavities, muscles, arteries, veins, and the periosteum
  2. intracranial structures: arteries, veins, dural sinuses

*headaches can be caused by impingement of an artery or vein: distend, contract, or dilate which cause pain

*damage or irritating sensory nerves can cause pain

*damage or irritation of the head and neck muscles can also cause pain

*trigeminal nerve conveys sensory info to the CNS from structures that are above the tentorium and bounded by the anterior and middle fossa of the skull

*sensory stimuli from below the tentorium and bounded by the posterior fossa, as well as from the infradural sinuses, are conveyed by the first 3 cervical nerves and to a lesser extent by vagal and glossopharyngeal nerves

*pain referral can also occur

Pain of Migraine headaches

*exact cause is unknown

*some type of arterial vasodilation takes place, neurogenic inflammation takes place (release of inflammatory mediators in the CNS causes pain), increase in the central pain transmission pathway during migraine headache

*one hypothesis: some even triggers extracranial vasocontriction=reduced blood flow=reduced oxygenation of the brain=hyperemia=aural symptoms. This vasoconstriction is accompanied by neurogenic inflammation. The inflammatory mediators are released: histamine, bradykinin, substance P, calcitonin-gene related peptide. The release of inflammatory mediators may be the cause of vasodilation

*Circulating enkephalin levels in migraine patients are dramatically reduced

Serotonin

*important neurotransmitter with respect to headaches

*5-HT receptors are located n cerebral and extracranial vessels and input is received from the dorsal raphe

*5-HT has two functions: constriction and dilation of vessels, but the primary effect is constriction

*5-HT also plays a dual role in endogenous pain control systems that projects from the periaqueductal gray area so inhibitory and stimulatory 5-HT receptors are present

*Bottom line: inappropriate modulation of the serotenergic system can cause enhanced pain to be felt

*role of 5-HT is very complex

Cluster headache mechanisms

*unknown mechanisms

*increase endogenous pain control pathway, constriction followed by vasodilation, inflammatory mediators are increased, calcitonin gene related peptide is increased

*affected arteries are intraocular, where most of the pain reported is felt

*picture of angiogram: vasodilation of the ipsilateral ophthalmic artery occurring at the height of the cluster headache attack

*another angiogram: artery ahs returned to normal after the headache has ceased

Tension headache mechanisms

*unknown mechanisms

*muscle contractions more common in the everyday-type that the chronic, recurrent type

*vascular changes are likely occurring

*in chronic recurrent, patients given a vasodilator like amyl nitrite ca precipitate an attack

*increase in central pain pathway activation

Pharmacological management of headaches

*Serotonin agonists

  1. good for treatment of migraine and cluster headaches
  2. MOA: vasoconstriction but also reduce the amount of inflammatory mediators being released
  3. Some actions may also be on the pain control pathway
  4. Ergots: first treatment used for headaches
  1. alkaloids that are obtained from fungus that grows on grains
  2. extreme vasoconstriction can occur in the periphery=gangrene
  3. spontaneous abortion can occur
  4. high doses=hallucinations
  5. Ergotamine and Dihydroergotamine: most commonly used ergots used for migraine headaches, “dirty drugs”, 5-HT agonists and alpha 1 and 2 adrenergic and dopamine agonists, produce relief in 1-2 hrs, given orally, rectally, sublingual, intramuscular, inhalation, intravenous
  6. Orally: high first pass effect, absorption in inefficient (caffeine taken simultaneously to enhance absorption)
  7. Rectal route gives highest level of ergot alkaloid, most reliable headache relief
  8. Pt. should take no more than 5 mg/attack and no more that 10 mg/ week, they should have a rest period of 48 hrs between treatment to avoid rebound headaches
  9. Ergotamine: 1mg taken initially, followed by 1 mg every 30 min (5 X total)
  10. Dihydroergotamine: .5 mg nasally every 30 min (3 X total), iv/im route produces the highest levels, intranasal next best
  11. Side effects: nausea and vomiting. Ergots can be combined with metochlorpromide or phenothiazines-anti-emetics, vasocontriction=angina like pain
  12. Contraindications: vascular disease, hypertension, ischemic heart disease, hepatic and renal disease, pregnancy, peptic ulcer disease
  1. “Triptan” drugs: agonists of 5-HT receptors
  1. Sumatriptan (Imitrex) first one developed, orally and subcutaneously administered, less side effects than ergot alkaloids, more selective to the 5-HT 1 receptors, especially 5HT1b and 1d receptors, can cause coronary vasospasm, not given intravenously, contraindications: CV disease, hypertension, MI, angina
  2. Zolmitiptan, Naratriptan, Rizatriptan: all similar to Sumatriptan
  1. Isomeheptene (Isocom)
  1. 5-HT agonist
  2. less potent vasoconstrictor, but still provides good relief
  3. given in combo with acetaminophen and dichloralphnazone in a capsule form (Myorin), contraindications=vascular disease

*Analgesics

  1. NSAIDS: aspirin, ibuprofen
  2. Acetaminophen
  3. Opioid analgesics like codeine

Prophylactic Treatment of headaches

* MOA: unknown for headaches

  1. Methysergide (Sansert)
  1. migraine and cluster type headaches
  2. 5-HT antagonist, but a weak partial agonist
  3. vasoconstriction activity is negligible
  4. stabilizes extracranial and intracranial vasculature
  5. adverse effects: fibrosis in retroperitoneal, pleuropulmonary, and cardiac tissues, pt should not take drug longer than 6 months, taper off the drug gradually because rebound headache can develop, vasoconstriction, angina-like pain, peripheral vascular insufficiency, nausea and vomiting, CNS disturbances, excitation, sleepiness
  1. Migraine Prophylaxis
  1. B-blockers: MOA is unknown, b-blockers with intrinsic sympathomimetic activity are ineffective
  2. Ca channel blockers
  3. Alpha 2 adrenergic agonists
  4. NSAIDS
  5. Antidepressants
  6. Cyproheptadine: 5-HT antagonist, antihistamine, too sedating for adults
  1. Cluster headache prophylaxis
  1. NSAIDS
  2. Lithium
  3. Corticosteroids: short course for 2-3 weeks, can terminate the cluster headaches
  1. Tension headache prophylaxis
  1. antidepressants
  1. Look at table on last page of notes: all headaches have a component due to stress, migraine/cluster headaches have some associated with food and drink triggers. Other considerations: association of migraine headaches with onset of menstrual period

***STUDY GUIDE***

*all test questions come from learning objectives

*three types of headaches: common features and differences

*drug list: know what type of headache it is used for, whether used prophylactically or acutely

*MOA if known, major side effects and contraindications