Antiepileptic Drugs

Seizures and Epilepsy Seizure rapid, synchronous, and uncontrolled spread f electrical activity in the brain Epilepsy a disorder characterized by recurring seizures A seizure is a symptom of epilepsy

Epilepsy Approximately 2.3 million Americans have epilepsy Approximately 180,000 new cases of seizures and epilepsy occur each year 50% of people with epilepsy develop seizures by the age of 25 years approximately equal number of people with epilepsy below age of 10 and above 60 mortality - approximately 1400 a year young adults with severe epilepsy 1100 a year Response to Medication

Groups at Increased Risk for Epilepsy above 1% of the general population develops epilepsy the risk is higher in people with certain medial conditions including: o mental retardation o Cerebral palsy o Alzheimers disease o stroke o autism o young children and older adultsp Epilepsy in Women Hormonal effects

o Hormonal changes during puberty, menopause, and the monthly cycle may affect seizure frequency o Polycystic ovary syndrome Sexuality & contraception o Sexual dysfunction o Birth control pills may be less effective When have high progesterone decrease the likelihood of seizures Pregnancy & motherhood o Need to continue medication o Slight increased risk for birth defects

Epilepsy in Older Adults epilepsy is common in the elderly, and is often unrecognized and undiagnosed older people face increased treatment risks o breaking down and metabolism, maintain independence is a challenge after the diagnosis of epilepsy Epilepsy is a symptom of numerous disorders but in the majority of sufferers the cause remains unknown Etiology Genetic o Malformations of cortical development, channelopathies Acquired brain insults o Prenatal, perinatal, postnatal o Head injury, stroke, brain tumors, vascular malformations, degenerative and demyelinating brain disorders, intracranial infections, etc Metabolic disorders o Hypoglycemia, hyponatremia, hypocalcemia Toxins and drugs o Alcohol, benzodiazepines, and AED withdrawal (antiepileptic drug) o Cocaine, heroin, ecstasy, amphetamine Environmental factors o Photic stimulation Pathophysiology Seizures Pathophysiology is only beginning to be determined All seizures involve abnormal synchronous discharge Classified according to their clinical manifestations 2 major types: o partial seizures begin focally o generalized seizures begin generally and involve both hemispheres

Partial Seizures Motor o Rhythmic jerking, posturing, head and eye deviation, other movements (eg cycling), automatisms (e.g. plucking), vocalization Sensory o Somatosensory, olfactory, gustatory, visual, auditory Psychic o Memories, dj vu, jamais vu, depersonalization, aphasia, complex visual hallucinations etc. Partial Seizure Pathophysiology initiation at the cellular level synchronization of surrounding neurons spread to adjacent regions (then called secondary generalized seizure) seizures begin focally 3 type: o simple partial: consciousness is not impaired; symptoms vary depending on location in brain; no change in mental status o complex partial: altered consciousness; classically preceded by an aura; involve brain regions such as language, memory, and emotions o partial seizure with secondary generalization: loss of consciousness Primary Generalized Seizures Pathophysiology seizures involve both hemispheres; activity begins in a focus but then spreads to subcortical areas. Generally does not begin with an aura. 3 types: o Absence seizure (petit mal) sudden, brief interruption of consciousness, blank stare, occasional motor symptom Typical vs. Atypical Typical absence seizures non-convulsive with muscle tone preserved. The seizure usually lasts less than 10 seconds Atypical absence seizures convulsive, longer in duration, loss in muscle tone, and tonic/clonic movements are observed o myoclonic seizure brief, muscle contraction, associated with systemic disease, no aura o tonic-clonic (grand mal) as above, but onset is abrupt, not preceded by symptoms, often aura present Tonic clonic seizures generalized convulsion occurring in the tonic phase and the clonic phase. Often this is preceded by an aura

Tonic phase muscles stiffen up, person loses consciousness, body grows rigid Clonic phase body extremities jerk and twitch Secondary generalized tonic-clonic seizures being locally with partial seizures

Potentially Dangerous Responses to Seizure Dont restrain person Dont put anything in the persons mouth Don try to hold the person down Dont attempt to give oral antiseizure medication Dont keep the person on their back face up Physiology Review AP is propagated by alternating currents in the cells of depolarizing Na+ influx and hyperpolarizing K+ efflux NTs diffuse across the synapse, binds to receptors, and initiates a response on the post-synaptic cell Duration and frequency of the AP is limited by the properties intrinsic to Na+ channels AP and Na+ channels 3 distinct states: resting state (closed), activated state (open), inactivated state (closed) Na channels will not open again until reaches the resting potential Both Na+ and K+ channels impose a limit on the frequency of firing Neural networks ensure specificity of signaling by restricting the effects of the AP to a defined area Co-activation of inhibitory GABA signals on surrounding neurons results in surround inhibition that insulates and protects against synchronicity in surrounding areas Factors Modifying Neuronal Excitability Post-translational modification of channels (phosphorylation, etc) Ion channel type, number and distribution Activation of second-messenger systems that affect channel function Modulation of gene expression of ion channels Changes in extracellular ion concentration Changes in extracellular space Modulation of transmitter metabolism or uptake by glial cells Normal CNS Function Always a balance of excitability and inhibition Physiological evidence for the pathophysiology of seizures

Genetic Evidence for Epilepsy Voltage-gated sodium channel gene mutations Voltage-gated chloride channel gene mutations Voltage- gated potassium channel mutations Neurotransmitter Receptor Mutations o GABA-receptor gamma-2 subunit o GABA-receptor alpha-1 subunit o Nicotinic acetylcholine receptor alpha-4 subunit o Nicotinic acetylcholine receptor beta-2 subunit Summary cellular mechanisms of seizure generation Excitation (too much) o Ionic - inward Na+, Ca++ currents o Neurotransmitter glutamate, aspartate Inhibition o Ionic inward Cl-, outward K+ currents o Neurotransmitters - GABA

Hyperexcitabaility reflect both increased excitation and decreased inhibition

Strategies in Treatment Stabilize membrane and prevent depolarization by action on ion channels (i.e. inhibit Na and Ca channels) Increase GABAergic transmission Decrease glutamate transmission Antiepiletic Drugs 5 Main Categories I. Drugs that enhance Na+ channel mediated inhibition Phenytoin Acts on Na+ channels to slow rate of channel recovery from inactivated state to closed state Largely acts on channels that open and close frequently inhibits sudden rapid neuronal firing Major drugs choice for partial and tonic-clonic seizures More than 95% bound to HSA (hormone serum albumin) Inactivated by liver Cyt P450therefore careful with other AED Cyt inducers life of 24 hrs chronic toxicity o dose related vestibular/cerebellar effects o behavioral changes o gingival hyperplasia o GI disturbances o Sexual-endocrine effects Hirsutism Carbamazepine Also acts on Na channel to slow rate of channel recovery from inactivated state to closed state Largely acts on channels that open and close frequently inhibits sudden rapid neuronal firing Major drug of choice for partial seizures Several doses are often taken daily Inactivated by liver Cyt P450 life of 10-20 hrs II. Drugs that inhibit Ca++ channels 2 classes Drugs that inhibit T type Ca++ channels Drugs that inhibit high voltage activated (HVA) Ca++ channels Ethosuximide Acts on T type Ca channels

T type channel is activated in absence seizures during the awake state Major drugs of choice for absence seizures Side effects in GI and CNS

Valproic Acid Limits activity of T type Ca channel Lower concentrations slows the rate of Na channel recovery from the inactivated state Increases the activity of GAD Inhibits the activity of GABA degradation enzymes One of the most effective AEDs Drug of choice for idiopathic generalized seizures Inhibit liver enzymes Gabapentin Inhibits HVA Ca channels Structural analogue of GABA Increase GABA in neurons Few interactions with other drugs Not a very good AED for most patients III. Drugs that enhance GABA mediated inhibition Benzodiazepines Increase affinity of GABA for the GABAA receptor and enhance GABA gating increase in Cl- influx Act on a subset of GABAA receptors Suppresses seizures by raising the threshold of the AP as well as strengthening the surround inhibition Used for treatment of partial and tonic-clonic seizures Used for acute attacks due to side effects of dizziness and drowsiness Barbiturates Binds to allosteric site on the GABAA receptor potentiates the action of endogenous GABA by increasing the duration of Clchannel opening Also GABAA receptor agonist Act on all GABAA receptors Used for treatment of partial and tonic-clonic seizures May also cause seizures Strong sedative effects, also folate and vitamin K deficiency IV. Drugs that enhance GABA transmission

Vigabatrin Irreversible inhibitor of GABA transaminase Potential to cause psychiatric disorders (depression and psychosis) Tiagabine Decreases GABA uptake by neuronal and extraneuronal tissues V. Drugs that inhibit glutamate receptors Felbamate Inhibits NMDA receptors Very potent Serious hematological and hepatic toxicities Generally used in patients with extremely refractory epilepsy

Anxiolytic Drugs
Anxiolytics drugs used to treat and prevent anxiety disorders. Anxiety an emotional state in which fear dominates a persons life Types of Anxiety Disorders Generalized Anxiety Disorder chronic anxiety, exaggerated worry with little or nothing to provoke it Obsessive- Compulsive Disorder recurrent, unwanted thoughts (obsessions) and repetitive behaviors (compulsions). Not acting on these thoughts or carrying out the behaviors causes anxiousness Panic Disorder unexpected episodes of intense fear with autonomic nervous system activation Post-Traumatic Stress Disorder prompted by a severe trauma and causing episodes with a sense of reliving part of the event Social Phobia overwhelming self-consciousness in public that prevents normal function

Pharmacological Treatment of Anxiety Disorders Benzodiazepines (modulate GABAergic neurotransmission) Barbiturates (modulate GABAergic neurotransmission) Serotonin (5-HT) receptor agonists Antidepressants trycyclics, SSRIs Beta-Blockers inhibit epinephrine mediated symptomsblock receptors in fight or flight response Review of Neurotransmission An AP reaches the axon terminal of the presynaptic cell and causes V-gated Ca++ channels to open Ca++ rushes in, binds to regulatory proteins and initiates NT exocytosis NTs diffuse across the synaptic cleft and then bind to receptors on the postsynaptic membrane and initiates response on the post synaptic cell Review Neurotransmitters There are at least 15 different neurotransmitters in the body Each neuron generally synthesizes and releases a single type of NT Depending on the type of ion channel which the NT opens, the postsynaptic cell membrane becomes either depolarized or hyperpolarized Voltage change at receptor site results in a postsynaptic potential (PSP) changes the probability of the post-synaptic neuron firing NTs acting on post-synapse results in influx of anions or an efflux of cations decrease membrane resistance = decrease responsiveness

hyperpolarized membranes = (-) voltage shift = inhibitory post-synaptic potentials NTs acting on post-synapse can cause cation channels to open increase membrane resistance increase responsiveness depolarized membranes = (+) voltage shift = EPSP

Review Neurotransmitters Signaling Each synaptic signaling results in either an inhibitory or excitatory input on the post synapse But each postsynaptic neuron may have synapses with 10,000 or more presynaptic neurons, often of many types Requires integration of signals PSPs add up, balance out, i.e. balance between IPSPs and EPSPs A neuron fires if sum of input > threshold o Sum of input = sum of excitatory input sum of inhibitory input Some Neurotransmitters

Neurotransmitter Basic Function

Acetylcholine Dopamine Epinephrine Norepinephrine GABA Serotonin Glutamate Mostly Excitatory Generally Excitatory Excitatory Excitatory or Inhibitory Inhibitory Generally Inhibitory Excitatory

Physiology of GABAergic Neurotransmission Widely distributed throughout the CNS Primary inhibitory neurotransmitter in the CNS Cell membranes of most vertebrate CNS neurons and astrocytes express GABA receptors Present in high concentrations in brain and retina GABA receptors influence many neural circuits and function GABA involved in the regulation of learning and anxiety Implicated in numerous neurological and psychiatric disorders including HD, PD, schizophrenia, dementia, anxiety, and epilepsy Drugs that modulate GABA signaling affect arousal and attention, memory formation, anxiety, sleep, and muscle tone

Brief History of GABA 1883 synthesized known to exist in plants and bacteria part of the Krebs cycle 1950 Roberts and Awapara each showed high GABA in the mammalian CNS l mg/gram tissue 1953 Florey showed unknown compound from horse brain inhibited crayfish stretch receptor 1955 Florey showed inhibition of the patellar reflex in cats 1957 Florey and Bazemore (Merck) purified GABA from 10 lbs of cow brainsshowed inhibition of crayfish stretch receptor Florey then proposed GABA was acting as an inhibitory neurotransmitter in the brain But many did not believe it was a NT due to: o Enormous abundance in the brain 1000x more than other monoamine o Simple structure o Role in Krebs cycle..therfore likely involved just in metabolism o Did not inhibit cat knee-jerk response (therefore did not work in organism that made it, and not found in organism it acted upon) o Not found in significant quantities in invertebrates By 1960 GABA demoted to a mere metabolite But rehabilitation was in the works 1963-64 Del Castillo et al. using nematodes sowed GABA abolished spontaneous APs in muscles; GABA mimic piperazine also abolishes the potentials inhibition caused hyperpolarization of the muscle, mediated by an increase in Cl- conductance 1966-67, Otsuka and Del Castillo showed stimulation of the inhibitory motor neuron in Ascaris and crayfish duplicated the observed effect by GABA application 1977 benzodiazepine binding sites discovered in the brain 1981 GABAA and GABAB receptors pharmacologically distinguished 1987 GABAA receptors cloned 1987, 1991 Guastella, Johnson, and Stretton, Kravitz found high concentrations of GABA in inhibitory neurons so now recognized as a full fledged NT early 1990s molecular composition of GABAA receptor elucidated mid 1990s genes required for GABA function further elucidated through C. elegans studied

GABA Metabolism

the synthesis of GABA is mediated by glutamic acid decarboxylase (GAD) via decarboxylation of glutamate to GABA in GABAergic nerve terminals

GABAergic Signaling

2 main types of GABA receptors Ionotropic and Metabotropic

Ionotropic- GABAA and GABAC receptors anion permeable ion channel (Cl-) Metabotropic GABAB receptors G protein coupled receptors mostly expressed in the spinal cord

Comparisons

Ionotropic Fast Ion flow in/out Milliseconds Metabotropic Slow Second messenger cascades Seconds Ionotropic GABA Receptors GABAA Receptors Anion permeable ion channel (Cl-) Multi-subunit complex (pentameric) Major inhibitory transmitter in the adult brain 2 molecules of GABA must bind for the channel to open 5 subunits- each subunit is largely one of 3 types , , each subunit contains 4 membrane spanning domains most abundant subtype is 22 mediates a fast synaptic IPSP GABAC also ionotropic pentameric ligand gated Cl- channels, but largely found in retina and involve other subunits Multiple subtypes of GABA receptors are expressed in brain GABA can be excitatory due to change in intracellular [chloride]

In immature neurons, [Cl-] is high so ECl- is depolarized relative to Vm In mature neurons, [Cl-] is low, ECl- is near RMP Expression of KCl transporter is developmentally regulated

Metabotropic GABA Receptors

GABAB Receptors No ion pore is formed - indirectly linked with ion channels on the PM via signal transduction mechanisms G protein coupled receptors Expressed in spinal cord GABAB receptors function as heterodimers of GABAB1 and GABAB2 subunits Presynaptic inhibit neurotransmitter release by reducing Ca++ influx Postsynaptic slow ISPs though activation of G protein activated K+ channels or GIRKS Pharmacologic classes and agents affecting GABAergic Neurotrasmission Compounds effect GABA metabolism or receptor activity Vast majority act on ionotropic GABAA receptors

Therapeutic agents that activate GABAA receptors are used for sedation, anxiolysis, hypnosis, neuro-protection following stroke or head trauma, and control of epilepsy

Non-receptor mediated modulators of GABAergic signaling Vigabatrin inhibits GABA transaminase conversion of GABA to succinic semialdehyde. Therefore high intracellular GABA and increase signaling. Used as an anticonvulsant in epilepsy, as well as drug addiction, OCD Tetanus toxin inhibits GABA and glycine release, convulsant Tiagabine - competitive inhibitor of GAT inhibits GABA reuptake increase synaptic GABA concentrations. Major clinical indication is for the treatment of epilepsy, anticonvulsant GABAA Receptor Modulators Benzodiazepines and barbiturates are modulators of GABAA receptors that enhances GABAergic neurotransmission they shift neurons away from the threshold of firing Benzodiazepines All have a benzene and a diazepine ring structure As a class, they all have similar CNS effects The major differences are the pharmokinetics Mechanism of action: enhances binding of GABA to GABAA receptors acts as positive allosteric modulators Examples: Diazepam, Clonazepam, Zolpidem Do not activate native GABAA receptors in the absence of GABA At low [GABA}, increase frequency of channel openings At normal [GABA], receptor deactivation is prolonged due to increased GABA binding and or increased channel opening probability Net effect: increase cellular Cl- influx, membrane hyperpolarization, decrease neuronal excitability decrease GABA dose response curve to left up to 3x Readily absorbed via oral, tansmucosal, intravenous very lipophilic Metabolized by cytochrome P450 enzymes and oxidized products secreted in the urine Decrease neuronal excitability Classes based in elimination kinetics o Short acting - t1/2 less than 6 hours midazolam, triazolam, o Intermediate acting - t1/2 6-20 hours - alprazolam, lorazepam, oxazepam, temazepam o Long acting - t1/2 > 20 hours - clonazepam, diazepam Anxiolytics, sedatives, anti-epileptics, muscle relaxants, EtOH withdrawl Anxiolytic inhibit synapses in the limbic system (involved in emotion and has high [GABAA] receptors. e.g. Diazepam)

o Also therapeutically used as muscle relaxant and anti-convulsant Treat insomnia facilitate sleep onset and increase overall duration of sleep; increase stage 2 REM. e.g. Zolpidem (Ambien) Antiepileptic effects anticonvulsant, sleep disorders e.g clonazepam (Klonopin) Benzodiazepine withdrawal o Similar to alcohol withdrawal o Symptoms start 24-48 hours after abrupt discontinuation o Symptoms more severe with higher doses for longer periods of time o Characterized by anxiety, muscle twitching, tremors, gastrointestinal disturbances, hallucinations/delusions, delirium and seizures

Barbiturates All are derivatives of barbituric acid used in the synthesis of riboflavin (B2) Adding an alkyl group or aryl group makes this a CNS depressant As a class, they have similar CNS effects There are major differences in the lipid solubility and pharmacokinetics of different barbiturates Mechanism of action o Site of action is linked to GABAA receptors and initially enhance the inhibitory function of GABA by prolonging the length of time that GABA-activated chloride channels remain open o At higher doses, it affects Ca++ and Na+ channels, and reduces glutamate effects by inhibitory action on NMDA-type glutamate receptors, and directly activate GABAA receptors o At toxic doses can affect K+ channels Classified by onset of effects o Short acting (onset within minutes rapidly redistributed), eg., Pentobarbital o Long acting (onset within an hour long duration of action) , eg., Phenobarbital Therapeutic uses hypnotic, muscle relaxant (phenobarbital), anticonvulsant (phenobarbital), anesthetic (phenobarbital) Extensive hepatic metabolism Adverse effects: sedation, motor incoordination, respiratory depression, dependence, abuse, fatal CNS depression Alcohol and the synapse Alcohol has multiple effects on neurons. It alters neurons membranes, ion channels, enzymes and receptors. It binds directly to receptors for acetylcholine, serotonin, (GABA), and glutamate . Alcohol and the GABA Receptor

When alcohol enters the brain, it binds to GABA receptors and amplifies the hyperpolarization effect of GABA (decrease likelihood of firing) The neuron activity is further diminished This accounts for some of the sedative affects of alcohol

Other GABA-associated Drugs Propofol induction of general anesthesia. Targets GABAA receptors. Also an agonist. Rapid onset, but effect in minutes. M. Jackson overdose. Baclofen treat spasticity associated with motor neuron disease (eg multiple sclerosis) or spinal chord injury. GABAB receptor agonist. Also modulates pain and may be useful for drug addiction. Chloral hydrate older sedative hypnotic used to alleviate insomnia. Incapacitate individuals in crimes. Physiology of Glutamatergic Neurotransmission Also exists throughout the CNS Primary excitatory neurotransmitter Involved in elevated pain sensation (hyperalgesia), cerebral neurotoxicity, memory Clinical applications are limited but will likely increase in the near future Glutamate Metabolism synthesis via a-ketoglutarate from the Krebs cycle, or via glutamine by glutamase

Glutamate Signaling

Glutamate Receptors Ionotropic Glutamate receptors 4 subunits homomeric or heteromeric TMs cross PM 3x Multi-subunit, cation-selective channels Na+ and K+ Mediates a fast excitatory synaptic response 3 main subtypes according to their selective agonist Specificity of the receptors arises from differences in mRNA splicing and post-transcriptional mRNA editing as well as different subunits o AMPA receptors located throughout the CNS activation results primarily in Na+ influx and some K+ efflux. o Kainate receptors expressed throughout CNS also rapid Na+ influx and K+ efflux in spinal chord kainate receptors contribute to pain o NMDA receptors expressed in hippocampus, cerebral cortex, and spinal chord requires binding of glutamate and glycine as well as depolarization of membrane, and results in K+ efflux and Ca+ and Na+ influx at rest Mg block channel

Metabotropic Glutamate Receptors (mGluR) 7 transmembrane-spanning domain coupled via G proteins to various effector molecules At least 8 subtypes of receptors with each belonging to one of three groups Group I causes neuronal excitation through phospholipase C activation and IP3 mediated intracellular Ca release, or through adenylyl cyclase activation and cAMP generation Group II and III receptors inhibit adenylyl cyclase and decrease cAMP production

Pathophysiology of Glutamatergic Neurotransmission Excessive excitoxicity can cause neuronal death, and has been implicated in neurodegenerative diseases, stroke, trauma, and hyperalgesia In Parkinsons disease, reduced DA transmission to the striatum results in the overactivation of glutamatergic synapses in the CNS, and contributes to the clinical signs of PD. Excessive excitoxicity has been implicated in epilepsy

A Movement Disorder: Parkinsons Disease

first described on 1817 by an English physician James Parkinson, in An Essay on the Shaking Palsy Parkinson: involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward, and to pass from a walking to a funning pace, thesenses and the intellects uninjured o Rhythmic tremor at rest o Rigidity with cog-wheel characteristic o Akinesia Symptoms become manifest when about 80% of dopamine neurons in substantia nigra pars compact are lost

Epidemiology of PD The most common movement disorder affecting 1-2% of the general population over the age of 65 The second most common neurodegenerative disease after Alzheimers Disease About 95% are idiopathic No cure May be less prevalent in Asian countries and in African American s Prevealnev rates in men are slightly higher than in women Etiology Age related attrition and death of dopamine producing neurons Genetic mutations 5% of PD cases directly related to mutations. Other cases likely due to genetic susceptibility Environmental factors may be due to combination of ongoing aging process with exposure to environmental factors that accelerate the process of nigral cell death Risk Factors Age the most important risk factor Positive family history Male gender Environmental exposure: herbicide and pesticide exposure, metals (manganese, iron), well water, farming, rural residence, wood pulp mills, and steel alloy industries Race Life experiences (trauma, emotional stress, personality traits such as shyness and depressiveness)? An inverse correlation between cigarette smoking and caffeine intake as well as others, in case-control studies

Clinical Features Stooped and rigid posture Shuffling gait Tremor A masklike facial appearance Pill rolling Resting tremor most common first symptom, usually asymmetric and most evident on one hand with the arm at rest Rigidity muscle tone increased in both flexor and extensor muscles providing a constant resistance to passive movements of the joints; stooped posture anteroflexed head, and flexed knees and elbows Bradykinesia difficulty with daily activities such as writing, shaving, suing a knife and fork, and opening buttons; decreased blinking, masked facies, slowed chewing and swallowing Postural instability: due to loss of postural effects Dysfunction of the autonomic nervous system: impaired GI motility, bladder dysfunction, excessive head and neck sweating, sialorrhea, and orthostatic hypotension Depression: mild to moderate depression in 50% of patients Cognitive impairment: mild cognitive decline including impaired visualspatial perception and attention, slowness in execution of motor tasks, and impaired concentration in most patients; at least 1/3 become demented during the course of the disease PD Statistics Progression highly variable. Within 10 20 years Patient age at onset affect progression (high rate in older) Prevalence 100 cases per 100,000 people in population Incidence 20 cases per 100,000 people annually Mortality not caused by the disease itself but due to complications reletd to immobility. Complication such as (Aspiration Pneumonia, cardiovascular and per se) Some general DA-associated biology DA synthesis Catecholamines consist of a catechol nucleus and an ethylamine side chain DA synthesized from the amino acid tyrosine Oxidation of tyrosine to L-DOPA is rate limiting step DAergic neurotransmission Two transporters required to sequester DA in synaptic vesicles Nerve cell stimulation vesicles fuse with PM releasing DA in synaptic cleft DAT transport back into the cell pre-synaptic terminal DA can be transported back into the vesicles or degraded by MAO or COMT

Catecholamine Metabolism MAO terminates DA in both brain and periphery MAO-A brain and periphery MAO-B in CNS catabolizes most CNS DA COMT breaks down DA extrasynaptically expressed in brain, liver, kidney, heart Dopamine Receptors G protein coupled receptors originally classified by their effect on the formation of cAMP o D1 class activation of D1 and D5 receptors leads to increase in cAMP excitatory o D2 class activation of D2, D3, D4 receptors leads to decrease in cAMP inhibitory o DA receptors have distinct distributions within the brains .and DA can act both as an excitatory and inhibitory neurotransmitter dependent on receptor expression o D2 receptors may also be autoreceptors on the presynaptic neuron limit DA tone o D2 receptors may play a significant role in schizophrenia Location of DA Receptors in the Brain D1 and D2 receptors are localized in the caudate and putamen (the striatum), nucleus accumbens, amygdala, olfactory tubercle, and hippocampus D1 receptors are also present in the cerebral cortex D2 receptors are also present in the substantia nigra, ventral tegmental area, and hypothalamus Central DA Pathways Nigrostriatal system largest DA tract contains 80% of the brains DA. The tract projects rostrally from cell bodies in the pars compacta of the substantia nigra to terminals in the caudate and putamen (striatum) and is involved in purposeful movement DA neurons that project from the substantia nigra to the striatum regulate movement DA neurons that project from the ventral tegmental area to the limbic system and prefrontal cortex involved in the regulation of mood and behavior Physiology of Nigrostriatal Pathways The majority of neurons in the striatum are GABA neuron and send their projections to 2 downstream targets that involve 2 separate athways 2 principal pathways in the basal ganglia regulate movement: indirect pathway and direct pathway direct pathway putamen to GPi to thalalmus to cortex

indirect pathway putamen to Gpe to STN to GPi to thalamus to cortex DA inhibits the indirect pathway and stimulates the direct pathway the sum results in purposeful movement The direct pathway primarily expresses D1 receptors projects directly to the globus pallidus, which tonically inhibit the thalamus which in turn sends excitatory projections to the cortex that initiate movement.therefore the direct pathways disinhibits the thalamus to then stimulate movement The indirect pathway primarily expresses D2 receptors, projects to the external segment of the globus pallidus, which then inhibits neurons n the subthalamic nucleus. These neurons are excitatory glutamatergic neuronstherefore this pathway disinhibits neurons of the subthalamic nucleus, which stimulates neurons in the internal segment of the globus pallidus to inhibit the thalamusthat inhibits movement

PD loss of DA signaling in striatum In PD, there is a selective loss of DA neurons in the subtsantia pars compactagreater than 80%

So why do the cells die..PD-pathology is important 1905 Tretiakoff identifies loss of pigmented cells n the substantia nigra 1912 Lewy describes Lewy body inclusions in the basal forebrain late 1950s DA found to be present in the mammalian brain with highest levels in the striatum 1960 Ehringer & Hornykiewicz identify dopamine loss in post mortem brain 1962 Birkmeyer & Hornykiewicz first treat patients with L-dopa 1966 Cotzias et al. introduce l-dopa/carbidopa but there is still no clue as to the cause or mechanism What could cause the DA neurons to degenerate? PD 1st clue environmental contribution? o 1983 Bill Langston et al. discovery that drug addicts that were exposed to a contaminated batch of meperidine containing MPTP had severe L-DOPA responsive PD symptoms, this suggested an environmental compound could cause PD Environmental neurotoxin contribute to developing PD? o DA neurotoxicity Cellular gateway for neurotoxin DAT antagonist block toxicity Generation of ROS (reactive oxygen species): Enzymatic Non-enzymatic Other mechanisms: Covalent interaction Inhibition of ETC Receptor-dependent o Toxicity

ROS and ATP auto-oxidation to quinones H2O2 and OH - synuclein first mutant gene associated with PD late 1990s o a major component of Lewy bodies o localizes largely to presynaptic terminal o physiological function is poorly understood. Studies indicate that synuclein binds to lipids and interacts with DAT o some mutations in synuclein causes autosomal dominant PD (A53T, age of onset of PD under 45 years)

Treatment of PD also problems medicines - can control may symptoms effectively for 5-10 years in most people before disabling side effects appear and control thenn becomes less effective surgery deep brain stimulation (DBS) is an alternative to earlier forms or surgery where lesions are cut in the area of the brain that controls fine movement of the limbs to stop shaking even if surgery is successful, it only relieves symptoms for a period of time; it does not halt progression of the disease Drug Therapy PD therapy aimed at bringing the basal ganglia back to balance pharmacological intervention 4 major classes of therapeutics o DA precursors o Inhibition of DA degradation o DA receptor agonist o Anticholinergics Dopamine and tyrosine are not used for PD therapy Dopamine does not cross the BBB

Large amounts of tyrosine decreases activity of the rate limiting enzyme tyrosine hydroxylase (TH) that converts tyrosine to dopamine has a feedback loop that will turn off TH

L-DOPA Therapy for PD L-aromatic amino acid decarboxylase converts L-DOPA to dopamine and is then stored into secretory vesicles until released during DA neurotransmission Late 1950s, a precursor of DA that crosses the BBB could restore brain DA levels and motor functions in animals treated with catecholamine depleting drug (reserpine) First treatment attempts at PD patients resulted in dramatic but short term improvememts; took years before it became an established and successful treatmemt Today, levodopa cornerstone of PD treatment; virtually all patients benefit Pharmacokinetocs: o Readily absorbed from the GI tract o Usually large doses must be given since ~1% actually crosses the BBB o Large amount of L dopa has to be given due to first pass effect o Metabolized by AADC in liver and periphery to dopamine o Secreted in urine unchanged or conjugated with glucoronyl sulfate o Most of L dopa converted in the periphery to NE and EPI Effects of L-DOPA on the Symptoms of PD o Eliminates most of the symptoms of PD (early on) o Bradykinesia and rigidity quickly respond to L-DOPA o Reduction in tremor with continued therapy o L DOPA less effective in eliminating postural instability and shuffling gait other NTs are involved in PD Effects of L-DOPA on behavior o L Dopa can affect by elevating mood o L Dopa Increases patient sense of well being o Significant number of patients have negative behavioral side effects Limitations of L-DOPA therapy o Efficacy tends to decrease as the disease progresses. o Chronic treatment associated with adverse events (motor fluctuations, dyskinesias and neuropsychiatric problems). o Does not prevent the continuous degeneration of nerve cells in the subtantia nigra, the treatment is therefore symptomatic. Long Term Therapy o Behavioral disturbances in 20 to 25% of population o Trouble in thinking (Cognitive Effects) o L Dopa can induce: Psychosis Confusion Hallucination

 Anxiety Delusion o Some individuals develop Hypomania which Is inappropriate sexual behavior; "Dirty Old Man", "Flashers"

Inhibitors of DA Metabolism Deprenyl ( Selegiline) Deprenyl Selectively Inhibits MOA-B Inhibits DA degradation but does not inhibit MOA-A (at low doses) Avoids toxic concerns with dietary tryamine Side effect can generate amphetamine loss of sleep, etc Inhibition of Peripheral COMT Entacapone increases the amount of L-DOPA and dopamine in the brain

Dopamine Agonists Mechanism mimic dopamine at receptors in the striatum Indication first-line treatment for symptomatic PD Apomorphine first DA agonist shown effective Ergot derivatives

o Agent bromocriptine o Half-life 6-27 hours o Adverse Reactions gastrointestinal distress, orthostatic hypotension, dyskinesias, hallucinations, sleep attacks, pulmonary or retroperitoneal fibrosis, Raynauds-like reaction, erythromelalgia, cardiac valve regurgitation Apomorphine First dopamine agonist - shown effective in 1951 Available in Europe since the 1980s Approved for use in the US in 2004 Subcutaneous injections used as a rescue treatment Onset of action is within 10 minutes Duration of action is 45-90 minutes Adverse Reactions o severe gastrointestinal reactions o orthostatic hypotension o dyskinesias o hallucinations Amantadine Mechanism multifactorial o promotes dopamine release o inhibits dopamine reuptake o anticholinergic actions o glutamate receptor antagonist Indications o early IPD o dyskinesias in late disease o theoretical neuroprotective benefit Metabolism excreted in the urine, unmetabolized Adverse Reactions mild anticholinergic side effects

Antipsychotics
Schizophrenia is a thought disorder Approximately 4.75 million people suffer in the U.S. 100,000 to 150,000 new cases diagnosed annually affects individuals I their late teems and early 20s, equally males and females may have multifactorial etiology, with both genetic and environmental components no split personality two categories of schizophrenic symptoms: o positive symptoms: involve the development of abnormal functions o negative symptoms: involve the reduction or loss of normal functions Schizophrenia The state of abnormal perceptions and thought processes associated with the withdrawal of interest to other people and the outside world Schizophrenia is a thought disorder characterized by one or more episodes of psychosis Psychosis: distortion of the capacity to recognize reality, communicate and relate to others to the degree of interfering with the demands of everyday life Positive Symptoms: delusions, hallucinations, disorganized speech and thinking, agitation and paranoia Negative Symptoms: limited range of emotion, decreased goal related activity and social interaction, poor judgment, poverty of speech The pathogenesis of Schizophrenia is unknown. Dopamine Hypothesis o Schizophrenia is caused by increased and deregulated levels of dopamine neurotransmission in the brain: imbalance in dopaminergic neuronal activity in the mesolimbic and mesocortical systems o Many antipsychotic drugs block dopamine receptors (particularly D2 receptor) o Dopmainen agonists (amphetamine, levodopa) exacerbate schizophrenia o Increased density of dopamine receptors in certain brain regions of untreated schizophrenics However changes in dopamine levels in mesolimbic and mesocortical systems may reflect downstream consequences of pathologic process Glutamate Hypothesis o Imbalance in glutamatergic neurotransmission plays important role Phencyclidine, an antagonist at NMDA receptors, causes symptoms similar to those of schizophrenia

Dopaminergic and glutamatergic neurons form reciprocal synaptic connections Serotonin receptors (5-HT2) also modulate glutamate transmission Dopamine receptor antagonist might alleviate the symptoms without treating the cause an imbalance in glutamatergic neurotransmission

Mesolimbic and Mesocortical Systems Mesolimbic system is a dopaminergic tract that originates in the ventral tegumental area and projects to the nucleus accumbens (ventral striatum), parts of amigdala and hippocampus, and other components of the limbic system This system is involved in the development of emotions and memory, thus might be responsible for the positive symptoms Mesocortical system represented by dopaminergic neurons orginated in the ventral tegumental area and projected into regions of the cerebral cortex, particularly the prefrontal cortex Because the prefrontal cortex is responsible for attention, planning and motivated behavior, it has been hypothesized that mesocortical systems plays role in the negative symptoms Dopaminergic neurons that serve the extrapyramidal motor system (EMS) arise from the substantia nigra and project to basal ganglia, corpus striatum, subthalamaic nucleus EMS controls and coordinates postural, static, support, and locomotor mechanisms

Aromatic L-amino acid transporter uses Na for a driving force for tyrosine uptake Tyrosine is a precursor for dopamine biosynthesis Tyrosine hydroxylase converts tyrosine to L-DOPA (rate limiting step), then to dopamine Dopamine is taken up into a vesicle using VMAT, a non-selective transporter, driven by H+; ATP is used a driving force to send protons into the vesicle to be used in DA transport A change in membrane potential causes an influx of calcium and the vesicle fuses with the membrane and is released into the synaptic cleft DA can be taken back up into the synapse by a selective dopamine transporter; it can be degraded using MAO to DOPAC The presynaptic neuron contains dopamine autoreceptors that inhibit the biosynthesis of dopamine; negative feedback actions

Antipsychotics Antipsychotics (or neuroleptics) are drugs used to treat psychotic states such as schizophrenia, delusional disorder, and other hallucinatory states o Neuroleptic emphasizes neurological actions that are manifested as side effects of the treatment o these complications called extrapyramidal effects (or symptoms): result from D2 receptor blockade in the basal ganglia and other areas of the brain o antipsychotics denotes the ability of the drug to abrogate psychosis and alleviate disorderly thinking in schizophrenia o no drugs have antipsychotic effects without neuroleptic effects! Extrapyramidal effects o akathisia (motor restlessness) o parkinsonian syndrome (bradikinic rigidity, tremor) o acute dystonic reactions (slow, prolonged muscle spasms of tongue, neck and face)

o tardive dyskinesia (rhythmic involuntary movements of the mouth, rapid involuntary movements of the limbs, dystonia, mostly irreversible); takes months to years of continuous treatment with antipsychotics to develop Mechanism of action: o antipsychotic action is mainly due to blocking of dopamine receptors, particulary D2 receptor, in the mesocortical and mesolimbic systems of the brain most antipsychotics have affinities at D2 receptors that parallel their clinical potency the typical antipsychotics are all considered to be equal in efficacy but different in potency antipsychotics block various receptors including cholinergic (muscarinic), adrenergic, dopamine, serotonin, and histamine receptors clinical applications o treatment of any agitated or psychotic state bipolar disorder, schizophrenia, especially positive symptoms o antiemetic therapy due to blockade of dopamine receptors in the chemoreceptor trigger zone o treatment of Tourettes syndrome haloperidol o treatment of intractable hiccups chlorpromazine o antipruritic therapy promethazine (because of histamine blockade)

Relative Receptor Blocking Actions of Antipsychotics

Typical Antipsychotics Low Potency Agents Chlorpromazine (phenothiazine) action: o D2 receptor blockade; also blocks norepinephrine alpha1 ,histamine and acetylcholine receptors therapeutic uses: o schizophrenia and other psychotic disorders, manic phase of bipolar disorder pharmacokinetics: o administered PO, IM or IV o following oral administration well absorbed but high first-pass metabolism o oral availability o t1/2 is biphasic: initial 2 hours, terminal 30 hours; o excretion: renal, almost entirely as metabolites adverse effects: o sedation, orthostatic hypotension and anticholinergic effects (dry mouth blurred vision, urinary retention, constipation. tachycardia); risk of extrapyramidal reactions is relatively low; risk of tardive dyskinesia is relatively low and the same as with all other low potency agents drug interactions: o can intensify responses to CNS depressants (antihistamines, benzodiazepines, barbiturates)

o can intensify responses to anticholinergic drugs (antihistamines, tricyclic antidepressants, atropine-like drugs) High Potency Agents Haloperidol Action: o D2 receptor blockade Therapeutic uses: o Antipsychotic action is equivalent to those of chlorpromazine; schizophrenia and other psychotic disorders, Tourettes syndrome Pharmacokinetics: o Administered PO or IM o Oral availability 60%; hepatic metabolism extensive o T1/2 is about 20 hours o Excreted in urine as a parent drug and metabolites Adverse effects: o Extrapyramidal effects occur frequently: o Risk of tardive dyskinesia is high relative to low potency agents o Sedation, orthostatic hypotension, and anticholinergic effects are uncommon o Can prolong the QT interval may pose risk of arrhythmias Atypical Antipsychotics In addition to blocking dopamine receptors, also produce significant blockade on serotonin receptors More effective at treating the negative symptoms of schizophrenia than typical antipsychotics Less risk of tardive dyskinesia and extrapyramidal effects Differing degrees of anticholinergic side effects - sedation, blurry vision, constipation

Clozapine (phenothiazine) Action: o Blocks predominantly D1 and D4 receptors o Less D2 antagonism than typical antipsychotics o Potent antagonism at some serotonin receptors Therapeutic uses: o Most effective drug for schizophrenia but can cause agranulocytosis reserved for patients who have not responded to other drugs Pharmacokinetics: o Rapid absorption following oral administration o 95% of the drug bound to plasma protein o undergoes extensive metabolism

o excreted in feces and urine, t1/2 is approximately 12 hours Adverse effects: o Agranulocytosis (1-2% of patients, death 1 in 5000) o Seizures (3%) o Weight gain o Myocarditis o Extrapyramidal effects are uncommon; TD has not been reported o Sedation orthostatic hypotension, and anticholinergic effects (dry mouth, blurred vision, urinary retention, constipation, tachycardia) Drug interactions: o Because of possible agranulocytosis contraindicated with drugs that can suppress bone marrow function (anticancer drugs)

Aripiprazole Partial agonist at D2 receptors 5-HT2 receptor antagonist and partial agonist at 5-HT1A receptors Milder anticholinergic actions t1/2 is approximately 75 hours Olanzapine More potent antagonist of 5-HT2 receptors than dopamine receptors Anticholinergic effects - sedation, orthostatic hypotension Causes significant weight gain Can induce hyperglycemia and diabetes t1/2 is about 21-54 hours Ziprasidone Antagonist at D2 and 5-HT2 receptors Modest selective serotonin reuptake inhibitor (SSRI)-like activity Prolongs QT intervals Does not cause weight gain t1/2 is approximately 2.5 (IM) -7 (PO) hours Quetiapine Antagonist at D2 and 5-HT2 receptors Potent actions at -adrenergic receptors Can cause weight gain and tachycardia Abuse potential - usually crushed and snorted, intravenous coadministration with cocaine, quell or "Susie-Q t1/2 is approximately 6 hours Risperidone Very high affinity at D2 and 5-HT2 receptors Little to no anticholinergic actions

Higher incidence of extrapyramidal symptoms at higher doses, but low incidence at low daily doses (i.e. 6 mg or less) Prolongs QT intervals Can cause weight gain More profound increases in prolactin than other agents t1/2 is about 20 hours

Affective Disorders (Antidepressants)

Depression is an effective disorder characterized by: intense sadness hopelessness and despair fatigue or loss of energy general loss of interest in the everyday aspects of life insomnia or hypersomnia changes in appetite and weight low self esteem recurrent thoughts of suicide or death At least 5 of these symptoms during 2 weeks o Major Depressive Episode Bipolar Disorder Episodes of mania or hypomania with or without intervening episodes of depression Mania At least a week of euphoria or irritability with at least 3 of the following o Grandiosity o Diminished need for sleep o Excessive pressured speech o Racing thoughts or flight of ideas o Distractibility o Increased level of goal focused activity at home or work o Excessive pleasurable activities gambling, purchases, sex Hypomania At least 4 days of manic symptoms described above Depression Monoamine Hypothesis 1940 1950s Iproniazid developed for TB treatment improved depression and found to e monoamine oxidase inhibitor (MAOI) first antidepressant Reserpine used to treat bp caused depression and found to reduce synaptic release of monoamines Imipramine developed as a sedative, improved depression and found to block re-uptake of norepinephrine and serotonin Depression must be due to synaptic deficiency of norepinephrine and serotonin

Too simplistic but Provided the major experimental platform for the discovery of new antidepressant drugs All available antidepressants (except bupropion) have primary actions on the metabolism, re-uptake or selective receptor antagonism of monoamines Difficulties with the Monoamine Hypothesis No decrease in brain level of NE or 5-HT Bupropion, an effective antidepressant, has minimal effects on brain NE or 5-HT systems o Antidepressants cause downregulation of monoamine receptors Antidepressants act fast, clinical effects are delayed Antidepressants Tricyclic Antidepressants (TCAs) TCAs have three ring nucleus: two aromatic rings attached to cycloheptane ring o Tertiary Amine Tricyclics Amitriptyline, imipramine, clomipramine, trimipramine predominantly affect 5-HT o Secondary Amine Tricyclics Nortriptyline , desipramine, amoxapine, maprotiline o The Secondary Tricyclics are less likely to cause sedation, hypotension and anticholinergic effects but they are more likely to induce psychosis o All are equally efficacious Mechanism of action o Increase levels of NE and 5-HT in the synaptic cleft by blocking neuronal re-uptake o Block histamine, cholinergic, and alpha adrenergic receptors (secondary) o Down regulate monoamine receptors o Interact with different ion channels Clinical indications: o Mood disorders, panic disorders, generalized anxiety disorder, PTSD, OCD (clomipramine), pain disorders, enuresis in children (imipramine) Well absorbed orally easily penetrates into the CNS, t1/2 is 20-60 hours, bound to plasma proteins Significant and variable first pass metabolism in the liver, metabolized by microsomal enzymes

Many of TCAs have active metabolites that are potent antidepressants : o Imipramine desipramine o Amitriptyline nortriptyline Conjugated with glucoronic acid and excreted through the kidneys Adverse effects: o Anticholinergic effects: nauseas, vomiting, anorexia blurred vision, hot dry skin, constipation, confusion, urinary retention, tachycardia o Antiadrenergic effects: orthostatic hypotension, drowsiness, dizziness, o Influence Na+ channels leading to ECG changes: widening of the QRS complex, arrhythmias o Weight gain, sedation due to histamine blockade o Possible lowering of seizure threshold o May precipitate mania in bipolar patients TCAs should not be give with MAOIs o High risk of serotonin syndrome: agitation, hyperthermia, tachycardia, muscle rigidity, myoclonus, mydriasis, rapid changes in mental status, severe convulsions and coma. Overdose o Most common agents used in suicide Narrow therapeutic index intentional overdosing o Signs Dilated pupils, dry skin/mucosa Initial excitement, seizures Cardiac arrhythmias, coma o Treatment Gastric lavage, activated charcoal Monitor ECG, treat arrhythmias Fluids, other supportive efforts

Time Course Mismatch in the Monoamine Hypothesis of Depression Although the uptake mechanism is inhibited almost immediately, antidepressant clinical effects may require 2-8 weeks to become apparent Antidepressant acutely increase the level of neurotransmitter in the synaptic cleft Stimulation of the presynaptic autoreceptors decreases neurotransmitter biosynthesis and release As a result, the initial exposure to antidepressants may not significantly increase post synaptic signaling delay in clinical effect Selective Serotonin Re-uptake Inhibitors (SSRIs) Fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox) Mechanism of action

o Inhibition of serotonin re-uptake without significant effects on NE and dopamine re-uptake Clinical applications o Depression o Fluoxetine is also used to treat OCD Route of administration o oral Metabolism o Metabolized by cytochrome P450 system; fluvoxamine, fluoxetine, paroxetine are potent cytochrome P450 inhibitors T1/2 is about 24 hours once a day dosing Side effects o In general SSRIs have fewer side effects than other classes of antidepressants o Nausea diarrhea, nervousness, insomnia, dizziness, sexual dysfunction (impotence, decreased libido, delayed or absent orgasm in 70% of patients) o All are inhibitors of different hepatic microsomal enzyme systems; need to watch other drug levels o May precipitate mania in bipolar patients Contraindications o In combination with MAOIs, may result in serotonin syndrome (hyperthermia, muscle rigidity, myoclonus, rapid changes in mental status) Fluoxetine (Prozac) The prototype agent Potent inhibitor of 5-HT re-uptake Well absorbed orally T1/2 of 24-48 hours for the parent compound, active metabolites (snorfluoxetine: t1/2 several days) Potent inhibitor of hepatic cytochrome P 450 enzyme system decreased dosage in patients with liver problems Not much affinity for other peripheral receptors; hence no TCAs side effects No weight gain Excretion is primarily through the kidneys

Serotonin/Norepinephrine Re-uptake Inhibitors (SNRIs) May be effective in cases where SSRIs are ineffective SNRIs with dual actions of inhibiting both serotonin and norepinephrine reuptake are often effective in relieving neuropathic pain associated with depression Mechanism of action:

o Inhibition of serotonin and norepinephrine re-uptake Venlaflaxine (Effexor) Potent inhibitor if serotonin re-uptake At higher doses inhibits NE re-uptake Mild inhibitor of dopamine re-uptake Has minimal inhibitory action on cytochrome P450 enzymes T1/2 is approximately 11 hours Common side effects: nausea, dizziness, insomnia, sedation, constipation; at higher doses an increase in bp Duloxetine (Cymbalta) Inhibits serotonin and NE re-uptake at all doses Metabolized in the liver to several metabolites: should not be administered to patients with hepatic insufficiency Metabolites are excreted in the urine: is not recommended in patients with end-stage renal disease T1/2 is approximately 12 hours, food delays the absorption of the drug Highly bound to plasma proteins Common side effects: nausea, dry mouth, constipation, diarrhea and vomiting, insomnia, dizziness, somnolence, sweating , sexual dysfunction Atypical Antidepressants A mixed group of agents that have actions at several different sites, mechanism of antidepressant effect is less defined They are not more efficacious than TCAs or SSRIs, but their side effects are different Bupropion (Wellbutrin) - Heterocyclic antidepressant act at unidentified site to alleviate the symptoms of depression relatively short t1/2 (~20 h), may require more than once-a-day dosing decreases craving for nicotine in tobacco abusers unique side effects: headache, nausea, tachycardia, restlessness, dry mouth, sweating, tremor, seizures at high doses no side effects related to sexual dysfunction such as those that occur with SSRIs Mirtazapine (Remeron) - Heterocyclic antidepressant blocks presynaptic 2-adrenergic autoreceptors increases NE neurotransmission

blocks postsynaptic 5-HT2 and 5-HT3 receptors potent antihistamine activity - sedative action does not cause antimuscarinic side effects as TCAs do does not interfere with sexual functioning as the SSRIs do side effects: sedation, increased appetite, and weight gain

Trazodone (Desyrel) - Heterocyclic antidepressant / 5-HT antagonist weak inhibitor of serotonin re-uptake, useful in treating insomnia therapeutic effect is related to blockade of 5-HT1 presynaptic autoreceptors - increases serotonin release also blocks postsynaptic 5-HT2 receptor metabolized in the liver, t1/2 approx. 8 hours, excreted by kidneys side effects: sedation, orthostatic hypotension, nausea, headache, dizziness, agitation

Monoamine Oxidase Inhibitors (MAOIs) Phenelzine (Nardil), tranylcypromine (Parnate), clorgiline, deprenyl MAO is a mitochondrial enzyme that is involved in the metabolism of catecholamine neurotransmitters and serotonin the highest concentrations in the liver, GI tract, and CNS MAO-A serotonin and NE MAO-B dopamine Clinical applications: o treatment of atypical depression with phobia or psychotic features o other antidepressants are more frequently used because they have fewer toxic effects

All are well absorbed, hydrophobic, readily cross BBB Inhibit both MAO-A and MAO-B Inhibition lasts 2-3 weeks after stopping drug due to irreversible blockade (MAOIs like phenelzine and tranylcypromine) Pharmacological effects: o elevates mood (2-6 weeks) o suppresses REM sleep o stimulates CNS: mild amphetamine-like stimulant effect with phenelzine and tranylcypromine Metabolized in liver by cytochrome P450 system to active metabolites Excreted by the kidney Adverse effects: hypertensive crisis possible if patient does not avoid eating food high in sympathomimetic tyramine (cheese, chicken liver, beer, red wine): high tyramine causes a release of catecholamines and activation of sympathetic nervous system - headache, nausea, tachycardia, arrhythmia, stroke orthostatic hypotension, dry mouth, blurred vision, weight gain hepatotoxicity may precipitate mania in bipolar patients use is limited due to complicated dietary restrictions

Newer MAOIs brofaromine (Consonar), caroxazone (Surodil), metralindole (Inkazan), minaprine (Cantor), moclobemide (Aurorix), pirlindole (Pirazidol) Reversible inhibitors of monoamine oxidase A (RIMAs) Do not inhibit MAO-B RIMAs are safer than the older monoamine oxidase inhibitors (MAOIs) like phenelzine and tranylcypromine RIMAs are displaced from MAO-A in the presence of tyramine rather than inhibiting its breakdown in the liver as older MAOIs do MAO-B remains free and continues to metabolize tyramine in the stomach: dietary restrictions are not stringent RIMAs still can cause serotonin syndrome or hypertensive crisis when combined with antidepressants or stimulants, migraine medications, certain herbs, or cold medicines Herbal Antidepressants St. Johns Wort Contains a variety of compounds that may contribute to its pharmacological activity Used as a dried hydroalcoholic extract of flowers Hypericin : o in high concentrations inhibits MAO-A and -B

o does not inhibit any of re-uptake systems Hyperforin o inhibits serotonin, norepinephrine, and dopamine re-uptake Might be effective for mild to moderate depressions but not for more severe depressions Adverse Effects - nothing serious, but can cause: o dizziness, skin rash o photosensitization (hypersensitivity to sun light) o hypomania o autonomic arousal o simultaneous administration of drugs with similar action should be used cautiously or avoided due to risk of serotonin syndrom

Drugs Used in Bipolar Disorder Lithium Carbonate Used primarily in bipolar disorder: prophylactically for treating maniacdepressive patients and in the treatment of manic episodes Also used as an adjuvant with antidepressants to treat major depression, and with antipsychotics to treat schizophrenia No effect on normal individuals in therapeutic doses, but in high doses is toxic Not a sedative, euphoriant, or depressant Mechanism of action o the precise mechanism of action is unknown o attenuates signaling via receptors coupled to the phosphoinositol bisphosphate (PIP2) o interferes with the re-synthesis (recycling) of PIP2, leading to its depletion in neuronal membranes o Hypothesis: By blocking regeneration of PIP2, lithium inhibits central adrenergic, muscarinic, and serotonergic signaling via IP3 and DAG Given orally, rapidly absorbed, and widely distributed No metabolism (it is an element) Mostly excreted by the kidney Narrow therapeutic index (0.6-1.0 mEq/L) Adverse effects: o GI disturbance, ataxia, confusion, convulsions, tremors, hypothyroidism, renal toxicity, dry mouth, polydipsia, polyuria, leukocytosis Regular monitoring of renal and thyroid functions is required Excessive intake of sodium lowers lithium levels Toxicity: treat with fluids, diuresis, and dialysis Contraindicated in pregnancy: teratogenic

Carbamazepine Anticonvulsant, reduces symptoms during manic and depressive episodes The drug of choice for treating seizures, trigeminal neuralgia Mechanism: o prolongs the inactivated state of Na+ channels Absorbed slowly when given orally Metabolized by the cytochrome P-450 system; induces P-450 enzymes accelerates its own metabolism Side effects: o acute intoxication can lead to respiratory depression, stupor, or coma o severe liver toxicity, requires frequent liver function tests o aplastic anemia requires complete blood counts including platelets o agranulocytosis o drowsiness, ataxia, nystagmus, vomiting

Valproic Acid Anticonvulsant, approved for treatment of bipolar disorder Mechanism: o prolongs the inactivated state of Na+ channels; suppresses Ca influx through T-type calcium channels; may increase GABA concentrations in the brain Well absorbed orally, approx. 90% is bound to plasma proteins Extensively metabolized in the liver by the cytochrome P-450 system, approx. 3% is excreted unchanged Adverse effects: nausea, vomiting, tremor, sedation, weight gain, liver toxicity Contraindicated in pregnancy: teratogenic

Anesthetics Local and General

Local anesthesia the loss of sensation in a body part without the loss of consciousness or the impairment of central control of vital functions General anesthesia the induction of a state of unconsciousness with the absence of pain sensation over the entire body, through the administration of anesthetic drugs Clinical Usage of Local Anesthetics Topical Anesthesia lidocaine Infiltration Anesthesia injection to treat a wart Peripheral Nerve Block saphenous nerve block Central Neural Blockade epidural Mechanism of Action Local anesthetics prevent or relieve pain by reversibly blocking nerve conduction (prevent AP propagation) Action Potential Activation of sodium channels underlies the upstroke of the action potential Subsequent activation of potassium channels causes repolarization of the cell membrane Local anesthetics target sodium channels

the degree of channel blockade is dependent on the activity of the nerves local anesthetic preferentially bind to inactivated sodium channels (inducing use-dependent block)

this block is called use-dependent or state-dependent binding because local anesthetic inhibition is greater with increases nerve activity local anesthetics blocks fast voltage-gated sodium channels and can affect all excitable tissues pH is important; uncharged drugs will cross the membrane but to bind to the channel the drug must be charged. Access to channel pore is from cytoplasmic side local anesthetics block fast voltage gated channels and can affect all excitable tissues o sensory nerves o motor nerves somatic autonomic o CNS o Cardiovascular system Heart Vascular smooth muscle o Other smooth muscle o Skeletal muscle

Toxicity of Local Anesthetics Averse experiences following the administration of local anesthetic agents are, in general, dose related and may result from high plasma levels caused by excessive dosage, rapid adsorption or inadvertent intravascular injection o CNS Stimulation (restlessness, tremor, convulsions) depression (drowsiness, sedation, respiratory failure) o Cardiovascular System Heart decreases conduction, decreased force of contraction, decreased excitability

 Rarely, low concentrations can cause cardiovascular collapse Vascular smooth muscle relaxation : decreased BP o Hypersensitivity Reactions Dermatitis, asthmatic attacks primarily seen with esters

Chemistry of Local Anesthetics Due to the difference in their intermediate bond amide and ester type anesthetics differ in the way they are metabolized Local anesthetic metabolism o Amides Degraded by hepatic cytochrome P450s (problem for patients with severe hepatic disease) o Esters Degraded by plasma esterases (plasma cholinesterase) Esters are more likely to cause allergic reactions due to specific metabolites Different sodium channel genes (or sodium channel isoforms) are expressed in different tissues o Sensory nerves have 3 unique isoforms o Possible drug target?

General Anesthesia The induction of a state of unconsciousness with the absence of pain sensation over the entire body, through the administration of anesthetic drugs often considered neither therapeutic nor diagnostic it exists to create a condition where surgery can be performed and complications reduced by o minimizing side effects of procedures o maintaining homeostasis during surgery o improving post-operative outcome Qualities of General Anesthesia amnesia loss of consciousness analgesia muscle relaxation Balanced anesthesia: anesthesia produced by safe doses of two or more agents or methods of anesthesia, each of which contributes to the total desired effect. The goal is that the desired actions summate and the undesirable actions are minimized Mechanism of Action for many years it was hypothesized that volatile anesthetics act nonspecifically on hydrophobic lipid components of cells o oil gas partition coefficient was calculated and it measures the solubility of a drug in oil; it was shown that the efficacy of these drugs were directly related to how soluble they were which provided support for this theory o then enantiomers (drugs with same physical properties but reverse orientation, bond flipped) were discovered with same oil/gas partition coefficient but different potencies which suggests that this theory of action is not completely accurate

now believed that general anesthetics increase the activity of GABA receptors and potassium channels and decrease the activity of acetylcholine receptors and glutamate receptors o specific molecular mechanisms of action are proposed including enhancement of inhibitory synaptic activity and reduction of excitatory synaptic activity

Characteristics of the ideal Anesthetic Agent The agent produces analgesia The agent causes amnesia The agent causes rapid loss of consciousness The agent relaxes skeletal muscle The agent suppresses autonomic, somatic, and endocrine effects The agent is free of adverse effects (not cardiotoxic) Permits rapid recovery when needed Pharmacology of General Anesthetics (not ideal and therefore require adjuncts) I. Intravenous (parenteral) Thiopental o Barbiturate o Rapid onset loss of consciousness o Poor analgesia, little muscle relaxation

o Toxicity includes: Decreased cerebral metabolism Decreased cerebral blood flow Decreased BP Decreased respiration Contraindicated in patients with porphyria o Terminated by redistribution A single dose given to a patient enters the plasma then goes to highly perfused tissues such as the brain, heart, liver and kidneys; then it leaves the brain and distributes to skeletal muscle, adipose tissue, but once it leaves the brain loses its effects so patient could wake up With single dose works within 8 seconds but effect is over after 10 minutes o Terminal half-lives longer with continued infusion Context sensitive half lives Has different decay phases, the first is rapid due to redistribution but the second is sloe decay phase that can last for several hours after surgery if the patient receives a constant supply of the drug

Propofol o Onset and duration similar to barbiturates (redistribution still important) o High degree of clearance (hepatic) so recovery is rapid after infusion o Can be used for maintenance and induction (less hangover than thiopental) o Poor analgesia o Toxicity includes: Decreased cerebral metabolism Decreased cerebral blood flow Decreased BP Decreased respiration Pain on injection Ketamine o Can be sued as an IV anesthetic by itself, usually for short procedures, but yu can give multiple injections (therefore can be used for maintenance). Also could be used for induction and followed by a different agent o Blocks glutamate receptors o Metabolized in the liver o Used in patients with risk for hypotension and bronchospasm since it increases BP and is a bronchodilator o Analgesic o Useful in children undergoing short painful procedures o Amnesia despite the patient being awake (dissociative state) o Toxicity includes: Emergence delirium (analog of PCP)

II.

Volatile (inhalation) Low safety margin Therapeutic indices range from 2-4 Among the most dangerous drugs in clinical use Each inhalation anesthetic has a different profile Minimum Alveolar Concentration (MAC) is used to compare the potency of inhalation anesthetics o Concentration of gas in the alveolar compartment that results in a lack of response to a noxious stimulus in 50% of subjects o At equilibrium the concentration in the alveolar compartment approximates the concentration in the expired air so MAC can be monitored in real time o Limitations of MAC 50% of patients still respond absence of response to pain may not indicate loss of consciousness

The amount of the gas with affinity for liquid (i.e. that which is soluble) does not contribute to partial pressure and thus is not available to enter other tissues

Some gases take longer to reach equilibrium than others

Halothane o Relatively high blood/gas partition co-efficient (2.4), thus induction of anesthesia slow o Largely used for maintenance of anesthesia, but use mostly discontinued in United States o Effective bronchodilator and some relaxation of skeletal muscle o Still may be used in developing countries (popular for pediatrics) o Weak analgesic o Significant metabolism (~20%) trifluoroacetylchloride o Toxicity Concentration-dependent reduction in arterial blood pressure Potent myocardial depressant Increased incidence of arrhythmias and bradycardia Increased cerebral blood flow with potential to increase intracranial pressure Inhibits ventilatory response to increased CO2 or to hypoxemia Liver toxicity - Drug-induced hepatitis and hepatic necrosis Malignant hyperthermia Side effect of halogenated inhalation anesthetics in people with certain genetic disposition and can be fatal

potentially fatal disease that predisposes patients to muscle rigidity and sudden rises in body temperature agents trigger an increase in intracellular calcium in skeletal muscle of patients with MH, which can directly cause the muscle rigidity. Treatment use dantrolene MAC = 0.75% POTENT

Sevoflurane o Low blood/gas partition coefficient (0.65) o Rapid onset, rapid recovery o Can be used for induction o Widely used for outpatient anesthesia and pediatrics since not irritating to airway o Small percentage metabolized (3%) with organic fluoride as one by-product o Potent bronchodilator o Direct relaxation of skeletal muscle o No significant tachycardia o Side Effects Concentration-dependent decrease in arterial blood pressure and cardiac output Reduced ventilation Increased cerebral blood flow o MAC = 2% Desflurane o Lowest blood/gas partition coefficient (0.42), low fat solubility o Very rapid onset, allows rapid changes, allows rapid emergence (5-10 minutes) o Minimal drug metabolism (<1%) o Effective bronchodilator, direct skeletal muscle relaxation o Useful for outpatient surgeries o Side Effects Concentration-dependent decrease in blood pressure, but cardiac output not affected Transient tachycardia Concentration-dependent increase in respiratory rate and decrease tidal volume (depressed ventilation) Increase cerebral blood flow with potential to increase intracranial pressure

Coughing, salivation, bronchospasm in awake patients Strong airway irritant and therefore not used for induction o MAC = 6% Nitrous Oxide o Insoluble in blood and tissues so rapid induction and emergence o Weak anesthetic agent, but produces significant analgesia o Used primarily as adjunct to other inhalational or intravenous anesthetics o N20 cannot be used at concentration above 80% since this will result in hypoxia. Therefore, N20 used as adjunct to other anesthetics at [50-70%] o Side Effects Accumulates in gas-filled spaces and can cause bowel distension, pneumothorax, pain with obstructed inner ear Need to give 100% oxygen at end of anesthesia to avoid diluting O2 in lung, causing diffusional hypoxia o MAC = 105%

Clinical Problems of Inhalation Anesthetics Depression of respiratory drive because of lower response to CO2 or to hypoxia Depressed cardiovascular drive Gaseous space enlargement by nitrous oxide Metabolite toxicity (trifluoroacetylchloride with halothane) Malignant hyperthermia with halogenated agents (all but N20), halothane may be worse than others Relationships Between General Anesthetic Action and Physical Properties

Blood-gas Low High MAC Low High

Induction time Short Long Potency Strong Weak

The lower the blood solubility of an anesthetic, the shorter its induction time

The lower the minimal concentration of an anesthetic required to prevent pain in 50% of subjects (MAC), the higher its potency

Immunosuppressants
General Principles Inflammation is the response to tissue injury or infection and is characterized by 5 classic signs: redness, heat, swelling, pain or hypersensitivity, loss of function The immune system is comprised of cells and soluble factor that eliminate an inciting inflammatory stimulus and initiate the process of immunological memory Inflammatory responses can be acute or chronic (inflammatory and immune component), and immune responses occur when inflammatory responses progress to chronic. Chronic inflammatory diseases include: peptic ulcer disease, asthma, osteoarthritis, gout Autoimmune diseases include: systemic lupus erythematosus, type 1 diabetes, and rheumatoid arthritis Strategies for drugs that target the immune system o Attenuate signaling mediators of the inflammatory response or modify components of the immune system o Modify underlying stimulus and thus remove the cause of the inflammation Functions of the Immune System Distinguish self from nonself (infectious organism, transplanted tissue, endogenous tissue mistaken for foreign) Protect organism from nonself or infectious agent Two types of Immune Response Innate (Natural) Immunity: sterotyped responses, broadly reactive, relatively low affinity, initiates and activates the response to an offending Adaptive (Learned) Immunity: creates a response that specifically neutralizes or kills an agent; antigen specific; requires priming Innate Cells Defend against infections by neutralizing or phagocytosis Digest molecules into small fragmenst that are linked to major histocompatibility proteins that activate the immune system Secrete cytokines/inflammatory mediators Adaptive Cells Generates specific response to antigens (MHC) Distinguish self o Tolerance o Co-stimulation

Produce humoral immunity (antibodies) Produce cellular immunity (cytotoxic T cells) Helper T cells act as regulators of adaptive immunity

MHC Molecules and T cell co-receptors These proteins account for all cell cell interactions Cytotoxic T cells and nucleated cells (CD8 and class I MHC molecules) Helper T cells and APC (CD4 and class II MHC molecules)

Cells of the Immune System Cell Type Innate Immunity Macrophages Tissue-resident cell, derived from monocyte Phagoctoses cellular and foreign debris Involved in chronic inflammation APC Transports and presents antigen to T cells in lymph nodes APC Phagocytoses and kills invading pathogens, especially bacteria Function

Dendritic Cell Neutrophil

Eosinophil Basophil Mast Cell Adaptive Immunity Cytotoxic T Cell (TC) Helper T Cell (TH) B Cell

Defends against parasites Release histamine, leukotrienes and other mediators after exposure to antigen

Effector of cellular adaptive immunity Controls adaptive immune responses Synthesizes and secretes antibody Antigen-presenting cell

Phases of the Inflammatory Response 1. Vasodilation 2. Plasma extravasation 3. Leukocyte Infiltration a. Vascular recruitment of immune cells b. Migration (chemotaxis) c. Innate or adaptive Immunity 4. Wound Healing Leukocyte adhesion When endothelial cells are actiavtd by inflammatory mediator, vesciles with secretin undergo exocytosis Selectins weakly adhere leaukocytes to enodothelium Then integrins are activated by platelet activating factor and tightly bind yo intercellular adhesion molecules (ICAMs) expressed on endothelial cells Chemotaxic factors signal leukocytes too migrate into tissues

Cytokines/Chemokines Protein hormones produced as part of innate immunity by multiple cells Released or activated by injury of cells Broad range of actions through endocrine, paracrine, and autocrine mechanisms Bind to specific tyrosine kinase (cytokines) or G protein receptors (chemokines) Cytokine actions redundant and can influence synthesis of other cytokines

Therapeutic Strategies for suppressing immunity/inflammation Inhibition of Gene Expression: Glucocorticoids Blocking intracellular signaling: Cyclosporine, tacrolimus Receptor antagonism: Antihistamines to block H1 or H2 receptors Montelukast, zafirlukast to block LT1 receptor Chemical Neutralization: Monoclonal antibodies to TNFa (infliximab) Pseudoreceptor binding of TNFa (etanercept) Costimulation Modulation: Abatacept Blockade of Synthesis: NSAIDs inhibition of COX1 or COX2 or both Zileuton inhibition of lypoxygenase Diminish Release: Cromolyn Sodium to stabilize mast cells Inhibit Immune Response: Methotrexate, azathioprine, mycophenolic acid Immunosuppressive Therapy Useful in: Preventing transplant rejection Treating autoimmune diseases (can in some circumstances diminish progression of the disease) Four major classes of the disease o Glucocorticoids o Calcineuriin inhibitors o Antiproliferative /antimetabolites o Biological modifiers Glucocorticoids Used with other immunosuppressive agenst to prevent and treat transplant rejection High doses of methylprednisolone (i.v.) for acute transplant rejection Efficacious in graft vs host disease used in autoimmune disorders Extensive long term use limited by toxicity Calcineurin Inhibitors Cyclosporine

Also called cyclosporine A Inhibitor of T cell mediated immunity Cyclosporine binds to cyclophilin and this inhibits production of IL-2 by blocking dephosphorylation of nuclear factor of activated T cells (NFAT) by calcineurin, thus NFA does not enter the nucleus Used for organ transplants and usually in combo with glucocorticoids, antimetabolites Used in severe rheumatoid arthritis Toxicity o Nephrotoxicity occurs in major of patients o Hypertension (~50% of renal transplant patients) o Neurotoxicity (tremor) o Hepatotoxicity o Hyperlipidemia o Hirsutism, gum hyperplasia Pharmacokinetics o Administered i.v. or orally o Oral absorption slow with 20-50% bioavailability o Extensively metabolized by CYP3A, thus dug interactions with other drugs metabolized by CYP3A including glucocorticoids, verapamil, and many more o Note: grapefruit juice inhibits CYP3A

Tacrolimus More potent immunopsuppressant with same mechanism as cyclosporine except it binds to FK protein Metabolized by CYP3A (interactions like cyclosporine)

Used for transplantation and rescue therapy in patients with rejection episodes Nephrotoxicity, neurotoxicity (headache, tremor, seizures) and others similar to cyclosporine Use therapeutic drug monitoring because high potential for nephrotoxicity

Lymphocyte Signaling Inhibitor Sirolimus (Rapamycin) Binds to FKBP (like Tacrolimus) but complex does not inhibit calcineurin, rather blocks IL-2 receptor signaling and arrests cell division by blocking the kinase, mTOR (molecular target of rapamycin) Side include hyperlipidemia. Leukopenia, thrombocytopenia Used for prophylaxis in organ transplantation: used with other therapies especially in patients with high risk for nephrotoxicity Metabolized by CYP3A, so consider drug interactions Aggravates cyclosporine renal dysfunction so do not co-administer Antiproliferatives/antimetabolites Azathioprine Prodrug of purine analog mercaptopurine which inhibits gene translation Azathioprine more effective than mercaptopurine as an immunosuppressant (pharmacokinetic/slow release of 6-MP) Major side effects are bone marrow suppression, increased susceptibility to infection Methotrexate Folate analog used as anticancer drug, in RA, and in graft vs. host disease (inhibits dihydrofolate reductase) Has cytotoxic and ant-inflammatory activity Mycophenolic Acid and Mycophenolate Mofetil Mycophenolic Acid inhibits inosine monophosphate dehydrogenase (IMPDH): rate limiting enzyme in guanosine formation Mycophenolate Mofetil is prodrug for Mycophenolic Acid with higher bioavailability Mycophenolic Acid preferentially affects lymphocytes since: o Lymphocytes depend on IMPDH for purine synthesis o MA preferentially inhibits IMPDH II which is highly expressed in lymphocytes Used for transplant rejection with glucocorticoids and calcineurin inhibitors but not Azathioprine Major side effects are vomiting, diarrhea, leukopenia, and increased risk of infection

Antibodies Anti-thymocyte Globulin (ATG) Polyclonal antibodies from rabbit injected with thymocytes Contains antibodies to T-cell antigens (CDs) and thus depletes circulating lymphocytes Used for induction of immunosuppression and acute renal rejection Can be used for delayed graft rejection in renal transplant patients to avoid early use of calcineurin inhibitors or for withdrawal of calcineurin inhibitors Major side effects: Cytokine release syndrome including fever, headache, tremor, nausea/vomiting, malaise, and general weakness OKT3 (Muromonab CD-3, anti-CD3) Mouse monoclonal antibody against human CD3 Depletes available pool of T-cells Indicated for organ transplant rejection Major side effect cytokine release syndrome, infection Mouse antibody so production of antibodies occurs in host (limits effects) Potentially fatal pulmonary edema, cardiovascular collapse and arrhythmias occur Biological Modifiers Daclizumab/Basiliximab Humanized anti-CD25 mouse monoclonal antibodies Daclizumab given prophylactically for renal transplants and with other immunosuppressants Binds to IL-2 receptor on activated T-cells (basiliximab has higher affinity) Major side effects: infection, anaphylactic reactions Belimumab Human monoclonal antibody against B-lymphocyte stimulator (BLyS) Major side effects: infection, severe allergic reactions, cardiac problems Abatacept/Belatacept CTLA-4 fusion protein Binds to B7-1, B7-2 to inhibit costimulation Used for RA, but should not be used with TNF inhibitors

Drugs of Abuse and Addiction

Addiction In 1954 James Olds and Peter Milner published a paper o Placed electrical wires in various regions in the rats brain o When the rats pushed the lever small electrical current went down the wire o When the wires were positioned in certain areas of the brain the rats would push the lever repeatedly to the exclusion of water, food and if left alone would push the bar until it died from dehydration o Researched showed that they increased the release of dopamine in the brain (one similar feature of all the addictive drugs) Results in a permanent rewiring of the brain such that the repetitive use of drugs is deemed the most rewarding thing a person can do The permanence of addiction is in part because of the release of glutamate and the formation of permanent memories Hallmark of Addiction Compulsive use despite negative consequences Drug craving (stress and cue evoked) Persistence over time High relapse rate Drugs have advantages over normal stimuli Larger increases in dopamine and glutamate Longer increases in dopamine and glutamate May increase memory pathways o Strengthening current circuits o Pruning other circuits (prunes circuits that are important and replace those with those that involve seeking out drugs) Classes of Drugs of Abuse Stimulants o Largest class of illegal abused drugs world wide o Amphetamines Methamphetamine Hallucinogen Ephedra Bath salts o Cocaine o Mechanism of action:

Involves increase extracellular concentrations of monoamines (NE, dopamine, and sometimes serotonin) in the brain Amphetamines Very potent they can work by increasing the release of monoamines, blocking re uptake or inhibiting their metabolism Cocaine Predominantly works on blocking the re-uptake of monoamines

o Clinical presentation Cause adrenergic response. Hallmarks include the following Cardiac o Tachycardia o Hypertension CNS o Agitation Diaphoresis Mydriasis Increased motor activity o Complications of use: Acute Seizures Strokes Myocardial infarctions Arrhythmias Rhabdomyolysis Fatal hyperthermia Chronic Psychiatric o Anxiety, psychosis, paranoia Neuro

o Treatment: Because the primary mechanism of toxicity related to stimulants is the increase CNS release of monoamines, the mainstay of treatment is to decrease the release of monoamines Primarily CNS depressants are given typically a benzodiazepine (these drugs hyperpolarize neurons, stimulant evoked release of monoamines is reduced) Antipsychotic may also be used because they block many of the receptors involved in stimulant toxicity Depressants o The common feature of all sedatives is that they hyperpolarize neurons making harder for neurons to reach their thresholds (they put neurons to sleep) o CNS depression o Can cause respiratory depression o Bradycardia o Decreased metabolic rate o Treatment: Mainly supportive care Do not wake because greater risk for CNS excitation than depression May also use flumazenil Flumazenil BZD Antagonist Antidote Rapid reversal Short life Acute withdrawal o Seizures o Precipitate arrhythmia (TCAs) Rarely used in overdoses o Opiates Morphine, codeine natural Heroin, oxycodone. Meperidine, hydrocodone etc synthetic Work by mimicking the effects of endorphins

o Seizures o Chorea (crack dancing) Dermatological o Formication (form of psychosis, spider bite) Dental decay

Endorphins = endogenous morphine o Peptides cleaved from precursor proteins Ligands at opioid receptors Inhibit painful NT Act in states of stress Opioid receptor 1: supraspinal & peripheral analgesia, euphoria 2: spinal analgesia, respiratory depression, dependence, miosis*, GI dysmotility*, CV effects : spinal analgesia, GI dysmotility, mood 1: spinal analgesia, miosis 2: dysphoria, psychotomimetic 3: supraspinal analgesia *Little tolerance develops Mechanism of action Opioids work by binding to opioid receptors and hyperpolarizing neurons. They work through three MOAs: o Inhibit adenylate cyclase o Open postsynaptic potassium channels o Block presynaptic calcium channels Opioid Toxidrome Miosis Coma Respiratory depression Accompanied by: o Hypotension o Hypogylcemia o Hypothermia Pulmonary complications o Non cardiogenic pulmonary edema o Talc o HIV and Pneumocystis Skeletal o Rhabdomyolysis Renal failure o Compartment syndrome o Nerve palsy o Skin breakdown Treatment: Naloxone Antidote for opioid intoxication Opioid mu recetor antagonist Any route

o Inhalants Volatile hydrocarbons, paint thinners, nitrates toluene, gasoline etc. Mechanism of action Similar to that of anesthetics (so not completely understood) One aspect if their toxicity is that they stimulate GABA receptors and hyperpolarize neurons Acute effects CNS depression o Anesthetic effects o Anoxia Cardiac Arryhthmias o Sudden sniffing death (idiopathic) Chronic Effects RTA Rhabdomyolysis Muscle weakness Gastroenteritis Headache Dizziness Confusion Hallucinogens

Rapid onset Half life 60-90 min Can precipitate acute withdrawal symptoms (rarely life threatening)

o Classifications Tryptamines

 DMT, 5-Methoxy DMT, Psilocin LSD Phenethylamine MDMA, Mescaline o Serotenergic Agonists Mechanism not yet known but thought to exert effects either by increasing the release of serotonin or act directly on serotonin receptors Clinical effects Sympathetic o Tachycardia, hypertension, hyperthermia Mydrasis Perceptual distortions Serotonin Syndrome o MDMA o NMDA Receptor Antagonist PCP, ketamine, dextromethorphan Other effects NE and Dopamine reuptake inhibitors Stimulates sigma receptors High concentrations o Nicotinic agonist o Muscarinic agonist Side effects Dissociative anesthesia (unique) o Conciousness o Memory o Motor o Sensory Catecholamines o Tachycardia o Hypertension o Agitation o Cannaboids Binds to central CB1 receptors Tachycardia Hypotension Sensory Perception Mild hallucinations

Opioid Drugs
Acute (nociceptive) Pain Immediate onset but can persist after the initial noxious simulation abates Can be cutaneous or viscera; Usually responsive to NSAIDs or opioids Chronic Inflammatory Pain Persistent pain secondary to chronic inflammatory disease Mechanisms involve both peripheral sensitization and central sensitization Pain usually responds to NSAIDs or opioids Relief of pain does not alter the underlying disease

Mechanism of Pain Nociceptive Circuit

Peripheral Transduction At the peripheral terminal different products bind to receptors and increase the influx of Na and Ca. increase works to depolarize the membrane and reach the voltage gated sodium threshold. Once threshold has been passed an AP is generated Neurotransmission in the Dorsal Horn of the Spinal Cord Once an AP is generated glutamate and neuropeptides are released into the synaptic cleft and bind to receptors on the post synaptic cell The ionotropic receptors bind glutamate and have a rapi response that causes depolarization of the post synaptic cell and eventually leading to an AP The metabotropic receptors bind the ligand and induce a slow modulatory response that eventually causes post synaptic cell depolarization and leads to the generation of an AP Sensitization Hyperalgesia o Increased sensitivity to a noxious stimulus Allodinia o Pain perceived after a non-noxious stimuli All products such as histamine, CGRP and other mediators bind and sensitize the neurons

Opioids Exogenous and endogenous compounds that have morphine like activity and have action at opioid receptors Act a specific sites (receptors) throughout the pain pathway to block release of pain transmitters and to inhibit pain signal and thus produce analgesia Have many pharmacological effects

Classification of Opioids
Class Agonist Definition A drug which, when bound to the receptor, stimulates the receptor to the maximum level; by definition, the intrinsic activity of a full agonist is unity A drug which, when bound to the receptor, fails completely to produce any stimulation of that receptor and blocks activity of agonists; by definition, the intrinsic activity of a pure antagonist is zero A drug which, when bound to the receptor, stimulates the receptor to a level below the maximum level; by definition, the intrinsic activity of a partial agonist lies between zero and unity A drug which acts simultaneously on different subtypes of receptors, with the potential for agonist action on one or more subtypes and antagonist action on one or more subtypes Example Morphine

Antagonist

Naloxone

Partial agonist

Buprenorphine (partial agonist)

Mixed agonistantagonist

Pentazocine (weak

and

antagonist; agonist)

Structure of endogenous opioids They share a conserved N terminus in their amino acid structure These products are present circulating in the body at all times Main Types of Opioid Receptors and Their Functional Effects

Actions and Selectivity of Opioids at the Various Opioid Receptor Classes

Mechanism of Action: In primary sensory neurons (presynaptic) morphine decreases Ca2+ influx and synaptic vesicle release in response to action potential Post-synaptic activation of mu-opioid receptor increases K+ conductance, hyperpolarizes plasma membrane thereby decreases the postsynaptic response to excitatory neurotransmission It also leads to the inhibition of adenylyl cyclase (AC) decrease of cAMP, and inhibition of Na channels o Morphine binds to the receptor and inhibits AC which derease cAMP, decreases PKA and decreases CREB (cAMP response binding element), which regulates the level of AC expression

Opioid Compounds Strong Agonists Phenanthrenes - Morphine Morphine is the active ingredient of the opium poppy The gold standard by which all opioids are judged The main pharmacological effects o Analgesia o Suppression of cough o Euphoria and sedation o Respiratory depression o Nausea and vomiting o Pupuillay constriction (miosis) o Reduced GI motility - constipation Given by injection (IV or IM) or orally as slow release tablets; has high first pass metabolism Metabolized I the liver to morphine 3-or6- glucoronide, which is more potet as an analgesic but more hydrophilic (less permeable); excreted in the urine as glucoronide o May cause problems with neonates Life threatening side effects o Respiratory depression and CO2 retention, which dilate cerebral vessels and increases the CSF, enhance cerebral and spinal ischemia o Bradycardia/cardiac arrest Overdose o Respiratory depression o Hypothermia o Pinpoint pupils o Coma Phenylheptamines - Methadone A synthetic opiate derivative with actions similar to those of morphine A longer duration of action (plasma half-life: >24 hours) Used for treatment of opioid abuse: in the presence of methadone morphine causes neither the normal euphoria, nor a physical abstinence syndrome Life threatening side effects: o Respiratory depression

Phenylpiperidines Meperidine Similar to morphine but less potent, shorter duration of action than morphine, no chemical resemblance to morphine Does not depress cough reflex and does not produce pinpoint pupil, rather dilates pupuil due to its anticholingeric activity (like atropine) Metabolizes in the liver to normeperidine excretion does not depend on glucoronidation Never give meperidine or other opioids to someone on MAOIs: severe respiratory depression. Hyperpyrexia, and convulsions are possible Fentanyl Similar to morphine but much more potent and fast acting opioid o Sufentanil is 5-7 times more potent than fentanyl o Alfentanil is considerably less potent than fentanyl but acts more rapidly, shorter action o Remifentanil is metabolized very rapidly, extremely short half-life Life threatening side effects o Arrhythmias bradycardia/cardiac arrest (large doses) o Bronchoconstriction o Convulsions (large doses) o Respiratory depression Mild Agonists: Phenanthrenes Codeine A morphine derivative used for moderate pain o Less efficacious than morphine rarely used alone o Often used in combination with aspirin or acetaminophen Life threatening side effects o Circulatory collapse, convulsions, respiratory depression Opioids with Mixed Receptor Actions Phenanthrenes Buprenorphine Partial mu agonist, potency approximately 25-50 times that of morphine Kappa antagonist ation equal to or up to 3 times greater than that of naloxone A longer duration of action due to slow dissociation from mu receptors

Treats moderate to severe post-operative pain, cancer, trauma, MI pain, trigeminal neuralgia Used to reduce opiate addiction and reverse fentanyl induced anesthesia Life threatening side effects o Respiratory depression

Pentazocine Agonist at kappa receptors Weak agonist at mu and gamma receptors Used to relieve moderate pain Analgesia primarily through action at kappa receptors In mu dependent individual precipitate withdrawal Side effects o Produces much less euphoria compared to morphine o In higher doses causes respiratory depression and decreases activity of GI tract o Can cause hallucinations, nightmares, tachycardia, dizziness o Increases blood pressure and thus myocardial workload - should not be administered in MI Opioid Antagonist: Naloxone The first pure opioid antagonist with affinity for all three types of opioid receptors Used in life threatening situations for narcotic overdose Short half life (1-2 hours); control and reverse effects of therapeutically administered opioids Side effects o Excessive dosage in narcotic overdose can cause reversal of analgesia o Blood pressure increase o Drowsiness, hyperventilation, tremors No substantial pharmacological actions at normal doses in normal individuals Naltrexone Similar to naloxone much longer duration of action (long half life, about 10 hours) Useful in detoxification Competes for opioid receptors; threy helping addicts to stay opiate free Side effects o Constipation, abdominal pain, dizziness, headache, nausea/vomiting, muscle pain, joint pain anxiety, eprssion, insomnia, irritability, nervousness, dry mouth, thirst o Life threatening effect hepatotoxicity

No substantial pharmacological actions at normal doses in normal individuals

Drug Tolerance After chronic use, the same amount of drug is insufficient to cause the desred effect and thus more drug is used Innate Tolerance o Inter individual variations in sensitivity to the drug that are present before its first administered Acquired Tolerance o Pharmacokinetic Develops when the ability to metabolzie or excrete the drug increases over time o Pharmacodynamics Results from changes in the drug receptor interaction Induction of Tolerance to Morphine Acute Short Term Tolerance: o Desensitization involves phosphorylation of the mu and gamma rectors by PKC, PKA and beta adrenergic receptor kinase Cross Tolerance o Tolerance to one of these drugs more than likely produces as tolerance to the others

Pharmacokinetics and Pharmacodynamics of a Fast-Acting Opioid (Heroin) Compared to a Slow-Acting Opioid (Methadone)

Opioid Replacement Therapy Methadone: Long half-life produces a longer but less stressful withdrawal Onset at 24-48 hrs, peak at 3-5 days Lessens the highs and lows of withdrawal Oral administration

Inflammation
Treatment of Pain NSAIDs Acteominophen- not anti-inflammatory (relives ut does not suppress the rest of the inflammatory response) COX2 inhibitors Treatment of Osteoarthritis NSAIDs Capsacin (found in peppers, involved in temperature, heat and pain sensation, can desensitize receptors if given chronically) Glucosamine/chondroitin Glucocorticoids COX2 Inhibitors Treatment of Gout NSAIDs Glucocorticoids Uricosuric Drugs Xanthine Oxidase Inhibitors o Allopurinol o Febuxostat Colchicine Diseases of Immune System Treatment of Rheumatoid Arthritis NSAIDs Immunosupressants Biological Modifiers Treatment of IBD/Crohns Disease Mesalamine (5-ASA) Based Therapies Glucocorticoids Antibiotics Immunosupressants Biological Modifiers Treatment of Psoriasis Topical Agents o Glucocorticoids o Vitamin D analogs

o Retinoids Light Therapy Immunosupressants Biological Modifiers

General Considerations for NSAIDs NSAIDS are thought to act primarily by inhibiting the formation of prostaglandins by blocking the actions of cyclooxygenase (COX1, COX2) Side effects likely result from blocking prostaglandin or thromboxane synthesis Drugs reduce symptoms associated with inflammatory disease, but do not affect the underlying disease Choice of drug for anti-inflammatory actions is largely empirical and may be related to relative degree of side effects, although the side effect profiles are similar (except for p-aminophenois)

Pharmacology of NSAIDs Therapeutic Actions Pain relief Reduce fever (antipyretic) major way we reduce fever Anti-inflammatory except acetaminophen Prophylactic to reduce risk of MI aspirin is the only drug that is used for this because it is the only one that irreversible block cyclooxygenase (platelets make thromboxane which cause aggregation and vasoconstriction, so block cyclooxygenase and since RBC have no nucleus very low dose aspirin suppresses thromboxane) Untoward Actions Gastric irritation major side effect Altered respiration Disturbances in acid/base balance

Increased bleeding Prolongation of gestation Potential renal damage

These drugs provide symptomatic relief but do not affect underlying disease Aspirin Toxicity Epigastric distress, nausea, vomiting; gastric ulceration, exacerbates ulcers Inhibit platelet aggregation and prolong bleeding Other CV actions minimal except with toxic concentrations which can depress circulation Aspirin intolerance, hypersensitivity (skin eruptions, asthma, anaphylaxis) Increased risk of developing Reyes Syndrome (persistent or recurrent vomiting, listlessness, irritability, combativeness, disorientation or confusion, delirium, convulsions, loss of consciousness, prognosis linked to severity of brain swelling) Hepatotoxicity Acute renal insufiiciency in patients with underlying disease (liver disease with ascites, CHF, renal disease) Low doses decrease urate excretion, antagonize actions of uricosurics and worsen gout Aspirin Poisoning Primary effects o CNS Tinnitus, mental confusion, hearing loss, convulsion, coma o GI nausea, vomiting o Hyperthermia, dehydration o Stimulation of respiratory center o Uncoupling of oxidative phosphorylation Secondary effects o Respiratory alkalosis o Metabolic acidosis o Water and electrolyte loss o Cardio and respiratory arrest with severe intoxication Contraindications of Aspirin Ulcer patients Patients with allergy to aspirin Patients with clotting disorder Pregnancy Gout (only high doses are uricosuric) Viral infection in children and young adults

o Associated with increased risk of Reyes Syndrome which manifests as increased intracranial pressure, nausea, vomiting, lethargy, disorientation, seizures, coma Acetaminophen Pharmacology Analgesic and antipyretic Not useful as an anti-inflammatory agent Weak affects onplatelets and no effect on bleeding time No uricosuric effects No alterations in acid-base balance Minimal effects on GI tract at therapeutic doses Advantageous in patients: o With peptic ulcer o With aspirin intolerance o On anticoagulants o Children or young adults with viral infections o With clotting disorder o With gout Overdose can cause fatal hepatic necrosis

Treatment of Acetominophen Poisoning Methionine N-acetylcysteine (IV) o Recycles glutathione, minimize the toxicity N-acetylcysteine (oral) Other NSAIDs Indole and Indene Acetic Acids o Indomethacin marked anti-inflammatory action, highly toxic o Sulindac prodrug, metabolized to active sulfide Heteroaryl Acetic Acids o Ketorolac used in parenteral preparation Arylpropionic Acids o Ibuprofen less GI side effects o Naproxen twice a day dosing

Fenamates o Mefenamic acid, meclofenamic acid Enolic Acid o Piroxicam long acting, taken once per day Pyrazolon derivatives o Phenylbutazone highly toxic, not recommended for use Pharmacology similar to aspirin except dont irreversibly bind, choice is empiric and may have to do with dosing

COX2 Inhibitors - Celecoxib Selective inhibition of COX-2 with minimal effect on COX-1 Incidence of GI side effects and renal toxicity less than other NSAIDs No significant inhibition of platelet aggregation These drugs have been largely removed from the market because of potential for MI or stroke in patients with underlying CV disease Celecoxib contraindicated in patients with sulfa sensitivity, report of GI bleeding/ulceration

Immunosupressants (Azathioprine, methotrexate, leflunomide, penicillamine) These drugs attenuate both inflammation and the destructive processsuppress immune cells that are cytotoxic (differentiate from NSAIDs, which only treat symptoms) Drugs must be stopped in 1-2 years (2-4 for methotrexate) Aggressive therapy with these drugs is proving useful in RA Combination therapy especially with biological modifiers improves outcome Drugs have serious side effects: o Infection, fever and chills o Anorexia/GI distress o Hepatotoxicity o Agranulocytosis o Anemia o Leukopenia/thrombocytopenia o Rash/allergic reaction o These side effects are for rapidly dividing cells Biological Modifiers for Inflammatory Disease Natalizumab (humanize monoclonal antibody to 4 integrin for Crohns disease, relapse in MS) Etanercept (construct of TNF receptor binding site for RA, Crohns Disease) Tofacitinib (JAK1 and 3 inhibitor blocking STAT-1 dependent gene expression) Biological Modifiers for Inflammatory Disease Side effects Secondary to injection include: o Pain o Swelling/itch

o Fever/chills/rash Major side effect is infection Only given by injection and cannot be given orally Additional side effects include nausea, vomiting, headache, abdominal pain Agents contraindicated in sepsis Potential for malignancies cancer cells recognized by bodies as foreign harder with suppressed immune system Infliximab reported to cause anaphylaxis or Lupus-like syndrome on rare occasion

Gold Compounds Auranofin, aurothioglucose, gold sodium thiomalate Used in management of progressive RA unresponsive to traditional therapies Relieve pain and stiffness and in some patients arrest the progression of the disease, but do not reverse damage Side effects severely limit use: o Rash dermatitis, o Thrombocytopenia o Agranulocytosis o Aplastic anemia o Acute tubular necrosis Acute Gout Intense inflammatory response to deposite of monosidum urate crystals 90% of first attacks are monoarticular in first metatarsophalangeal joint symptoms include severe pain (allodynia), inflammation, limited range of motion may observe slight fever, leukocytosis, increase erythrocyte sedimentation rate symptoms can resolve in one week or longer even with no treatment Chronic (Recurrent) Gout presentation often polyarticular in joints in upper extremities disease in elderly often associated with diuretic use or renal insufficiency symptoms include severe pain (allodynia), inflammation, limited range of motion tophi present after years of inadequate treatment tophi can cause deformation and lead to tissue damage and joint destruction kidney stones seen in 10-15% of patients with chronic gout Causes of Hyperuricemia Increased Uric Acid Production o Nutritional with high purine intake o Hematological disorders such as myeloproliferation o Medications such as cytotoxic agents

o Genetic factors resulting in altered hypoxanthine metabolism o Obesity, alcohol consumption, excessive exercise Decreased Uric Acid Excretion o Use of diuretic and other medications o Disease factors affecting renal function (hypertension, renal disease) o Genetic factors resulting in reduced clearance or excretion of urate o Obesity, toxemia in pregnancy

Treatment of Acute Gout NSAIDs Glucocorticoids Colchicine o Recommended use in patients when NSAIDs not affective or contraindicated o Not uricosuric o Inhibits cell migration to the site of inflammation and thus decreases inflammatory response o Side effects: limit therapy and include GI distress with abdominal pain, myopathy, and neuropathy associated with weakness in patients, blood dyscrasias Drugs to Prevent Hyperuricemia Drugs to increase renal clearance of Uric Acid decrease uptake o Probenecid, Sulfinpyrazone o Can precipitate uric acid crystals in renal tubules o Drugs can produce rash and hypersensitivity reactions o GI irritation can occur so caution in patients with peptic ulcers Drugs to Decrease Uric Acid Production o Allopurinol, Febuxostat o Inhibits xanthine oxidase in metabolic pathway for production of uric acid o can produce rash and hypersensitivity reactions o fever, malaise, muscle aches o rarely see leukopenia

Asthma Hormones of the Adrenal Cortex Glucocorticoids intermediary metabolism, anti-inflammatory actions Mineralocorticoids electrolyte balance Androgens androgenic activity When glucocorticoids are given for treatment they act as a negative feedback on endogenous glucocorticoid secretion; if given chronically can shut off production

Primary and Secondary Adrenal Insufficiency Addisons Disease: selective destruction of adrenal cortex by T cell mediated autoimmune disease Secondary Insufficiency: decrease in ACTH causes decrease in cortisol and androgen production; stopping high glucocorticoid therapy Characterized by weakness, fatigue, hyperpigmentation, hypotension, hypoglycemia, salt craving Adrenal Excess ACTH secreting tumors (primary Cushings) Excessive glucocorticoid therapy (iatrogenic Cushings) Characterized by centripetal adipose redistribution, hypertension, osteoporosis, immunosuppression, diabetes mellitus Glucocorticoids Cortisol (hydrocortisone): major endogenous steroid with glucocorticoid activity Cortisone, Prednisone: inactive until metabolized by 11-hydroxysteroid dehydrogenase I Prednisolone, Methyprednisolone: 4-6 times more potent than cortisol woth no mineralocorticoid activity Fludrocortisone: higher mineralocorticoid activity Dexamethasone: greater than 18 times more potent than cortisol with no mineralocorticoid activity Inhaled Glucocorticoids=: deliver higher concentrations of glucocorticoids to the lungs (less system toxicity) Fluticasone Beclomethasone

Funsiolide Triamcinolone Mechanism of Action: alteration of Gene Expression Glucocorticoids Actions: Metabolic effects o Antagonizes insulin action and promotes gluconeogenesis (increase blood glucose) o Increase muscle catabolism (increased amino acids) o Augments growth hormone action on lipolysis (increase triglycerides) Anti-inflammatory actions o Decrease inflammatory response o Reduces cytokine release o Reduces production of eicosanoids Pharmacokinetics Well absorbed from the GI tract Cortisol highly bound to CBG and albumin: synthetics less bound Lipophilic Metabolized by the liver and extrahepatic enzymes No 11-hydroxysteroid dehydrogenase I in fetal liver has 11hydroxysteroid dehydrogenase II, so prednisone in mother live converted to prednisolone, but back to prednisone before seen by the fetus, thus use prednisone during pregnancy Note: to minimize systemic toxicity local delivery often used (inhalation, topical, intraarticular) Therapeutic Uses: Replacement Therapy: generally use the lowest effective dose or oral hydrocortisone Anti-inflammatory: immune suppression (asthma, RA, Crohns Disease, immune rejection). Note: Symptomatic relief only; therapy does not improve underlying disease Inhaled glucocorticoids for asthma while minimizing systemic actions Topical dosing can use higher concentrations than systemic administration for psoriasis and dermatitis Depot injections (intra-articular) for arthritis, gout, usually metylprednisone Immunosuppressive therapy for transplant rejection Toxic Side effects: Increased susceptibility to infection Icreased glucose levels and diabetes mellits Secondary hyperparathyroidism

Osteoporosis Edema Suppression of linear bone growth in children Steroid psychosis Cushings syndrome Withdrawl rebound phenomenon: adrenal insufficiency Myopathy

Definition of Asthma Pulmonary disease characterized by o Airway hyperresponsiveness with obstruction o Chronic inflammation o Affect increasing number ppl Hyperresponsiveness (marks severity of disease and inflammation) is assessed by histamine bronchoprovocation Two Major Strategies for Treating Asthma Bronchodilation o Beta2 receptor agonists o Methylxanthines o Muscarinic antagonist Reduce inflammation o Glucocorticoids o Inhibit mass cell degranulation o Leukotriene antagonism o Anti-IgE antibody

Beta2 Adrenergic Agonist Therapeutic action is due to bronchodilation secondary to B2 receptor activation of cAMP in bronchial smooth muscle Can produce tachycardia, mild hypotension Note: beta receptor agonist can trigger severe bronchoconstriction Although isoproterenol has B1 and B2 action, is not sued extensively because of potential toxicity B2 agonists not recommended for monotherapy since they do not affect inflammation Side effects include tremor, tachycardia, patienst with underlying cardiac disease or on MAOIs Selective Beta2 Adrenergic Agonists o Short acting Albuterol Levabuterol [(R)-albuterol] Metaproterenol Terbutaline

o Long acting Salmeterol Formoterol Methyxanthines Maintenance therapy for asthma/COPD Not used as much since potent, long acting Beta2 agonist available Relaxes smooth muscle/increases cAMP/blocks adenosine A2 receptors Side effects similar to caffeine: insomnia, agitation, tachycardia, tremor Muscarinic Receptor Antagonist Pharmacology is similar to atropine but atropine does used due to CNS toxicity Quaternary so minimize CNS side effects and effects after inhalation limited to lung Used in COPD, asthma with other bronchodilators Useful in patients who cannot take B2 agonist (patients taking MAOIs, patients with cardiac arrhythmias, or with unstable angina) Glucocorticoids Used in severe asthma attacks refractory to therapy with bronchodilators Not useful for chronic systemic use because of side effects Beclomethazone dipropionate used in inhaler (daily inhalation) to suppress inflammation Other agents include triamcinolone, flunisolide, fluticasone Maor side effects: hoarse voice, oral candidiasis Concern of systemic absorption with daily use (swallowed: rinse nouth or use spacers in inhalers to minimize deliver of too much drug) Inhibition of Mast Cell Degradation Stabilize mast cells by an unknown mechanism Used by inhalation to prevent mild to moderate asthma attacks by reducing airway reactivity Used with glucocorticoids to prevent moderately severe asthma Minimal adverse side effects including bad taste, cough, wheezing, bronchospasm, headache Do not relieve acute asthmatic symptoms Leukotriene Receptor Antagonist Prevents actions of cysteinyl leukotrienes at CycLT1 receptors Adminiserd orally for prophylactic treatment of asthma Minimal side effects except rare inflammatory conditions including pulmonary infiltrates, neuropathy,skin rashes , vasculitis

5-Lipoxygenase Inhibitor Inhibits formation of 5-lipoxygenase products including leukotrienes Administered orally for the treatment of mild asthma Although this drug has a wider profile of inhibition then cys-LT receptor blockers it doe not significantly more efficacious Minimal side effects except are elevated liver enzymes Humanized Monoclonal Antibody Binds to Fc domain of IgE (binding site for IgE binding receptor) thus prevents IgE from interacting with receptor Administered i.v. or subcutaneously every 2-4 weeks Reduces airway responsiveness and decreases need for other asthma drugs Concern for infection, pain on injection