Furr and Reed Ch 4, 7, 9, 25, 32; Spinal Cord Injury MDR

What % of all drugs does the BBB exclude from entering the brain from the blood?

>95%

What does diffusion of compounds across the BBB depend on?

• Lipid solubility

• Molecular weight

• Electrical charge and ionization

What kinds of drugs will have a diminished capacity to cross the BBB?

Highly protein bound drugs

What drugs cross the BBB most readily?

Drugs that are lipid-soluble, have a small molecular size, and are nonionized at CSF pH

How does meningeal inflammation affect the penetration of drugs across the BBB?

Meningeal inflammation will increase the penetration of many drugs

Elimination Half-Life for Drugs in the CNS or CSF

Elimination half-life for drugs in the CNS or CSF is frequently longer than serum allowing for accumulation

What mechanism removes chemicals from the CSF independent of their physicochemical properties?

Bulk flow

Active Mechanisms of BBB that Influence CNS Drug Concentrations

• Low-capacity facilitated diffusion system in the BBB for some penicillins and cephalosporins to transport from the blood into the extracellular fluid of the CNS

• Mechanism for active efflux from the CSF using the multidrug resistance transporter protein

Factors that Influence CNS Concentration of Drugs

Presence of BBB

Lipophilicity of compound

Protein binding

Physical size/radius

Molecular charge

Active transport

Active efflux

Bulk flow

Presence or absence of meningeal inflammation

Penicillin in the CNS

• CSF concentration 10% of serum concentration

  • Ampicillin achieves higher concentration in the CSF but only with meningeal inflammation

Cephalosporins in the CNS

• Third and fourth generation cephalosporins ceftazidime, cefotaxime, and cefepime achieve good CSF concentrations and have a favorable spectrum of activity

• Do not uniformly cross the BBB

• Ceftrioxone can be used for treatment of bacterial meningitis in horses but is cost prohibitive other than in foals and small ponies

• Cefotazime used with success in foals with meningitis

• Cephapirine not consistently found in the CSF following IM dosing and therefore is likely not useful in treatment of CNS infections in horses

• Ceftiofur unable to be detected in CSF after repeated dosing

• Expense of cephalosporins limits use to neonates in many cases

Chloramphenicol in the CNS

• Favorable spectrum of activity and achieves almost 60% of serum concentrations in CSF

• Short half-life requires frequent dosing

• 25-59 mg/kg PO q6h

Trimethoprim/Sulfamethoxazole or Ormentoprim/Sulfadimethoxine in the CNS

• CSF concentration not adequate against many equine pathogens

• Meningeal infection does not appear to enhance CSF concentration of TMP/SMZ

• Not ideal drug for use in CNS infections

• Coadministration of DMSO had no effect on CSF concentration of TMP or SMZ

• Sulfonamide administration associated with potential complications including diarrhea and anemia and potentially neurologic signs

Fluoroquinolones in the CNS

• Highly lipid-soluble

• Reported to achieve high concentrations in the CNS following parenteral administration

• Enrofloxacin CSF concentration approximately 15 and 25% of corresponding serum concentrations at 74 and 84h following treatment

• Valuable for treatment of bacterial meningitis

• Use in foals associated with high risk of arthropathy

• High doses as a bolus have resulted in seizures assumed to result from transient high CSF concentrations and binding of GABA receptors in the CNS

Rifampin in the CNS

• Achieves high CSF concentrations

• Must be administered with other antibiotics due to rapid development of resistance

Metronidazole in the CNS

• Highly lipophylic

• Achieves high concentrations in CSF

• Used almost exclusively for anaerobic infections which have not been reported in the CNS of horses so use is limited

Aminoglycosides in the CNS

• Does not result in measurable concentrations in the CNS

Tetracyclines in the CNS

• Doxycycline doesn't result in measurable concentrations in the CNS

• Minocycline results in adequate CSF concentrations and may be useful in treatment of CNS infections

Macrolides in the CNS

• Entry of erythromycin into CNS and CSF considered poor

• Azithromycin may have value in treatment of CNS abscesses caused by sensitive organisms

Antibiotics with Good Concentrations in the CSF

Ceftriaxone

Cefotaxime

Chloramphenicol

Rifampin

Metronidazole

Enrofloxacin

Antibiotics with Intermediate Concentrations in the CSF

TMP/SMZ

OMP/S

Minocycline

Antibiotics with Poor Concentrations in the CSF

Penicillin

Ampicillin

Cephapirin

Ceftiofur

Doxycycline

Acyclovir

• Acyclovir proposed for the treatment of EHV-1 myeloencephalopathy

  • Acyclic nucleoside analog

  • Has good activity against herpes simplex virus type 1 and 2

  • Oral availability poor

  • Used at 20 mg/kg q8 in one EHV-1 outbreak, but no clear benefit

  • Current evidence doesn't support use in horses with EHV-1 associated disease

Valacyclovir

• Prodrug of acyclovir

• Appears to have much better bioavailability

• Converted to acyclovir following oral administration

• Oral dose of 20-40 mg/kg q8h recommended for treatment of suspected susceptible infections

• In one study had no effect on clinical signs, viral shedding, or magnitude of viremia in EHV-1 infected ponies

• Unknown utility in equine viral infections

Anti-Inflammatory Drugs in CNS Disease

• Prostaglandins and thromboxanes are produced in the CNS in seizures, inflammation, TBI, and cerebral vascular disease

• Relative concentrations of and ability to produce eicosanoids appear to vary depending upon the region of the CNS affected

• NSAIDs should be useful in horses with neuroinflammation as well as attenuating fever, myalgia, and perhaps improving appetite

Use of Corticosteroids for Neuroinflammation

• Effective in treatment of cerebral edema and attenuate tissue injury by inhibiting host mediators at several steps in the inflammatory process

• Concern for potential for immunosuppression allowing progression of infection

• Studies in people with bacterial meningitis have found administration of dexamethasone reduces risk of death, hearing loss, neurologic sequelae and was associated with a low risk of side effects

• Assumed general beneficial effects upon cerebral inflammation would exist for horses as well

• Risk of laminitis must be considered

• Short-term course of corticosteroids in horses with bacterial meningitis seems warranted

Use of Corticosteroids in Viral CNS Disease

• Used successfully in people with West Nile virus encephalitis and proven beneficial in acute viral meningitis

• In horses with neurologic deficits due to viral encephalitis that are severe enough to require hospitalization, a short course of corticosteroids is strongly indicated

DMSO for Neuroinflammation

• Clinical experience suggests an anti-inflammatory effect but no conclusive evidence

• Calcium flux as a result of exictotoxic amine release causes neuronal cell death

  • DMSO decreases exictotoxic cell death of neurons

  • DMSO enhances the drug-induced blockade of calcium channels

• Dose of 0.5-1 g/kg as a 10% solution (IV) 2 times per day recommended in cases of neuroinflammation

• Solutions greater than 20% can cause hemolysis

• Dosages of 4 g/kg IV were associated with toxic signs in horses including muscle trembling, loose stool, and colic which stopped after stopping drug administration

Mechanism of Hypertonic Saline to Reduce ICP

• Beneficial effects of hypertonic saline persist even when followed by normal crystalloid solutions and appear to be due to ability to draw water from the cell, decreasing tissue pressure

Mechanism of Mannitol to Decrease ICP

• Osmotic theory to explain effects of mannitol on ICP states that the CNS shrinkage is a result of osmotically driven movement of fluid from the tissue into the vascular component

  • Additional theories include reduction of CSF production and direct vascular effects

Mannitol for Neuroinflammation

• Rapid reduction of ICP noted following bolus dosing of mannitol

  • Rebound effect may occur after treatment is stopped and repeated dosing leads to progressively reduced effects due to accumulation of mannitol in tissues

• Mannitol should not be used in horses with subarachnoid or intraparenchymal hemorrhage due to potential to exacerbate bleeding or increase ICP

What are anticonvulsants used for?

To reduce the incidence, severity, or duration of seizures

What does epileptical activity arise from?

From an imbalances between excitatory and inhibitory neural transmitters, which induces and abnormal hypersynchronous electrical activity of neurons

Principle Excitatory Neurotransmitter in the Brain

Glutamate

Principal Inhibitory Neurotransmitter in the Brain

GABA

Action of Glutamate in the CNS

• Depolarization reaching the presynaptic nerve terminate induces release of glutamate

  • Glutamate binds to NMDA receptors on postsynaptic membrane, opening sodium and calcium channels

  • Sodium and calcium enter the postsynaptic neuron

  • Leads to post-synaptic depolarization and generation of excitatory postsynaptic potential

Actions of GABA in the CNS

• When GABA attaches to the post-synaptic GABA_A receptor, chloride channels are opened

  • Chloride enters the postsynaptic neuron causing a state of hyperpolarization and an inhibitory postsynaptic potential

What do anticonvulsant drugs act on and what is their action?

• Anticonvulsant drugs act on pre- and postsynaptic ion channels to stabilize the neuronal membranes and limit the development and spread of the epileptical focus activity

Phenobarbital MOA

• Activates GABA-gated chloride channels, increasing intracellular chloride conductance and inducing hyperpolarization of neuronal cells

• Also inhibits postsynaptic potentials produced by glutamate and inhibits voltage-gated calcium channels at excitatory nerve terminals

Phenobarbital

• Barbiturate

• Overall result is increase in seizure threshold

• Very good bioavailability (~100%)

• For acute management - 12-20 mg/kg IV diluted in saline given over 30 mins, followed by 1-9 mg/kg q8-12h

• Maintenance therapy usually oral, 11 mg/kg q24h in adults

MOA of Benzodiazepines

• Bind to GABA_A receptors in the CNS and activate GABA-gated chloride channels to increase chloride conductance, making the cell more resistant to depolarization

Benzodiazepines for Seizures

• Preferred drugs for acute treatment of seizures, including status epileptics, because they rapidly cross the BBB due to high lipid solubility

• Highest density of benzodiazepine binding sites are in cerebral cortex, cerebellum, limbic system, and peripheral tissues

• Benzodiazepines don't activate GABA receptors directly but require GABA to produce their effect

• Recommended dosage 0.05-0.2 mg/kg (~50 mg for adult horse) IV or IM PRN

• Short duration of action (10-15 min) so repeated doses may be needed

• Caution with prolonged usage as can cause respiratory depression or arrest in foals

• If no response to initial bolus, CRI can be implemented at rate of 0.1 mg/kg/h

Potassium Bromide for Seizures

• Mechanism unknown

• Believed that it hyperpolarizes neuronal membrane through its action on chloride channels and by its synergistic effect with barbiturates and benzodiazepenes

• Primarily used to treat seizures refractory to phenobarbital

Carbamazepine

• 1.6-2.4g, q6 in combination with cyproheptadine reported to be effective in treating horses with headshaking, without apparent side effects

Gabapentin MOA

• Main mechanism of action is due to inhibition of voltage-dependent calcium channels, inhibiting glutamate release

Gabapentin

• Synthetic GABA analog that crosses the BBB

• Rapidly absorbed

• Peak plasma levels occurring ~2h after 5 mg/kg oral administration

Antipsychotic Drugs (Neuroleptics)

• Suggested that increased activity of dopamine plays an important role in stereotypies

• Antipsychotic drugs have a greater affinity for central dopamine receptor (primarily D2) than dopamine so they decrease dopamine activity and synthesis

• Dopamine depletion causes calming, depression, and extrapyramidal signs

• Not commonly used with the exception of acepromazine (phenothiazine tranquilizer)

Acepromazine MOA

• Blocks postsynaptic dopamine receptors in the CNS

• Also have some antagonistic effects on alpha-adrenergic, histaminergic, serotonergic, and muscarinic receptors

Acepromazine as an Antipsychotic

• Short-acting phenothiazine neuroleptic

• 0.02-0.1 mg/kg IV

• Produces calming, reluctance to move, and mild ataxia

• Onset of action is slow with peak effects reached within 15 min and 1 h after IV and oral administration, respectively

• As a CNS depressant, it blocks a range of central effects including respiratory response and locomotor activity

• Hypotension may develop as a result of alpha-1 adrenergic receptor blockage and decrease of sympathetic tone

• May lower seizure threshold and potentiate seizures in predisposed animals

Fluphenazine

• Highly potent phenothiazine neuroleptic

• Used extra-label in young, nervous, or fractious performance horses for training and/or transport

• Suggested to reduce self-mutilation and other stereotypies

• High potential for abuse

MOA of SSRIs

• Bind to serotonin transporters and block the reuptake of serotonin by the presynaptic nerve terminal, therefore prolonging its exposure to receptors on the postsynaptic membrane

SSRIs

• Have little effect on reuptake of norepinephrine so are more specific

• Fluoxetine (Prozac) used to manage aggression in horses

  • May require 4-6 weeks to become maximally effective

Benzodiazepines as Anxiolytics

• Produce anxiolytic and muscle-relaxant effects in addition to anticonvulsant effects

• Diazepam potentiates most common anesthetic agents so is usually coadministered with opioids and nonopioid analgesics for additive sedative effects

  • Peak drug effects reached 10 mins after IV administration, 20-40 mins after IM administration, and 1 h after oral administration

  • High doses can cause muscle weakness, ataxia, and recumbency

• Reversed with flumazenil and sarmazenil

Buspirone as an Anxiolytic

• Partial agonist for serotonin receptor

• Lacks sedative and muscle relaxant side effects so may be better for treatment of anxiety disorders in horses

Therapy for Headshaking

• Cyproheptadine, a histamine (H-1) blocking agent, believed to be efficacious in some horses because of its serotonergic blocking antagonist properties

  • Serotonin plays a role in pain sensitization

  • Also has anticholinergic and sedative effects

  • Side effects include mild depression, anorexia, and lethargy

Reserpine

• Noradrenergic depleting agent as it blocks a vesicular monoamine transporter and inhibits the uptake of norepinephrine and other monoamines into storage vesicles of sympathetic neurons

• Not approved for use in horses but sometimes administered as a sedative because of efficacy at low doses and long duration of action

• Side effects include hypotension, bradycardia, and diarrhea

Seizure

Paroxysmal event that arises due to excessive discharges of the cerebrocortical neurons

Seizure vs Epilepsy

Seizures are specific clinical events vs epilepsy is reoccurring seizures from a chronic underlying process

Clinical Signs of Seizures

• Mild alterations in consciousness

• Focal muscle fasciculations

• Recumbency with tonic-clonic struggling - stiff, hypertonic limbs with repetitive, rhythmic struggling

  • Rhythmic patterned movements help to discriminate true seizure from struggling

• Nonarousable vs horses that are struggling are somewhat responsive to examiner

Prodromal Phase (Preictal or “Aura”)

Restless or distracted or demonstrates other changes in mentation

Postictal Phase

•  Usually a period where horse remains depressed, quiet, and may be blind

  • Blindness usually transient in adults, can last for several days in foals

Partial Seizure

• Arise from a discrete area of the cerebral cortex

• Results in localized clinical signs (facial or limb twitching, self-mutilation)

• Appear to be the most common classification in horses

Partial Seizure with Secondary Generalization

Progression and spread diffusely through the cortex

Jacksonian March

Progression of a very localized abnormal movement to involve more of the extremity

Represents spread of the seizure focus over progressively large areas of the cerebral cortex

Complex Partial Seizure

• If consciousness is impaired

  • Common in neonatal foals

  • Commonly seen as "chewing-gum fits", jaw chomping, and lip smacking

  • Automatisms - involuntary automatic behaviors

Generalized Seizure

Arise from both cerebral hemispheres simultaneously

Primary Generalized Seizure

Generalized from the onset

Secondary Generalized Seizure

Secondary to a partial seizure

Status Epilepticus

Rapid succession of seizures

Uncommon in adult horses

Reactive Seizures

Presence of a temporary systemic disease with a normal brain function

Symptomatic Seizures

Presence of identifiable structural brain lesion

Genetic Origin of Seizures

Arabian foals with juvenile idiopathic epilepsy

Likely Causes of Seizures in Foals

Hypoxic-ischemic encephalopathy, trauma, congenital disorders, metabolic derangements

Common Causes of Seizures in Adult Horses

Trauma

Hepatoencephalopathy

Toxicity

When is CSF collection from the AO space contraindicated?

If the horse is showing signs of increased CSF pressure such as mydriasis or papilledema

Causes of Bloody CSF

Trauma

Verminous migration

Tumors

Causes of Xanthochromic CSF

Slight is normal in neonates up to 10 days of age, prior hemorrhage, and/or diffuse inflammatory conditions

EEG

• Graphic recording of rhythmic bioelectrical activity arising predominantly from the cerebral cortex

• Can be performed on awake, sedated, or anesthetized animals

  • In humans and small animals optimal on awake patients because sedation and GA influences EEG patterns by altering cortical activity but does significantly reduce artifacts caused by head, ear, and eye movements

  • Can record electrooculographic, electromyographic, and electrocardiographic activities and behavior to identify bioelectrical artifacts

  • Sedation or GA usually needed in horses

• Assess the background for abnormal frequency and amplitude, the presence of asymmetrical patterns between regions, and the presence of paroxysmal activity

  • Most common abnormalities associated with cerebral diseases are the change in either amplitude or frequency, or both

• EEG reflects the process occurring, not pathognomonic of disease

Epileptiform Paroxysmal Activity

• Abnormal paroxysmal transient events, such as spikes, sharp waves, and spike and wave discharges

  • Supports the diagnosis of seizures

  • Lack of epileptic activity doesn’t rule out seizures - use of tranquilizers can increase seizure threshold and recording window may be too short to capture

Limitations of EEG

• Only electrical activity arising from the superficial part of the cerebral cortex is recorded

• Establishment of normal values difficult because frequency and amplitudes are state-dependent and vary with age

• Requires expertise for interpretation

• Limited to large private practices and neurological referral institutions

Goals of Treatment of Seizures Disorders

Stop the seizure

Correct underlying disease

Maintain seizure-free status

Medications for Initial Therapy to Control Seizures in Adult Horses

Diazepam

Phenobarbital

Phenytoin

Pentobarbital

Chloral hydrate

Guaifenesin

Medication for Maintenance Therapy to Control Seizures in Adult Horses

Potassium bromide

Phenytoin

Medications to Control Cerebrocortical Edema in Adult Horses

Dexamethasone

Methylprednisolone

DMSO

Mannitol

Furosemide

Antioxidant and NMDA Receptor Blockade Therapy in Adult Horses

Vitamin E

Ascorbic acid

Allopurinol

Magnesium sulfate

Proper Hydration and Nutritional Support in Adult Horses with Seizures

Cautious fluid therapy

Oral feeding (if tolerated)

Correcting Metabolic Derangements in Adult Horses with Seizures

Oxygen therapy

Glucose supplementation

Minimizing Chances of Trauma in Adults Horses with Seizures

Provide thick bedding, heavy padding, helmet, and leg wraps

Initial Therapy for Controlling Seizures in Foals

Diazepam

Midazolam

Phenobarbital

Phenytoin

Primidone

Pentobarbital

Chloral hydrate

Guaifenesin

Maintenance Therapy for Preventing Seizures in Foals

Phenobarbital

Phenytoin

Primidone

Controlling Cerebrocortical Edema in Foals

Prednisolone

DMSO

Antioxidant and NMDA Receptor Blockade Therapy in Foals with Seizures

Vitamin E

Ascorbic acid

allopurinol

Magnesium sulfate (HIE)

Providing Respiratory Support to Foals with Seizures

Oxygen supplementation

Caffeine

Positive pressure ventilation

Providing Proper Hydration and Nutritional Support to Foals with Seizures

Cautious fluid therapy

Oral feeding (if tolerated)

Parenteral nutrition

Support body temperature

Providing Metabolic Support to Foals with Seizures

Glucose supplementation

Electrolyte supplementation

Thiamine (HIE)

Minimizing Chances of Trauma in Foals with Seizures

Provide thick bedding, heavy padding, head helmet, and leg wraps

Action of Benzodiazepines in Short Term Control of Seizures

• Hyperpolarize neuronal cells by binding to the gamma-aminobutyric (GABA) receptor, amplifying the action of GABA on chloride channels in the cell membrane

• Increased chloride conductance hyperpolarizes the neuronal cell membrane, making the cell more resistant to depolarization

• Results in increased seizure threshold and decreased electrical activity of the seizure focus

Diazepam

• Distributed rapidly to the CNS after IV administration

• Short half-life (10-15 min)

• Prolonged usage can lead to respiratory depression or arrest in foals

• Slower clearance reported in foals <21 days old

• >0.2 mg/kg in adults may cause muscle weakness and ataxia

• May exacerbate clinical signs with hepatoencephalopathy due to upregulation of benzodiazepine receptors

• CRI can be run @ 0.1 mg/kg/h

Midazolam

• 0.05-0.1 mg/kg IV or IM

• CRI in foals with recurrent seizures @ 1-3mg/h for 50 kg foal

• Large volume of distribution and fairly long T1/2

Negative Effects of Xylazine for Seizures

• Xylazine reduces cerebral blood flow after transiently increasing intracranial pressure