GMS 6520 Nervous

Overdose can be treated with a sulfhydryl reagent such as __ which replenishes glutathione levels.

Acetylcysteine (Mucomyst®)

Sedative hypnotic/CNS depressant. Increases the activity of GABAA receptors in the brain. At low concentrations reduces anxiety.

Alcohol

Typical Antipsychotics are

Also called neuroleptics Chlorpromazine (Thorazine®), Haloperidol (Haldol®)

Lamotrigine

Blocks sodium channels, blocks calcium channels, inhibits glutamate neurotransmission. Treatment for simple partial, grand mal, and petit mal

Topiramate

Blocks sodium channels, enhances GABA activation, maybe blocks calcium channels, inhibits glutamate neurotransmission. Treatment for simple partial, grand mal, and petit mal

proliferative diabetic retinopathy

Blood vessels abnormalities

Several intracellular signal transduction cascades, especially those mediated by cAMP, have been implicated in the long term effects of elevated corticoids with one significant end point being a reduction in

Brain Derived Neurotrophic Factor (BDNF). BDNF promotes neuronal survival, sprouting and increased synaptic plasticity.

a2 agonist for glaucoma

Brimonidine (Alphagan)

Alpha-adrenergic Agonists for glaucoma mechanism of action

Brimonidine (Alphagan) • It binds to both pre- and postsynaptic a2 receptors. • By binding to presynaptic receptors it decreases neurotransmitter release from sympathetic nerve stimulation (NE), thus decreasing AH formation. • By binding to postsynaptic receptors it decreases AH formation by reducing cAMP production• Causes vasoconstriction resulting in decreased AH formation (occurs within 3 hours) • Also causes increased uveoscleral outflow (on the order of days)

Names of Dopamine Receptor Agonist

Bromocriptine, Pramipexole, Ropinirole

respiratory actions of ephedrine

Bronchodilation via beta2-ARs in lung

Partial mu receptor agonist (lower efficacy than morphine) with high affinity. Long duration of action (slow unbinding from receptor) Used to treat opioid addiction. Low level activation of opioid receptor prevents full-blown withdrawal and blocks heroin induced euphoria. Limited respiratory depression; considered safer than methadone.

Buprenorphine: (Subutex ® or Suboxone ® in combo with naloxone)

Has been assigned a special indication for smoking cessation.

Bupropion monoamine uptake blocker (NE 5HT and DA).

The decrease in cholinergic function correlates closely with cognitive deficits in patients. The major neurotransmitter change in the brains of patients with Alzheimer's disease is a 30% to 90% decrease of the biosynthetic enzyme ___ in the cerebral cortex and hippocampus.

choline acetyltransferase

Muscarinic Agonists

choline esters and alkaloids

What is part of local function within the brain?

cholinergic interneurons

____ make and release the neurotransmitter acetylcholine

cholinergic neuron

CNS acting drugs

clonidine

GI: Therefore, NSAIDs with COX-1 inhibitory activity will produce opposite effects, leading to:

Gastric distress (dyspepsia, heartburn) Gastric bleeding/ulcers Sudden acute hemorrhage (effects are dose-dependent)

Actions of ____ • Chemoattractant for polymorphonuclear leukocytes • Long lasting bronchiolar constriction • Increase post-venule capillary permeability

LTB4 (Leukotriene B4), LTC4 and LTD4

Symptoms of withdrawal from opioid within 8-12 hours

Lacrimation Rhinorrhea Yawning Sweating

Alkaloids

Muscarine Pilocarpine

Agonists with specificity for parasympathetic target organs

Muscarine, Pilocarpine

• Formation of Aqueous Humor is an active process. • It involves transport of electrolytes such as __ and __ . • Transport of ____ is dependent on ____ in the ciliary processes. • Inhibition of ____ in the ciliary processes decreases AH formation.

Na+ and HCO3-, HCO3-, carbonic anhydrase, carbonic anhydrase

Pegylated derivative of Naloxone Used for treating opioid-induced constipation Does not enter CNS (peripherally-restricted)

Naloxegol (Movantik®):

pure antagonist- i.v., nasal spray (zero bioavailability) used for reversal of opioid toxicity has a relatively short half-life (compared to most opioid agonists) Combined with oral opioids to prevent abuse by i.v. route

Naloxone (Narcan®)

Nerve cell body, collection of nerve bodies, bundle of nerve fibers for both systems are called

Nerve cell body: CNS (Neuron), PNS (Ganglion Cell) collection of nerve bodies: CNS (Nucleus), PNS (Ganglion) bundle of nerve fibers: CNS (Tract), PNS (Nerve)

Cholinesterase inhibitors

Prolong the presence of acetylcholine in the synapse Used for: Myastenia gravis, Glaucoma, Reversal of neuromuscular blockade after surgery

Non-selective beta-AR antagonist:

Propranolol

major dopaminergic pathways in brain

Schizophrenia: mesocortical (motivation), mesolimbic (reward and desire) Tuberinfundibular (inhibits prolactin release) Nigrostriatal (motor control)-Parkinson's disease

muscarinic antagonist, used for motion sickness

Scopolamine

___Suppression of responsiveness to a constant level of stimulation seen at low doses, but tolerance usually develops within days.

Sedation

These drugs are also inhibitors of reuptake of biogenic amines by virtue of their action at the transporter in presynaptic membrane, but they are rather specific in blocking the reuptake of Serotonin (5HT).

Selective Serotonin Reuptake Inhibitors (SSRI)

Names of MAO-B inhibitor

Selegiline, Rasagiline

Side effects and interactions of benzodiazepines

Side effects: depression to the medullary respiratory center, euphoria, paradoxical excitement, anterograde amnesia Interactions: A. Additive or even synergistic CNS depression with other sedative hypnotics and alcohol B. Functional cross tolerance with ethanol and other sedative hypnotics observed C. Oral contraceptives reduce diazepam-elimination. D. Asymmetric metabolic cross tolerance with ethanol and barbiturates:

Methadone (Dolophine)

Similar analgesic efficacy as morphine Long half-life compared to other agonists Used to treat opioid addiction (with longer half-life withdrawal symptoms are minimized, thus easier to break the habit). Methadone blunts i.v. heroin induced euphoria. Significant respiratory depression can occur. Variable pharmacokinetics can increase risk of overdose.

Cardiovascular actions of isoproterenol:

Similar to low dose Epinephrine with subtle difference e.g. slight decrease in mean B.P. due to greater decreases in T.P.R. and diastolic pressure (still not enough to impact reflex effects)

Various manifestations, depending upon the affected brain region. Key feature is preservation of consciousness

Simple partial seizures

__ is an anticonvulsant that is FDA approved for the treatment of acute mania in patients with bipolar disorder.

Sodium valproate

____ inhibits some CYP enzymes (including CYP2C9): increases the plasma concentration of phenytoin, carbamazepine & phenobarbital

Valproic acid

___ is effective in inhibiting both NE and serotonin (5HT) reuptake without blockade of muscarinic-cholinergic, histaminergic or alpha1 adrenergic receptors seen with the tricyclics. Well-tolerated with a side effect profile similar to that of SSRI's.

Venlafaxine

Photodynamic therapeutic; activated by nonthermal laser; generates ROS, vessel damage, platelet activation, and occlusion of choroidal neovascularization

Verteporfin

Mild atypical; weight neutral, prolongs QTc interval

Ziprasidone

___, act at benzodiazepine binding site, but have unique structures. May have a receptor subtype specificity that increases sedative/hypnotic effects over anxiolytic effects and maybe lower abuse potential.

Zolipidem, Zaleplon (the Z drugs)

Acetaminophen induced hepatoxicity: Metabolized in the liver

a cytochrome P450 metabolite, NAPQI, depletes glutathione

Non-selective a-AR antagonists are

Phenoxybenzamine (irreversible), Phentolamine (reversible) Phentolamine is short acting, phenoxybenzamine is long acting.

Non-selective a-AR antagonists:

Phentolamine and Phenoxybenzamine

Alpha-1: selective agonist: ___ selective antagonist: ___

Phenylephrine, Prazosin

Sodium channel blockers include

Phenytoin, carbamazepine, lamotrigine, topiramate, valproic acid

Which anti-seizure drugs have high protein binding?

Phenytoin, valproic acid

Examples of Cholinesterase Inhibitors

Physostigmine (uncharged molecule, enters CNS) Neostigmine (charged molecule, does not enter CNS) Alzheimer's disease: Donepezil (Aricept) Galantamine

Nonselective muscarinic agonist; increases outflow through the Trabecular Meshwork

Pilocarpine

Used to stimulate salivation. Treat glaucoma (in combination with an anticholinesterase)

Pilocarpine

Cholinergic Drugs for glaucoma mechanism of action, side effects

Pilocarpine • Cause constriction of the pupil that helps the drainage of aqueous humor, by increasing its outflow through the trabecular meshwork and the canal of Shlemm. • Have the disadvantage of permanently constricted pupil. • On chronic use, may lead to blurred vision and headache. • Slow release preparations minimize these adverse effects. • Cholinergic drugs should be used with caution in patients who have increased risk of retinal detachment. • Muscarinic agonists (Pilocarpine) is preferred over cholinesterase inhibitors (physostigmine) in patients developing cataract.

___: At any point in time, 5-6% of the population is depressed. ___: 10% of people may become depressed during their lives.

Point prevalence, Lifetime prevalence

norepinephrine

Principle transmitter of most postganglionic fibers. Found in some CNS fibers.

atypical psychotics

clozapine, olanzapine, risperidone, aripiprazole, quetiapine, ziprasidone

10% _____ is metabolized to morphine - significant to therapeutic effect and 10% of caucasians have nonfunctional _____. Small percent are ____ ultrarapid metabolizers

codeine, CYP2D6, CYP2D6

Research on treatment of depression with psychotherapies such as __ and __ indicates that some patients respond well to these non-pharmacological approaches.

cognitive behavior therapy (CBT) and interpersonal psychotherapy (IPT)

Hydrocodone (in Lortab®, Vicodin®)

combos with NSAID.

a bundle of fibers crossing the midline of the telencephalon or diencephalon

commisure

Opposite side of the midline

contralateral

other minor effects from opioids: urinary retention, slight decrease in body temperature, _____

convulsions (at high doses, delta receptor)

Opioids decrease transmission to

cortex (emotional)

The number and arrangement of neurons and other cells in a particular region of the brain

cytoarchitecture

Carbamazepine, phenytoin, phenobarbital: all induce a variety of ____: increase metabolism of each other

cytochrome P450 enzymes (especially, CYP2C, CYP3A families)

Receptor sites for ACh

alpha-1 & delta, alpha-1 & gamma alpha-1 & delta, alpha-1 & epsilon

Sympathetic radial muscle (iris)

alpha-1, contraction (mydriasis)-dilation

Chronic nicotine increases the expression of a high sensitivity form of the ___

alpha-4 beta-2 receptor

Which site is alpha-bungarotoxin sensitive?

alpha-7 (alpha-9 and alpha-10 inner ear)

Short to intermediate-acting benzodiazepines

alprazolam, lorazepam, midazolam, oxazepam, triazolam

4 types of neurotransmitters

amino acids, amines, peptides, acetyl choline

Sodium channel blockers specifically bind to and

and prolong the inactivated state of voltage-activated sodium channels.

COX-2 derived PGI2 can antagonize catecholamine- and ___

angiotensin II-induced vasoconstriction (NSAIDs can elevate blood pressure)

Lithium has a very low therapeutic index. Lithium intoxication causes

anorexia, nausea, vomiting, diarrhea, thirst and dry mouth, ataxia, blurred vision, slurred speech, muscular weakness, convulsions, coma and death.

Sympathetic stimulation or hypotension affect kidney, then

kidney releases renin, then converted to angiotensin 2. This results in systemic vasoconstriction and increased aldosterone and increased blood volume

Try to withdraw drugs at _____ before pregnancy. If it doesn't work, monotherapy with careful drug monitoring to keep the blood concentration in low therapeutic ranges (usually safer than untreated epilepsy). Folate supplement

least 6 months

a ribbon

lemniscus

What type of receptor is acetylcholine?

ligand-gated ion channel

___ is conjugated then excreted

lorazepam

What neurotransmitter works on g-protein coupled receptors in the brain?

dopamine: reward, motivated behavior, motor coordination

which neurons are lost in parkinson's disease?

dopaminergic neurons leading to loss of dopamine: substantia nigra, ventral tegmental area

cholinesterase inhibitor (charged molecule, does not enter CNS)

neostigmine

The ____ forms from surface ectoderm

neural plate

Opioid ligands that bind to kappa receptors are

dynorphin A, dynorphin B, alpha neoendorphin

Summary of kappa selectivity

dynorphins

Fibers that carry output away from a structure

efferent

Opioid peptides:

endogenous peptides (endorphins, enkephalins, dynorphins)

Summary of delta selectivity

enkephalins, beta-endorphin

COMT inhibitors

entacapone/tolcapone

Neurotransmitters are cleared from synapse by ____ or ____

enzymatic degradation, reuptake

Cotransmitter and hormone

epinephrine

Calcium channel blockers include

ethosuximide, valproic acid, lamotrigine

In a seizure ____, ____, and ___ occur

excitation of glutamate, inhibition of GABA, impulse generation and propagation of sodium and potassium channels

Nonproliferative diabetic retinopathy

exudates, macular edema, microaneurysm, hemorrhages

A bundle

fasciculus

Major classes of nAChR

neuromuscular & neuronal/ganglionic

CNS selective nicotinic agonist

nicotine

Lacrimal glands are pre-dominantly ____. ____ would give same effect and ____ would counteract it

muscarinic, atropine, muscarinic agonist

The ___ receptor is only weakly activated by nicotine

muscle-type. So, breathing is not effected.

Narcotic:

narcosis, stupor, sleep inducing (legal term)

Anti-seizure drugs are taken over long periods of time and many drugs have _______, adverse effects frequently occur and require a change in drug or drug dose.

narrow therapeutic indexes

prosecephalon

forebrain

What is part of the lateral ventricle?

frontal (anterior) horn, central part, temporal (inferior) horn, occipital (posterior) horn

A cord

funiculus

Symptoms potentially due to hyperexcitability of neurons, particularly ____ neurons. ______ which inhibit NE neurons, can treat symptoms of withdrawal.

noradrenergic, Alpha-2-adrenergic agonists

Neurotransmitter synthesized in locus coeruleus which affects hippocampus, basal ganglia, and cortex

norepinephrine

primary transmitter

norepinephrine

Tricyclic antidepressants block __ and __ uptake.

norepinephrine (NE) and serotonin (5HT)

Three endogenous amines:

norepinephrine, dopamine, epinephrine

Examples of biogenic amines

norepinephrine, epinephrine, dopamine, serotonin (indolamine)

The interior of the brain contains a number of

nuclei and tracts

Sodium channel blockers common side effects

nystagmus (abnormal eye movement), diplopia (double vision) ataxia (problems in balance and coordination)

Tolerance to opioids is _____ (cellular response) rather than pharmacokinetic (change in metabolism)

pharmacodynamic

bronchodilator, used for asthma

ipratropium

Same side of the midline

ipsilateral

AH flows into the anterior chamber drains into canals between the

iris and cornea

Aspirin (acetylsalicylic acid) covalently modifies and ___ inhibits platelet COX-1. The enzyme is inhibited for the lifetime of the platelet (~8-11 days).

irreversibly

Adrenergic drugs elicit ___ in response to primary effects.

reflex effects

kappa receptor

relevant receptor in spinal cord mediated analgesia, dysphoria

Patients (particularly elderly and volume depleted) are at risk of

renal ischemia with NSAIDs.

This low dose action of aspirin is antagonized by

reversible COX-1 inhibitors

COX-1 and COX-2 generated prostanoids (PGE2, PGI2, PGF2a, TxA2) can both increase and decrease ___ , usually in response to changes in tubular chloride, extracellular tonicity or low BP.

sodium retention (natriuresis predominates)

Opioids: Biliary Tract: constriction of _____ with subsequent rise in pressure in the common bile duct.

sphincter of Oddi

delta receptor

spinal and supraspinal analgesia, convulsions, role in tolerance

nicotine is an agonist of nicotinic receptors that

stimulates ganglionic nicotinic receptor, stimulation followed by depression, cns stimulant: smoking and addiction.

Dopamine receptor agonists: directly activate DA receptors in the_______ , bypassing DA deficiency

striatum

closed angle glaucoma is treated by open angle glaucoma is treated by

surgery, drugs

sweat glands: Predominant tone & Effect of ganglionic blocker

sympathetic-cholinergic; hyperthermia

Male sex organs

sympathetic: alpha-1 ejaculation Parasympathetic: M-erection

GI: motility/tone

sympathetic: decrease, minor para: M increased

Albuterol is longer lasting as a beta2-AR selective agonist than _____ because ____ is degraded by COMT.

isoproterenol

veins: Predominant tone & Effect of ganglionic blocker

sympathetic; decreased cardiac output

arterioles: Predominant tone & Effect of ganglionic blocker

sympathetic; hypotension, postural hypotension

Initially the effects the transmitters on the receptors of the presynaptic cells provide ___ which opposes the increase in serotoneric tone. After extended treatment, the inhibitory elements ___, allowing the antidepressant drugs to have increased post-synaptic effects.

negative feedback, desensitize

Neurons make connections at ___

synapses

Diencephalon

thalamus, hypothalamus, epithalamus

Respiratory Depression: primary consequence of opioid overdose; decreased respiratory rate, responsiveness to CO2, loss of upper airway control (less tolerance ______ )

than analgesia, but more than constipation

Activation of muscarinic receptors in the target tissues can lead to various cellular responses including:

the activation of phospholipase C, opening or closing of ion channels, and the regulation of adenyl cyclase

____: the drug of choice for absence seizure

valproate

Drugs that decrease glutamate neurotransmission:

valproic acid, topiramate & lamotrigine

partial agonist of brain nicotine receptors associated with addiction

varenicline

NSAIDs reduce __, __, and __ associated with inflammation i.e. acute phase as compared to corticosteroids that inhibit all stages of inflammation.

vasodilation, edema and pain

Examples of peptides

vasopressin, somatostatin, neurotensin

Choline esters

Acetylcholine Methacholine Carbachol Bethanechol

Sinemet®

L-DOPA + carbidopa

Mood Stabilizers:

LITHIUM (Lithobid) DIVALPROEX (Depakote) CARBAMAZEPINE (Tegretol)

Platelets: Inhibition of platelet COX-1 derived ___ with the net effect of inhibiting ____ )

TxA2, platelet aggregation

weak cholinesterase inhibitor (enters CNS), used for Alzheimer's disease

donezepil, galantanime

A modulatory transmitter in ENS and kidney

dopamine

Dopamine is converted to NE by

dopamine beta hydroxylase

Mechanism of action of anti-seizure drugs

(1) Blocking action potentials (sodium channel block) (2) Increasing the inhibitory tone of the brain (increasing GABA transmission) (3) Reducing neurotransmitter release (calcium channel block) (4) Reducing excitatory neurotransmission (decreasing glutamate neurotransmission)

Mechanism of action of a seizure

(1) Voltage gated Na+ channel Action potential (2) Ca++ entry through Ca++ channel (3) Neurotransmitter release- glutamate: excitatory- GABA: inhibitory (4) Changes in postsynaptic membrane potential

Risk of depression increases if there is

(1) a family history of depression, (2) during postpartum period, (3) when patient is on certain drugs, or (4) undergoing unanticipated stress.

Seizures typically have 3 stages

(1) focal discharge (paroxysmal depolarization) (2) spread (3) termination

Carbidopa permits more L-DOPA to enter the brain, therefore it ___ and ____.

(1) increases the potency of L-DOPA(decreases the required total daily dose) (2) decreases dopamine toxicity in peripheral tissues, reducing side effects (nausea, vomiting, postural hypotension).

Pharmacokinetics of ASA

-Absorption: rapid, partly in stomach, mostly from upper small intestine. -Distribution: widely, bound to plasma protein (~80 %). -Metabolism: Aspirin (acetylsalicylic acid) is rapidly converted to salicylate. Zero order metabolism of salicylate. -Excretion: Metabolites and as free salicylate (excretion enhanced by alkalinization).

ASA side effects

-GI distress and bleeding -Prolongation of bleeding time: as stated above, important for those with coagulation problems (contraindicated in patients taking Warfarin). -Contraindication in children with chicken pox or influenza (Reye's syndrome) -Salicylism:• Mild: headache, dizziness, sweating, and tinnitus• Severe: CNS disturbances, skin eruptions, fever, nausea, acid-base disturbances (respiratory alkalosis followed by respiratory and metabolic acidosis).

Cardiovascular actions (low dose) of epinephrine:

-No change or slight increase in mean BP Increase systolic - beta1-AR (contractility) Decrease diastolic, decrease TPR. - beta2-AR (vasodilation) Increase HR, SV, CO - beta1-AR effects Decrease renal and cutaneous blood flow -a1-AR (vasoconstriction)

The plasma level of lithium should be maintained between __ to __ for optimal therapeutic management.

0.6 to 1.0 mM

Steps for acetylcholine

1) choline is taken up by the cell, 2) acetyl-coa is a product of cell metabolism 3) choline-acetyl transferase synthesizes ACh, 4) ACh is pumped into vesicles and stored, 5) nerve impulse reaches the terminal 6) calcium enters the cell, 7) release of ACh into the synapse, 8) AHh binds to receptors on the post synaptic cell, 9) ACh may also bind to presynaptic receptors, 10) ACh is broken down by esterases, 11) membrane is recycled

GI: Prostaglandins, PGE2, generated via COX-1

1) inhibit stomach acid secretion 2) enhance mucosal blood flow 3) promote intestinal secretion of cytoprotective mucus.

Cardiovascular risk of COX-2 inhibitors

1) inhibition of anti-thrombogenic prostaglandins (e.g. PGI2) 2) increased blood pressure 3) increased oxidative stress 4) decreased lipoxins 5) inhibition of vascular remodeling

1) The side effects profile of the SSRIs are 2) These drugs inhibit

1) nausea, vomiting, headache, and sexual dysfunction. Overall they do not cause cardiac problems like TCAs, and are also less toxic in cases of suicidal overdose. 2) the microsomal drug metabolizing cytochrome-P450 enzymes in the liver and alter the plasma levels of concomitant medications.

dopamine then goes into.....

1) packaged into vesicles and transported out of the presynapse. 2) Norepinephrine by dopamine betahydroxylase

Steps for biosynthesis and Release of Catecholamines--mechanisms of removal

1) reuptake, 2) diffusion, 3) active transport

How to chronically treat alcoholism?

1. Behavioral modification 2. Aversive therapy, Disulfiram [Antabuse®] Prevents metabolism of acetaldehyde. Not very toxic by itself -Ethanol and Disulfiram leads to buildup of acetaldehyde. headache, flush, nausea, vomiting 3. Opiate antagonist: Naltrexone

Phenobarbital (Luminal®):

1. Binds to allosteric regulatory site on the GABAA receptor and enhances GABA mediated Cl-influx 2. Induces microsomal enzymes 3. Its long plasma t1/2 (about 100 hr) simplifies maintenance of a fairly constant blood level. 4. Though less sedating than other barbiturates, it frequently causes sedation at efficacious doses.

Ethosuximide (Zarontin®)

1. Blocks T type calcium channels 2. Particularly effective for absence (pure petit mal drug) and lacks the hepatotoxicity of valproate 3. The most common adverse effect is gastric distress: idiosyncratic side effects are extremely rare.

Tiagabine (Gabitril®)

1. Blocks reuptake of GABA into nerve terminals and glia by inhibiting GABA transporter, GAT-1. 2. Side effects: generally mild.

Acute CNS effects from alcohol

1. Continuous CNS depressant, like general anesthetics and barbiturates. 2. CNS effects are generally in proportion to the concentration of alcohol in blood. 3. Anticonvulsant in amounts that cause general CNS depression; however, this is followed by a long period of hyperexcitability; therefore, (1) alcohol is contraindicated in epilepsy and (2) alcohol withdrawal in heavy users may cause seizures. 4. Enhancement of CNS depression occurs with sedatives, hypnotics or tranquilizers (patients taking such agents should be warned).

Valproic acid (Depakene®)

1. First drug effective against both absence and tonic-clonic seizures. 2. Discovered by accident -it was the "placebo" liquid in animal studies. 3. Blocks sodium channels and T type calcium channels. Also increases synaptic GABA concentration by inhibiting GABA turnover in neurons. 4. Hepatotoxicity is a major concern (including a rare but severe fulminant hepatitis, especially < 2yr old) 5. Reduces serum protein binding of some drugs (e.g. phenytoin). 6. Inhibits CYP enzymes: increases plasma concentration of phenobarbital and phenytoin 7. Teratogen: spina bifida

Drugs that enhance GABA neurotransmission

1. GABAA receptor modulators (postsynaptic) barbiturates (phenobarbital) benzodiazepines (diazepam, lorazepam) 2. Drugs that increase synaptic GABA levels (presynaptic)- Valproic acid, tiagabine, gabapentin

Clozapine (Clozaril®)

1. Less likely to cause EPS (better compliance) 2. Most efficacious among antipsychotics; effective for ~30-50% of refractory (to typical antipsychotics) cases; may be effective against negative symptoms 3. 1-2% of patients may develop agranulocytosis(diminished WBC): life threatening infection, mechanism unclear 4. Other side effects: weight gain, sedation, hyperlipidemia, lowering seizure threshold 5. Strict blood monitoring is mandatory (weekly for 6mos)

Ziprasidone (Geodon®)

1. Low affinity for Ms, α1 & H1 receptors Less sedation or postural hypotension, and weight neutral 2. Prolonged QTc interval (contraindicated for patients with heart problems)

MAO-B blockers mech of action, side effects

1. MOA: blocking dopamine metabolism by inhibiting monoamine oxidase (MAO) in the striatum 2. MAO-B: preferentially metabolizes dopamine 3. Modestly effective vs. L-DOPA; neuroprotection claimed (more research required) 4. May be used alone in the early stage 5. Drug Interactions: 5a. Contraindicated with meperidine or tricyclic anti-depressants; possible hyperthermic or hypertensive interactions 5b. Use with L-DOPA: potential hypertension?

Lamotrigine (Lamictal®)

1. Mechanism of action: (a) Blocks voltage sensitive sodium channels. (b) Inhibits calcium channels. (c) Inhibits glutamate release. 2. Broader spectrum: even absence 3. Adverse effects include diplopia, skin rash(hypersensitivity reaction that may be life threatening in up to 2% of pediatric patients)

Topiramate (Topamax®)

1. Mechanism of action: (a) Inhibits sodium channels. (b) Modulates GABAA receptors. (c) Blocks glutamate receptors. 2. Broad spectrum: even absence 3. Also useful for preventing migraine headaches.

Risperidone (Risperdal®)

1. Most potent D2 blocker among atypical antipsychotics 2. Less potent anti-muscarinic activity 3. Side effects: EPS and hyperprolactinemia at higher dose;sedation

Three endogenous opioid peptides

1. POMC (pro-opiomelanocortin): yield beta-endorphin 2. Proenkephalin: yield met- and leu-enkephalins 3. Prodynorphin: yield dynorphin A and B, and alpha- and beta-neoendorphins (leu-enkephalin). They are three pre-cursor polypeptides or proteins

Aripiprazole (Abilify®)

1. Partial D2 agonist: high affinity for D2 but activates only ~30% of intrinsic DA activity 2. Also used to treat depression; contraindicated in elderly with dementia 3. Minimally sedating: staying alert at work

Two examples of gene therapy

1. Reintroduction of a functional RPE65 gene using AAV2 (AAV2-RPE65) 2. Introduction of a functional RBGR gene using AAV

Olanzapine (Zyprexa ®)

1. Second most effective next to clozapine; most commonly prescribed in the US (Risperidone also commonly used); 2. Comparable efficacy compared to typical anti-psychotics; treat acute psychosis 3. Relatively strong histamine receptor (H1) antagonism 4. Side effects: sedation, metabolic syndrome, seizure

Ascending pathway

1. Senses painful stimuli 2. Transmits pain signal to cortex Emotional and sensory

Gabapentin (Neurontin®)

1. Structurally similar to GABA, but has no effect on GABA-receptors. 2. Appears to increase GABA-transmission by unknown mechanism (modify GABA release?). 3. Well tolerated. 4. Not metabolized by the liver : no known drug interaction

Quetiapine (Seroquel®)

1. Structurally similar to clozapine 2. Strong histamine H1 receptor antagonism 3. May be used to treat psychosis in PD patients 4. Side effects: sedation, weight gain

Muscarinic receptor antagonists mechanism and side effects

1. The oldest class (anti-cholinergics); reduces tremor in ~50% of patients; may be ineffective for bradykinesia or rigidity 2. Anti-parasympathetic side effects: dry mouth, reduced sweating, increased heart rate 3. Contraindicated in elderly PD patients (confusion and memory loss)

Benzodiazepines for seizures

1. Used for status epilepticus (emergency situation): intravenous lorazepam (Ativan®) or diazepam (Valium®) 2. Not used for long-term therapies (kinetics as well as tolerance)

Carbamazepine (Tegretol®):

1. Very similar 3D structure and mechanism of action as phenytoin. 2. Considered the drug of choice for controlling partial seizures and generalized tonic- clonic seizures. 3. Induces microsomal CYP enzymes 4. Diplopia and ataxia are the most common dose-related side effects. Skin rash (hypersensitivity reaction) is also common. Serious hematological conditions including aplastic anemia (depletion of red blood cells due to bone marrow suppression: 1/200,000) and agranulocytosis(1 / 75,000) rarely occur. 5. Also used for pain control (initially marketed for trigeminal neuralgia)

At least three of the following occur with patients in the manic phase of bipolar disorder:

1. grandiosity 2. decreased sleep 3. more talkative than usual 4. racing of thoughts 5. increased distractibility 6. increased motor activity 7. excessive involvement in high risk pleasurable activities

___ of the population suffers from a specific form of effective disorder called Bipolar Disorder (Manic-Depressive Illness), Prevalence for depression in women is ___ that of men, equal for bipolar disorder.

1.2%, twice

Phenytoin (Dilantin®):

1.Binds to and prolongs the inactivated state of voltage gated sodium channels. 2. Acute toxicities: nystagmus, ataxia, diplopia. 3. Long term side effects: gingival hyperplasia (> 20% of patients), hirsutism (excessive hair growth), teratogen 4. Very low therapeutic index: gradual dose increase, blood drug monitoring (therapeutic plasma level: 10-20mg/ml) 5. Pharmacokinetics are highly variable and dose-dependent

If that same person took oxazepam before they started to take barbiturates the oxazepam half-life might have been ___. If they take oxazepam after they had developed a metabolic tolerance to barbiturates the oxazepam half might be only be ___

10 hours, 5 hours

About __ of treatment with antidepressants are required to notice improvement in mood. The duration of treatment should be at least __.

2 weeks, 6-8 weeks.

While the pharmacological effects of antidepressants (i.e. inhibition of reuptake or breakdown) occur rapidly, there is a ___ delay in therapeutic relief of depression.

2-3week

Codeine

3-O methyl morphine) good bioavailability (~60%); low potency (metabolized to morphine); good anti-tussive

Maximize dose of antidepressant and treat for appropriate trial (___). Consider switching to antidepressant with different mechanism if no improvement is noted.

4-6 weeks

Miosis induction:

Acetylcholine (Miocol-E) and Carbachol; used to constrict the pupil during surgery; also reduce intraocular pressure (IOP).

withdrawal of opioids lasts

7-10 days

Alcohol does what to the Liver?

Accumulation of fat in liver caused by: a. increased NADH/NAD ratio b. mobilization of fat from peripheral tissues

___ cross tolerance‚ with barbiturates and benzodiazepines

Asymmetric metabolic

Rapidly metabolized by acetylcholinesterase. Not used clinically, except with eye surgery

Acetylcholine

Benzodiazepines: Mechanisms of action

A. Benzodiazepine does not stimulate the receptor by itself. It is not an agonist. B. When a benzodiazepine binds to the GABA receptor, the receptor binds to GABA with a higher affinity. C. Therefore, benzodiazepines increase GABA transmission, but only through GABA that has already been released into the synapse.

Therapeutic uses and contraindications of barbiturates

A. Intravenous Anesthetic-[thiopental]: Ultra-short acting B. Sedatives[pentobarbital] C. Epilepsy [phenobarbital] Often have anticholinergic side-effects e.g. dry mouth Contraindicated for pregnant women

Actions and mechanism of Barbiturates

A. Sedative-Hypnotic B. Anticonvulsant properties (seldom used anymore, Diazepam preferred) C. Induction liver microsomal enzymes Potentiation of inhibitory neurotransmission, GABAa receptor

Pharmacokinetics of benzodiazepines

A. These determine the choice of benzodiazepine most often (except alprazolam for panic disorders and agoraphobia). B. Most benzodiazepines metabolized by liver C. There are many active metabolites with long 1/2 lives, over 24 hr (exceptions: lorazepam, oxazepam, which are fast acting, and rapidly metabolized).

Sudden onset, abrupt cessation (usually less than 10 sec). Brief loss of consciousness, sometimes with motor involvement. Occurs in childhood and often disappears during maturation; may be frequent. Characteristic 3 Hz spike and wave EEG

Absence (Petit mal)

Dependence: Homeostatic changes occur during prolonged opioid use. _____ initiated with withdrawal or after administration of an antagonist.

Abstinence syndrome

Names of Anti-Viral Agent

Amantadine

First discovered as Antiviral agent; also found to increase DA release and inhibit DA re-uptake. What is the name of this drug and side effects?

Amantadine (Symmetrel®) Less efficacious than L-DOPA Tolerance may occur within weeks Side effects: restlessness, depression, livedo reticularis(purplish, mottled skin discoloration), edema, hypotension, hallucinations

Therapeutic Mechanism Of Antidepressants

Antidepressants either block norepinephrine (NE) and/or serotonin (5HT) uptake by presynaptic nerve endings (tricyclics, hetrocyclics, and SSRIs) or slow the breakdown of such monoamines.

Drugs to treat GAD

Antidepressants, Buspirone [Buspar] Very slowly acting novel structure, Benzodiazepines

_____, which nourishes the eye (and in particular the avascular tissues), is continuously produced in the ciliary processes behind the the iris in the posterior chamber.

Aqueous humor (AH)

Partial D2 agonist, low sedation, Treat depression (NO with dementia)

Aripiprazole

L-dopa is converted to dopamine by

Aromatic L-amino acid decarboxylase (AADC)

Horizontal plane

Axial, parallel to floor

___ can induce the liver enzymes that metabolize BOTH barbiturates and benzodiazepines

Barbiturates

___ increase the amount of opening by GABA and at high concentration can open the channel in the absence of GABA.

Barbiturates

___ are relatively ineffective at inducing the liver enzymes. If a person took these drugs, over a period of time the half-life of those drugs in that individual will remain the same.

Benzodiazepines

___ do not induce the liver P450 enzymes

Benzodiazepines

___ increase the affinity of GABAa receptors for GABA, but alone do not open the channel.

Benzodiazepines

Names of Muscarinic Receptor Antagonist

Benztropine

Summary of Mu selectivity

Beta endorphine endomorphin (enkephalins, dynorphins)

Other drugs to treat anxiety (not sedatives)

Beta-adrenergic blockers: decrease sympathetic tone. May give symptomatic relief of anxiety, e.g. for speaking engagements Alpha2 agonist: Clonidine Tricyclic antidepressants (panic attacks)

ß1 AR selective antagonist for glaucoma

Betaxolol

Not metabolized. Used to increase urinary voiding

Bethanechol (Urecholine)

VEGF-A monoclonal antibody given by intravitreal injections.

Bevacizumab (Avastin) Ranibizumab is an affinity-matured version of Bevacizumab

Naltrexone (Trexan®):

Bioavailable antagonist Used to maintain addicts in a drug free state. Reduces cravings of an alcoholic.

Valproic Acid

Blocks sodium channels, GABA turnover decreased, blocks calcium channels, inhibits glutamate neurotransmission. Treatment for simple partial, grand mal, and petit mal

Dopamine receptors are found

CNS and renal localization

Gastrointestinal effects of NSAIDs are due to inhibition of ____

COX-1

____ is a constitutive enzyme found in a variety of tissues including stomach and colon, kidney, vascular smooth muscle, and platelets (involved in many "housekeeping" functions of prostanoids).

COX-1 (PGHS-1/PTGS1)

___ derived thromboxane promotes platelet aggregation while ___ derived prostacyclin inhibits aggregation

COX-1, COX-2

Anti-inflammatory, analgesic, and antipyretic effects of NSAIDs are due to inhibition of ___ ; anti-inflammatory effects require relatively high doses

COX-2

___ derived prostaglandins promote wound healing, thus NSAIDs can slow this process.

COX-2

___ is upregulated in atherosclerotic plaques

COX-2

____ is involved in inflammatory responses, fever, and analgesia (typically induced). Also expressed in blood vessels, kidney, heart, and brain.

COX-2 (PGHS-2/PTGS2)

NSAIDs tend to promote sodium retention and can therefore increase BP. Counteractions include:

Can counteract effects of many anti-hypertensives (diuretics, ACE inhibitors and b-AR antagonists).

___ is an anticonvulsant that is also being used as a mood stabilizers in clinical practice.

Carbamazepine

Names of Peripheral AAD/DDC Inhibitor

Carbidopa

___ is a AAD/DDC inhibitor that cannot cross the blood brain barrier. L-DOPA is always administered together with this drug.

Carbidopa

Enzymes in active transport are

Catechol-O-methyltransferase (COMT) : catalyzes O-methylation Monoamine Oxidase (MAO)

___ Substances which can produce a sympathomimetic response. May be endogenous or synthetic.

Catecholamines: adrenergic agonists

Mesencephalon (midbrain)

Cerebral peduncles, midbrain tectum, midbrain tegmentum

When administered alone, the majority of L-DOPA is converted to dopamine by ____ in the periphery before entering the brain

DDC/AAD

Long acting benzodiazepines

Chlordiazepoxide Diazepam Flurazepam

1st antipsychotic, low EPS, sedative

Chlorpromazine

___ is important for cognitive function. Also, ___ show early sensitivity in Alzheimer's Disease.

Cholinergic function, Cholinergic neuron

Toxicities, interactions, side effects with MAOI

Chronic toxicity may include hepatotoxicity, tremors, insomnia and hyperhidrosis. Convulsions and a peripheral neuropathy may occur. interfere with the metabolic degradation of a variety of drugs including some general anesthetics, sedatives, antihistamines, alcohol, analgesics, anticholinergic drugs and tricyclic antidepressants. potentiate the cardiovascular effects of direct and indirectly acting sympathomimetic amines, especially tyramine. Hypertensive crisis is the most serious toxic result from the interaction of the MAOI with other substances.

Alpha-2: selective agonist: ___ selective antagonist: ___

Clonidine, Yohimbine

Treat refractory schizophrenics; Agranulocytosis

Clozapine

Timolol + Brimonidine

Combigan

Mydriasis induction:

Combination of Tropicamide: Anticholinergic used to dilate pupil and p-Hydroxyamphetamine: Indirect sympathomimetic

Ephedrine is a

Combination of sympathomimetic and sympatholytic actions. Mainly indirect action but some direct (a- and beta-AR). Long duration of action

Localized onset followed by widespread discharges (usually bilateral), Confused behavior, impairment of consciousness. Most arise from the temporal lobe. Almost always involves limbic system

Complex partial seizures

____: Failure to inhibit motor output ____: inability to generate motor output

Convulsions, Absence seizures

Timolol + Dorzolamide

Cosopt

____ are enzymes that catalyze two step reactions. Arachidonic acid is converted to PGG2 via COX activity and then PGH2 is generated from PGG2 via peroxidase (POX) activity.

Cyclo-oxygenases

Treatment for nicotine addiction

Decreasing the reward and managing the withdrawal associated with dependence.

_____: d isomer of the codeine analog levorphanol; no analgesic effects; good anti-tussive(anti-tussive actions not blocked by naloxone)

Dextromethorphan

Anticonvulsants: ___ is used for status epilepticus and alcohol withdrawal.

Diazepam

______ low solubility, antidiarrheal (active ingredient in Lomotil®, w/atropine)

Diphenoxylate

Pro-drug converted to epinephrine in the eye

Dipivefrin

Sympathomimetics

Direct Acting: act directly at receptor (NE, Epi, Isoproterenol) Indirect Acting: effect catecholamine levels in synapse, e.g. catecholamine release or uptake (Amphetamine, Tyramine, Cocaine, Imipramine).

___ adrenergic drugs bind to α and β receptors.

Direct acting

Reinforcement of nicotine addiction

Dopamine "reward"from rapid delivery to the brain. Requires alpha-4 and beta-2 containing receptors. Enhanced by alpha-6 beta-3 containing receptors

Agonist selectivity for dopamine

Dopamine >>Epi

Dopamine is a

Dopamine receptor, beta1-, and a-AR agonist

Combination: have mixed actions of sympathomimetics and sympatholytics

Dopamine, Ephedrine

• ____ does not cross the blood brain barrier • ____ can enter the brain

Dopamine, L-DOPA

CAII inhibitor; decreases AH production

Dorzolamide (Trusopt)

Opiate:

Drug derived from opium poppy - morphine, codeine, thebaine

___, loss of interest or pleasure in all or most usual activities and pastimes.

Dysphoric mood

chronic low grade depression is called

Dysthymia

____ expressed in CNS and gut, precursor proteins are processed (_____) and then peptides are packaged in vesicles, released into synaptic cleft.

Endogenous opioid peptides, post-translationally,

Names of COMT inhibitor

Entacapone, Tolcapone

Agonist (non-selective) potency rank for a-ARs:

Epinephrine (Epi) > Norepinephrine (NE) >>Isoproterenol (Iso)

___do induce the liver P450 enzymes.

EtOH and barbiturates

__ and __: inhibit "T type" calcium channels that are enriched in thalamic neurons and involved in the generation of rhythmic action potentials responsible for absence seizures.

Ethosuximide & valproic acid

___sometimes used in suicide attempts

Ethylene glycol

Clinical use of antimuscarinics

Eye examinations: to induce mydriasis Asthma: blocks cholinergic component of bronchoconstriction Myocardial infarction: blocks vagal response to pain permits increased heart rate Insecticide poisoning: antidote for anticholinesterases Oral surgery: to inhibit salivation

Selective Serotonin Reuptake Inhibitors(SSRI):

FLUOXETINE (Prozac) PAROXETINE (Paxil) SERTRALINE (Zoloft)

Beta-3:

Fat cell (stimulation of lipolysis and thermogenesis)

Benzodiazepine antagonist:

Flumazenil: Short half-life, I-V only

dopamine

Found in extrapyramidal system. Found in mesocortical and mesolimbic pathways.

Primary inhibitory neurotransmitter in the brain is

GABA

Phenobarbital

GABA activation Treatment for simple partial, grand mal.

Benzodiazepines for seizure

GABA activation Treatment for simple partial, grand mal

Gabapentin

GABA release increased? Maybe blocks calcium channels? Treatment for simple partial, grand mal

Sodium channel blockers effect

Generally effective against partial seizures and generalized tonic clonic seizures.

How is diazepam converted?

Goes into liver, converted to desmethyldiazepam then to oxazepam then conjugated then excreted

BP =

HR x SV x TPR

Typical; treat acute psychosis, high EPS

Haloperidol

Haloperidol (Haldol®)

High potency class: Strong D2 antagonist; more EPS and Hyperprolactinemia, less other side effects; relatively clean drug, inexpensive; • Treat acute psychosis Fluphenazine; Trifluoperazine

Fast acting benzodiazepines the best, usually short acting if antianxiety action not wanted.

Hypnosis

The cranial nerves

I olfactory, II optic, III oculomotor, IV trochlear, V trigeminal, VI abducens, VII facial, VIII vestibulocochlear, IX glossopharyngeal, X vagus, XI accessory, XII hypoglossal

Tricyclic Antidepressants:

IMIPRAMINE (Tofranil) AMITRYPTILINE (Elavil)

When there is a decrease of BP, the sympathetic nervous system does what?

Increase heart rate, increase contractile force, increase venous tone, increase of peripheral vascular resistance

Cardiovascular actions of ephedrine

Increase in contractility Increase in HR / Tachycardia at low/moderate doses (due to indirect effects High dose: Increase in systolic, diastolic and mean B.P. with reflex bradycardia (due mainly to direct a-AR effects)

Cardiovascular actions of dobutamine:

Increase in contractility, HR and CO (less tachycardia than Isoproterenol) High dose: Increase in TPR (a-ARs)(No effect on renal dopamine receptors) Used after cardiac surgery. Increase CO without a major increase in HR.

Cardiovascular actions of NE:

Increase in total peripheral resistance (TPR.), increase in blood pressure (BP), and increase in stroke volume (SV) Reflex in decrease heart rate (HR) No change in cardiac output (CO)

Symptoms of withdrawal from opioid within 48-72 hours

Increased Irritability *Insomnia Marked Anorexia Sneezing Nausea/Vomiting Increased Heart Rate and Blood Pressure Marked Chilliness (alternating between flushing and sweating) Gooseflesh (pilomotor activity) *Abdominal Cramps *Exaggerated Respiratory Response

___ adrenergic drugs do not bind to α or β receptors. Instead these act through release of stored norepinephrine.

Indirect acting

Antimuscarinic signs:

Inhibition of sweating vasodilation (a CNS effect) xerostomia, dry eyes CNS effects, hallucination in high dose mydriasis blurred vision due to cycloplegia, urinary retention

Opioids enhance

Inhibitory Modulation (sensory)

Tiagabine

Inhibits GABA reuptake Treatment for simple partial and grand mal

_____ is only a risk factor for glaucoma

Intraocular pressure

Dependence of nicotine addiction

Involves changes in receptor expression and sensitivity to both ACh and nicotine stimulation.

What is Antimuscarinic drug?

Ipratropium (Atrovent): bronchodilator given as an inhaled aerosol charged molecule stays in lung limiting systemic effects

Beta-1: Agonist potency rank: selective antagonist:

Iso > Epi = NE Metoprolol

Beta-2: Agonist potency rank: selective agonists:

Iso > Epi > NE Metaproterenol, Albuterol, Ritodrine

Names of Dopamine Precursor

L-DOPA

____ inhibits another type (high voltage activated) of calcium channels.

Lamotrigine

PGF2a analogs that increase AH outflow through the uveoscleral tract

Latanoprost (Xalatan); Bimatoprost

Prostaglandins mechanism of action, side effects

Latanoprost, Bimatoprost, Travoprost • PGF2awas found to reduce intraocular pressure but has intolerable local side effects. • A number of PGF2a analogs, which have more acceptable side effects, are now used. • These drugs reduce intra-ocular pressure by increasing AH outflow through trabecularmeshwork and uveoscleral pathways. • Side effects include discoloration of the eyes, and increased density, diameter, and length of eyelashes.

_____ peripherally restricted (excluded from CNS by p-glycoprotein transporter); low solubility

Loperamide: antidiarrheal (Imodium AD®)

Chlorpromazine (Thorazine®)

Low potency class: less EPS; relatively high muscarinic and other receptor blocking activity, e.g., strong autonomic side effects and sedative compared to other antipsychotic drugs; weight gain

Parasympathetic sphincter muscle (iris) and ciliary muscle (lens)

M-constriction (miosis), M-Contraction (accommodation)

Parasympathetic mechanism of bronchial muscle

M-contraction

Most common muscarinic receptors in the brain are

M1 and M3

___ reverse the psychomotor retardation of depressed patients and also may increase the psychomotor activity to a hypomanic or manic state. Similar to other antidepressants, they require several weeks for a therapeutic effect.

MAO inhibitors

Heterocyclic Antidepressants:

MIRTAZAPINE (Remeron) VENLAFAXINE (Effexor) BUPROPION (Wellbutrin, Zyban)

How does alcohol affect tolerance?

Metabolic: associated with increased metabolism, inducible enzymes in the liver, esp. microsomal oxidizing enzymes. An alcoholic will have cross tolerance with barbiturates Functional: Most of the pharmacodynamic effects of ETOH are due to the fact the ETOH changes the lipid environment of cell membranes, "fluidizes". Changes the functional properties of many membrane. Chronic ETOH leads to more rigid membranes, more ETOH for the same effect. Behavioral: Recovery of the ability to function socially in spite of the drug. May refer as much to the how others perceive the drug user.

Metabolized slowly. Used to test bronchial reactivity

Methacholine (Provocholine)

Beta1-AR selective antagonists are

Metoprolol, Atenolol

Examples of sympatholytics

Metyrosine, a-methyl DOPA, Guanethidine

_____- very effective at treating certain types of pain (chronic post-operative pain, pain from inflammation, integumental pain, premenstrual syndrome headache, and myalgia). Achieved with "ordinary" doses of NSAIDs (e.g. 650 aspirin or 400 mg ibuprofen).

Mild analgesics

Opioids: ______: constriction of the pupil (no tolerance to this effect) - may mask pupillary changes in head trauma

Miosis

•_____- Pupil constriction •_____- Pupil dilation •_____- Paralysis of the ciliary muscle, preventing accomodation

Miosis, Mydriasis, Cycloplegia

___ effectively enhances neurotransmission at serotonin receptors by blocking alpha2 adrenergic receptors as well presynaptic serotonin receptors. May have anxiolytic properties as well. Side effect profile similar to SSRI's but without the nausea.

Mirtazapine

Sexual dysfunction (especially impotence) is a common side effect for many of the antidepressants including the SSRI's. Two drugs which are relatively free of this side effect:

Mirtazapine, Bupropion

Descending pathway

Modulates pain signal Sensory

___ refers to a group of mitochondrial enzymes that oxidatively deaminate monoamines including catecholamines (norepinephrine and dopamine), serotonin (5-hydroxytryptamine) as well as other naturally occurring amines such as tyramine.

Monoamine oxidase (MAO)

___ have proven effective at reversing cognitive deficits in animal models of cholinergic hypofunction.

Nicotinic channel activators

Cholinergic receptors in the brain

Nicotinic: Usually not at synapses Presynaptic/perisynaptic somatic: Neuromodulation

Propranolol, Nadolol are

Non-selective beta-AR antagonists Propranolol decrease renin secretion, because renin contributes to an increase of BP.

Widely used atypical; treat acute psychosis; MS, seizure

Olanzapine

Dopamine receptor agonists and side effects

Older agonist: Bromocriptine (Parlodel®, ergot derivative); Major side effects: hypotension, nausea, dyskinesia Newer agonists: Pramipexole (Mirapex) Ropinirole (Requip) • Less on/off phenomenon (relative to Sinemet) • Side effects: hypotension, nausea, dyskinesia, edema (lower legs), sleep disturbance, hallucination/confusion, memory issue, risky behaviors • Neupro (skin patch); Apokyn (rescue injectable; $$$$)

What produces myelin?

Oligodendrocytes (CNS) and Schwann cells (PNS)

Mast cells. Dendritic cells and lymphocytes

PGD2

Most of the actions of the NSAIDs can be attributed to inhibition of the enzyme cyclo-oxygenase (COX).This enzyme metabolizes arachidonic acid (fatty acid component of membranes) to the endoperoxide intermediates and ultimately to the formation of the prostanoids (__, __, __, __, and __).

PGD2, PGE2, PGF2a, PGI2, and TXA2

Inhibition of cyclo-oxygenase (COX-2) prevents formation of prostaglandins (____) at peripheral sites.

PGE2

Made by a variety of cells and tissues (Most abundant prostanoid)

PGE2

Centrally mediated effect via resetting of the temperature control center in the hypothalamus (IL-1 (Interleukin-1) mediated stimulation of prostaglandin (___) production). NSAIDs inhibit _____ and ultimate production of prostaglandins in the brain.

PGE2, cyclo-oxygenase (COX-2)

Female reproductive organs. Elevated in arthritis

PGF2a

First line- Second line- Third line- Final attempt to decrease IOP-

PGF2a analogs Latanoprost, Bimatoprost, or Travoprost ß1/(ß2) antagonists Timolol or Betaxolol Carbonic Anhydrase inhibitors Dorzolamide or Brinzolamide Systemic Carbonic Anhydrase inhibition (Acetazolamide)

Vascular cells including endothelial cells, vascular smooth muscle and endothelial progenitor cells

PGI2

endothelial COX-2 derived ___ inhibits platelet aggregation (inhibition augments aggregation by ___).

PGI2, TxA2

The Monoamine Oxidase (MAO) Inhibitors

PHENELZINE (Nardil)

Pegylated anti-VEGF aptamer; single chain nucleic acid binds VEGF165, blocking its binding to VEGF receptors

Pagaptanib

Stomach

Para: M-increased acid secretion

Mixed agonist-antagonist Kappa receptor selective agonist (mu receptor partial agonist) Used for chronic severe pain Lower abuse potential, less respiratory effect NX: _______

Pentazocine (Talwin®, TalwinNX), in combination w/ Naloxone

Actions of ____ • Vasodilation, Vasoconstriction, Increase capillary permeability • Contracts other smooth muscle (uterine, GI, bronchial)/relax bronchial smooth muscle • Promote or inhibit platelet aggregation • Inhibit mast cell secretion • Decrease intestinal secretion of gastric acid • Stimulate Na and water excretion from kidney; increase Na retention • Stimulate mucus secretion and "cytoprotection" • Pyrogenic • Sensitize nerve endings to other analgesic mediators

Prostanoids: PGD2, PGE2, PGF2a, PGI2 (Prostacyclin), TXA2 (Thromboxane A2)

_____ (for example, ethosuximide) are contraindicated for other types of seizures, and vice-versa.

Pure petit-mal drugs

H1 blocking; Treat psychosis in PD patients; sedation, weight gain

Quetiapine

Pharmacokinetics of alcohol

Rapid absorption from gut, peak in 40 minutes "on an empty stomach". Optimum concentration for bioavailibility ≈ 20 % EtOH Distributes easily to all tissues. (volume of distribution = .7L/kg) Metabolized mainly in liver, but some is metabolized in the gut, particularly in men. Zero-order kinetics

Effector organ receptors

Receptor blockers: alpha-1 prazosin, beta- propranolol, muscarinic: atropine

Opioid Receptors

Receptors are in GPCR superfamily

Mechanism of action of albuterol

Relaxation of airway smooth muscle (used as aerosol in asthmatics to directly reach beta2-AR in lungs). For treatment of asthma attacks and COPD.

Cardiovascular actions of Beta1-AR selective antagonists:

Results due to beta1-AR antagonism: decrease in HR, contractility, and CO Little to no effect on airway resistance (bronchial muscle) and peripheral vascular resistance if dose is selective for beta1-AR

Mechanism of action of propranolol and nadolol

Results due to beta1-AR antagonism: decrease in HR, contractility, and CO Results due to beta2-AR antagonism: Acute increase in peripheral vascular resistance (unopposed a-AR vasoconstriction) Increase airway resistance Precautions: asthma

Strong D2 blocker; EPS; MS

Risperidone

muscarinic cholinergic actions:

SLUD: Salivation, Lacrimation, Urination, Defecation -and decreased HR, decreased AV conduction, vasodilation, bronchoconstriction, miosis, increased GI motility and secretions

____ is defined by one continuous seizure or recurrent seizures without regaining consciousness for greater than 30 min (but many neurologists believe 5 min is enough).

Status epilepticus Life threatening. Should be treated immediately with i.v.lorazepam or diazepam.

Cardiovascular actions of dopamine

Stimulates renal dopamine receptors--increases vasodilation. Moderate dose: Increase in contractility and HR(beta1-AR),(tachycardia less than Isoproterenol) Increase in CO High dose: Increase in TPR (a-ARs) When admin peripherally does not pass BBB.

In Parkinson's Disease, 60-80% loss of dopamine neurons in

Substantia Nigra

Fentanyl: very potent, used in anesthesia to lower MAC of a general anesthetic (congeners: ____, _____, ____ ), transdermal only for opioid-tolerant

Sufentanil, Alfentanil, Remifentanil

Kidney

Sympathetic: Beta-1 increased renin secretion

Skeletal muscle

Sympathetic: Beta-2 increased contractility

Uterus

Sympathetic: Beta-2 pregnant, relaxation

Liver

Sympathetic: Beta-2: increased glycogenolysis and increased gluconeogenesis

Sweat glands

Sympathetic: alpha-1 increased apocrine sweat (armpits) M- increased eccrine sweat (skin)

Urinary: sphincter

Sympathetic: alpha-1 retention

Salivary glands

Sympathetic: alpha-1 viscous secretion, alpha-1 decreased blood flow Parasym: M-watery secretion

GI sphincters

Sympathetic: constriction, minor Para: M-relaxation

Deplete stores of catecholamines, block sympathetic transmission

Sympatholytics

Types of Barbiturates

THIOPENTAL (ultra short acting) PHENOBARBITAL (primarily used as anti-epileptic drug) PENTOBARBITAL (hypnotic with high abuse potential whose use has been largely displaced by safer benzodiazepines) Chloral hydrate (largely restricted to institutional use, inexpensive but may have significant toxicity) Oral preparation for pediatrics

The 5-HT1A receptors on presynaptic neurons act to inhibit the firing of serotonergic neurons, Additionally, both presynaptic alpha2 adrenoreceptors and presynaptic 5-HT receptors act to inhibit the release of serotonin.

The biogenic amine hypothesis

Beta-adrenergic Antagonists for agents for glaucoma side effects and contraindications

There is risk of bronchospasm episodes in patients with asthma and COPD because of some absorption of ß-adrenergic antagonists from the eye drops. • Also contraindicated in patients with dysrhythmias(bradycardia and heart block). • Betaxolol, selective for ß1 receptors, has fewer systemic effects (bronchospasm) than the non-selective drug Timolol.

Nonselective ß-AR antagonist for glaucoma

Timolol

Nicotine works on specific receptors in the brain

Tobacco

Major convulsions (tonic body muscle spasms followed by synchronous clonic jerking). Prolonged depression of all central functions after seizures (postictal depression)

Tonic-clonic (Grand mal)

Symptoms of withdrawal from opioid within 12-14 hours

Tossing, restless sleep *Dilated Pupils Anorexia Goosebumps ("Cold Turkey") Restlessness, Irritability Tremor

Mu receptor agonist; also inhibits NE and 5HT uptake

Tramadol (Ultram®) and Tapentadol

Anticholinergic properties (__ and __) from antidepressants include: dry mouth, blurred near vision, constipation, urinary hesitancy or retention; potentially confusion, agitation, delirium, and tachycardia in severe cases.

Tricyclics and most hetrocyclics

Mechanism of action and side effects of TCA drugs and toxicity

Tricyclics block muscarinic-cholinergic, histaminergic and alpha1 adrenergic receptors resulting in significant side effects affecting treatment compliance. These side effects include atropine-like symptoms of dry mouth, blurring vision and constipation as well as mild sedation, hypotension and fatigue. Cardiac toxicity: quinidine-like effect slowing intracardiac conduction. Risk of death with overdose.

Platelets and macrophages

TxA2

Epinephrine is a

a1-, a2-, beta1-, and beta2-AR agonist beta1 = beta2 > a1 = a2

Norepinephrine is a

a1-, a2-, beta1-AR agonist a1 = a2 = beta1 >> beta2

Phenylephrine is a

a1-AR agonist

Prazosin is a

a1-AR selective antagonist

___ has anti-pyretic and analgesic effects

acetaminophen

Primary neurotransmitter

acetylcholine

agonist, used in eye surgery

acetylcholine

Increased levels of ___ with the use of ___ produce a modest improvement in cognitive function for some patients.

acetylcholine, acetylcholinesterase inhibitors

Neurons that use ___ are critical to memory and learning, and it is primarily ___ neurons that show changes and degeneration in early Alzheimer's disease.

acetylcholine, cholinergic

____ make and release the neurotransmitter norepinephrine

adrenergic neuron

Neuron blockers

adrenergic: reserpine, cholinergic: botulinum

Fibers that bring input to a structure

afferent

Parkinson's Disease risk factors:

age, genes, drug or toxin exposure

An ___ drug is used to treat chronic anxiety, i.e. apprehension, restlessness, tension

anxiolytic

Beta-adrenergic Antagonists reduce __ and __ by acting at the b1(b2)-adrenergic receptors on the ciliary body.

aqueous humor formation and intraocular pressure Timolol & Betaxolol

Histamine

arousal, attention

Examples of amino acids

aspartic acid (excitatory), glycine (inhibitory), glutamic acid (excitatory), GABA (inhibitory)

____ cortex makes up the bulk of the cerebral hemispheres

association

What is closely opposed to the synapse, wraps blood vessels, and is part of the BBB?

astrocyte

_____ are the most numerous cell type within the central nervous system (CNS) and perform a variety of tasks, from axon guidance and synaptic support, to the control of the blood brain barrier and blood flow

astrocytes

Manic Phase of Bipolar Disorder. Distinct period of persistently elevated or irritable mood for

at least one week.

muscarinic antagonist, blocks slowing of the heart and CNS effects of nerve gas

atropine

Muscarinic antagonists

atropine and scopolamine

The nicotinic receptors of the ___ and ___ have different specificity for agonists and antagonists

autonomic ganglia and neuromuscular junction

Type A drugs include

barbituates, alcohol, chloral hydrate, GHB, and some general anesthetics

If a person takes ___, over a period of time the half life of the ___ in that individual becomes shorter.

barbiturates

The ___, the major source of cholinergic innervation to the neocortex and hippocampus, shows progressive neuronal loss in Alzheimer's disease.

basal forebrain

How to acutely treat alcoholism?

benzodiazepines for weeks to avoid seizures and arrhythmias

Type B drugs include

benzodiazipines

Muscarinic receptor antagonists

benztropine (Cogentin)

Which sites of the neuronal nAChR have a high nicotine affinity in the brain?

beta-2 and alpha-4

Dobutamine is a

beta1- and some a-AR agonist activity

Isoproterenol is a

beta1-, beta2-AR agonist

Albuterol is a

beta2-AR selective agonists

agonist, used for urinary voiding

bethanecol

Ethosuximide

blocks calcium channels Only treats petit mal.

Carbamazepine

blocks sodium channels. Treatment for simple partial and grand mal.

Phenytoin

blocks sodium channels. Treatment for simple partial, grand mal.

The ____ is a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from non-selectively crossing into the extracellular fluid of the central nervous system where neurons reside.

blood-brain barrier (BBB)

Names of Dopamine Receptor Agonist

bromocriptine, pramipexole, ropinirole

Long term treatment with antidepressants has been shown to upregulate ___ through the activation of 5-HT and NE receptors. Increased ___ produces increase levels of BDNF and reverses the effects of chronic stress.

cAMP signaling, cAMP

Relatively weak Central Nervous System (CNS) stimulant. Stronger stimulants include cocaine and amphetamine

caffeine

Telencephalon

cerebral cortex, subcortical white matter, basal ganglia, basal forebrain nuclei

A partial list of foods containing tyramine includes:

cheeses, beer, wine, yeast, coffee, broad-bean pods, chicken livers, pickled herring and canned figs.

Chronic stress produces long term elevation in corticosteriods which in turn has been shown to produce ___ and ___.

diminished synaptic plasticity and decreased hippocampal volume.

Administration of lithium results in a dose dependent disruption of _______ in the kidney manifesting in polyuria.

distal tubular reabsorption

Monoamine oxidase does what?

deaminates catecholamines

When there is an increase of BP, the parasympathetic nervous system does what?

decrease heart rate, decreased contractility

Cardiovascular actions of prazosin:

decrease in TPR decrease in BP in upright individual: (postural hypotension) No change (or slight decrease) in BP in supine individual Less reflex in HR (compared to non-selective antagonists)

Cardiovascular actions in non-selective alpha-AR antagonists:

decrease in TPR decrease in BP in upright individual: (postural hypotension) No change (or slight decrease) in BP in supine individual Reflex increase in HR and blood volume

The point where a tract crosses the midline

decussation

Functional tolerance of alcohol leads to

dependence

Heroin

diacetylmorphine, rapid entry into brain, metabolized to 6-monoacetylmorphine (6-MAM) and then to morphine

Treatment for methanol and ethylene glycol

dialysis, ethanol to saturate metabolism, or use Fomepizole

mAChR, catecholamine R are receptors that

diffuse release sites, slow responses

Pharmacokinetics of opioids metabolism: excretion: duration of action: Drug interactions/side effects:

glucuronidation, renal, most are 4-5 hrs, avoid other CNS depressants (e.g. barbiturates, benzodiazepines, alcohol, phenothiazines, tricyclic antidepressants)

Main neurotransmitter for excitation in the brain is ___. For inhibition is ___

glutamate, GABA

Neurotransmitter in the spinal cord

glycine

Opioids are contraindicated in ____ - potentiates respiratory depression and CO2 retention leads to cerebral artery vasodilation and increase in intracranial pressure. Use cautiously in patients with ___ and ___ .

head trauma, COPD and asthma

Ganglionic blockers (does not enter CNS)

hexamethonium

Ganglionic antagonists

hexamethonium: no CNS penetration Mecamylamine: will block CNS effects of nicotine Trimethapham: short acting. Not orally active sometimes used in neurosurgery Side effects: interrupt transmittion of both sympathetic and parasympathetic ganglia. Manifested as an antagonism of the dominant tone in any given organ

Opioids: Cardiovascular system: no major effects on H.R. and B.P. Opioid agonists can stimulate the release of _____ and thereby cause hypotension.

histamine

Opioid Receptor Effector Systems: potassium channels: agonists open channels causing neuronal _____. calcium channels: agonists reduce channel opening, thereby inhibiting ____

hyperpolarization, calcium-dependent neurotransmitter release

Combining MAOI with SSRls has resulted in excess of serotonin ("central serotonin syndrome") which can lead to __, __, __.

hyperpyrexia, confusion, and death.

A ___ drug produces drowsiness and facilitates the onset and maintenance of sleep.

hypnotic

Many anticonvulsants appear to ____ , including phenytoin, carbamazepine, valproic acid (_____), and even some of the more recent drugs with shorter clinical track-records (topiramate).

increase the likelihood of birth defects (overall, about 2 fold) spina bifida

The actions of an ___ are dependent upon the presence of endogenous catecholamines.

indirect agent

Hydromorphone (Dilaudid®)

injectable, more potent than morphine

epinephrine

major hormone of the adrenal medulla.

Ganglion blockers

mecamylamine

Ganglionic blockers (uncharged molecule, enters CNS)

mecamylamine

mu receptor mediates:

mediates spinal and supraspinal analgesia, respiratory depression, euphoria, sedation, miosis, GI effects

Myelencephalon

medulla

_____not first-line; less G.I. effects than morphine; anti-muscarinic effects; seizures due to renally-cleared metabolite ; severe _____ ).

meperidine (Demerol), interaction with MAO inhibitors

Opioid ligands that bind to mu receptors are

met-enkephalin, leu-enkephalin, beta-endorphin, dynorphin A, dynorphin B, alpha neoendorphin, endomorphin 1

Opioid ligands that bind to delta receptors are

met-enkephalin, leu-enkephalin, dynorphin B, alpha neoendorphin, endomorphin 1

Rhombencephalon (hindbrain)

metencephalon and myelencephalon

agonist, tests bronchial reactivity

methacholine

____a misguided ethanol substitute (Drug discrimination). It may be inhaled and reach toxic levels. Copying or embalming fluids

methanol

Diabetic Retinopathy (DR) is associated with

microaneurisms (MAs), exudates (EXs), and hemorrhages (HMs)

What is the neuronal macrophage?

microglia

Serotonin

mood, dreams, reality

low bioavailability (~20%) due to significant first pass metabolism, given i.m. or i.v. Morphine-6-glucuronide (metabolite) has significant biological activity.

morphine

Morphine-like (phenanthrenes)

morphine, codeine, heroin

Opioid:

morphine-like (pharmacological actions), also includes antagonist drugs

mu receptor

morphine-preferring; many of the clinically used opioid drugs are selective for this receptor.

Subtypes of opioid receptors:

mu, kappa, delta

agonist (no clinical use)

muscarine

GPCR are what type of receptors?

muscarinic and noradrenergic receptors

____ orally active, as potent as morphine. Used in combo with NSAID (Percocet® and Percodan®).

oxycodone

morphine-like semi-synthetics include:

oxycodone, hydrocodone, hydromorphone, oxymorphone

Urinary: detrusor

para: M-urination

Coronal plane

parallel to face

GI: Predominant tone & Effect of ganglionic blocker

parasympathetic; constipation

ciliary muscle: Predominant tone & Effect of ganglionic blocker

parasympathetic; cycloplegia (loss of accommodation)

iris: Predominant tone & Effect of ganglionic blocker

parasympathetic; mydriasis (dilation)

heart: Predominant tone & Effect of ganglionic blocker

parasympathetic; tachycardia (increased heart rate)

urinary bladder: Predominant tone & Effect of ganglionic blocker

parasympathetic; urinary retention

salivary glands: Predominant tone & Effect of ganglionic blocker

parasympathetic; xerostomia (dry mouth)

Nicotine partial agonists:

partial activation of alpha-4 and beta-2 containing receptors. Blunt the phasic responses to nicotine and ACh on up-regulated response

Vareniciline is a

partial agonist for high affinity nAChR

Drugs that enhance GABA neurotransmission are generally effective against

partial seizures and generalized tonic clonic seizures.

sagittal plane

perpendicular to face, midline.

norepinephrine is converted to epinephrine by

phenylethanolamine-N-methyltransferase in adrenal medulla

Some of the potentially most important effects of lithium have been noted on second messengers such as cAMP and intracellular calcium signaling through the __ and __ These pathways regulate long-term changes in synaptic function.

phosphoinositide pathway and protein kinase C.

cholinesterase inhibitor (uncharged molecule, enters CNS)

physostigmine

Due to decrease of parasympathetic tone, there is a decrease of salivary secretions ( treat with ___)

pilocarpine

agonist, stimulates salivary glands

pilocarpine

Metencephalon

pons and cerebellum

Effect achieved at a very low dose. Selective inhibition of COX-1 due to impact on platelets in ___ .

portal circulation

Opioid receptors regulate ___ and ___ channel activity

potassium and calcium

Norepinephrine is transported out of ____

presynapse.

Both Codeine and Heroin are

pro-drugs

In renal failure, prostaglandins facilitate renal perfusion by

promoting vasodilation of afferent arterioles.

____ play an important role in modulating the PNS following injury and inflammation. These resemble the astrocytes of the CNS and assist in regulating the external chemical environment.

satellite cells

A ___ drug decreases activity, moderates excitement and calms the patient.

sedative

Cardiovascular actions (high dose) of epinephrine:

see Norepinephrine Increase in total peripheral resistance (TPR.), increase in blood pressure (BP), and increase in stroke volume (SV) Reflex in decrease heart rate (HR) No change in cardiac output (CO)

MAO-B blockers

selegiline (Deprenyl/Eldepryl®), rasagiline (Azilect®)

Opioids reduce both __ and ___ the components of pain.

sensory and emotional

Opioids Inhibit

sensory neurons (A delta and C fibers)

Aspirin: irreversible inhibition of COX via acetylation of active site __

serine

Cardiovascular actions of phenylephrine:

similar to Norepinephrine, but may decrease CO

Partial Seizures: localized onset. Types include

simple partial seizures, complex partial seizures

Opioids: Constipation: acts on nerves (enteric nervous system) and not on _____ or ______, increased muscle tone and decreased propulsive peristaltic movement in small intestine and colon (intermediate tolerance)

smooth muscle or secretory cells

beta 2-AR

smooth muscle: bronchodilation (lung) and vasodilation (e.g. vessels in skeletal muscle)

Activation of nicotinic receptors causes opening of channels which are permeable to ___ and ___

sodium and potassium

The permeability of lithium through __ and __ to may allow lithium to especially accumulate in active neurons.

sodium channels and synaptic ion channels (especially glutamate receptors)

It is also essential to maintain an adequate __ to avoid lithium intoxication.

sodium intake A low sodium diet and lithium treatment are contraindicated.

Generalized Seizures include

tonic-clonic (Grand mal) and absence seizures (Petit mal)

Prostaglandins sensitize nociceptive receptors to analgesic mediators. PGE2 can potentiate the action of ____ on sensory neurons.

transient receptor potential (TRP) ion channels

Which benzodiazepines has the shortest duration of action and has an active metabolite?

triazolam

Up to ___ of depressed patients do not get treatment for their disease.

two-thirds

Biosynthesis of Dopamine

tyrosine --> tyrosine hydroxylase --> L-DOPA --> Aromatic-Amino Acid Decarboxylase (AAD) or DOPA Decarboxylase (DDC) --> dopamine --> MAO-B: monoamine oxidase isoform or BCOMT: catechol O-methyltransferase --> metabolites

Food is consumed, phenylalanine comes into the axon then is converted to

tyrosine by phenylalanine hydroxylase

tyrosine is converted to L-dopa by

tyrosine hydroxylase

Administration of tricyclics to patients with bipolar disorder has been associated

with a switch into mania.

• Sympathetic (NE) activity on the ciliary epithelium increases the secretion of AH. • There are __, __, and __ on the ciliary epithelium. • Stimulation of __ and __ increases AH formation. • Stimulation of ___ reduces AH formation.

ß1, ß2, and a2 adrenergic receptors ß1 and ß2 adrenergic receptors a2 adrenergic receptors

Motor Symptoms & Co-morbidities of Parkinson's

• Bradykinesia • Resting tremor • Rigidity • Postural instability • Secondary non-motor symptoms: depression (~30%), dementia (~50%) and autonomic dysfunction. • Currently no cure; anti-PDs to manage motor symptoms

Carbonic Anhydrase Inhibitors mechanism of action, side effects

• Carbonic anhydrase inhibitors (acetazolamide) used orally for their diuretic action also act on the eye and reduce AH formation. • Development of a topical carbonic anhydrase inhibitor (Dorzolamide) took many years but was an important event because of lack of side effects of oral drugs. • Dorzolamide inhibits CA (isozyme II) that is present in the ciliary body epithelium reducing the formation of bicarbonate required for the aqueous humor production. • CAIs reduce intra-ocular pressure by decreasing AH formation. • Have a synergistic action with b-adrenergic antagonists and other drugs. • In fact, timolol has been combined with dorzolamide in a single medication (Cosopt). • Such combinations reduce the number of drops needed and improve compliance.

Dipivefrin mechanism of action, side effects

• Dipivefrin (Propine) is a lipophilic pro-drug that is converted to epinephrine in the eye. • It is much better tolerated than epinephrine but still may cause epinephrine-like side effects (localized irritation and hyperemia).

Dopamine Hypothesis of Schizophrenia

• Excessive DA activity in limbic system • Antipsychotics block D2 receptors in mesolimbic system • Drugs that increase DA activity produce psychosis • DA receptor density is increased in brains of schizophrenics(increased mesolimbic D2 - positive symptoms vs. deficient mesocortical D1 - negative/cognitive symptoms)

Non-selective COX-1 and COX-2 inhibitors

• Ibuprofen, Naproxen (Aleve®), Fenoprofen, Ketoprofen, Flurbiprofen (all propionic acid derivatives)(Naproxen has a relatively long plasma half-life) • Indomethacin (Indocin®), Sulindac, Etodolac • Tolmetin, Diclofenac, Ketorlac (ketorlac as oral or i.m.)• Piroxicam, Meloxicam• Fenamates (Mefenamic acid, Meclofenamate sodium) • Nabumetone (Relafen®) - non-acidic drug converted to an acidic metabolite in liver • Phenylbutazone

COMT inhibitors do what?

• Inhibits L-DOPA metabolism in the periphery and/or DA metabolism in the brain (striatum); may combine with Sinemet to reduce wearing-off effects • Use together with L-DOPA, no benefit on its own • Side effects: diarrhea, increased sensitivity to L-DOPA (more dyskinesia, hallucination, etc.) • Tolcapone (Tasmar®): central and peripheral COMT inhibition; hepatotoxicity (fulminant hepatitis) • Entacapone (Comtan®): peripheral COMT only; expensive # Stalevo® : levodopa + carbidopa + entacapone

How to increase Aqueous Humor Drainage?

• Parasympathetic (ACh) activity enhances AH outflow. • Prostaglandins also increase AH outflow.

Symptoms of schizophrenia

• Positive (hallucination, delusion, aggressive behavior) • Negative (lack of speech or emotional expression, social withdrawal) • Cognitive (difficulties with concentration & memory, problems in executive decision)

Trypan blue-based formulations:

• Visionblue for visualization of the lens • Membraneblue used as a guide for excision of tissue

Problems with L-DOPA therapy:

• ~ 1/3 non-responders• Protein-rich food interference? dependent on the individual • Wearing off: after years of use, a current dose of L-DOPA may lose effectiveness before the next dose • On-Off Phenomenon: move normally vs. slow/freeze; dyskinesia happens while the drug is on board Sinemet CR (slow-onset, longer duration, less potent, take at bed-time); or more frequent dosing; or drug combination Side effects: nausea & vomiting; postural, hypotension; sleep disturbances, etc. Dyskinesia: disordered involuntary movement including insuppressible, stereotyped, automatic movements that cease only during sleep