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Q8 Pharmacology

Terms in this set (123)

Therapeutic uses of synthetic glucocorticoids
• Anti-inflammatory agents (Transactivationn* - up regulation of anti-inflammatory factors and enzymes involved in gluconeogenesis)
• Immunosuppressants (Transrepressionn* - down regulation for genes involved in immune response)
• Anti-proliferative (malignancies)
• Replacement for insufficient endogenous cortisol
• Developmental - helps produce surfactant in the lungs
• Used to treat asthma, Crohn's disease, rheumatoid arthritis, severe allergic reactions, and some cancers
Systemic effects of glucocorticoids
• Liverr* - increases glycogenolysis and gluconeogenesis from glycerol and amino acids
• Skeletal musclee* - increased protein catabolism, decreased photosynthesis, inhibition of glucose uptake (use fatty acids instead)
• Adiopose tissuee* - release of free fatty acids and glycerol
• Bonee* - decreased osteoblast activity, decreased calcium absorption from GI tract, mobilization of osteoclasts, decreased calcitonin secretion -> can lead to osteoporosis in children and women
• Decreased production of prostaglandins, cytokines, and interleukins
• Decreased proliferation and migration of lymphocytes and macrophages
What regulates the release of mineralocorticoids?
• ACTH from the anterior pituitary
• Renin-angiotensin system
• [K+]
What systemic and local effects does angiotensin II have?
• Increases thirst
• Induces arteriolar vasoconstriction
• Induces release of vasopressin/ADH from the posterior pituitary -> water resorption in collecting duct
• Induces release of aldosterone from the adrenal cortex -> tubular Na and Cl resorption -> water follows
• Activation of the sympathetic nervous system
Effects of mineralocorticoids
• Retention of Na+ in kidney tubules
• Cl- passively resorbed as well
• H20 follows -> increased BP
Pharmacokinetics of Glucocorticoids
• Rapid absorption in GI tract, synovial spaces, and conjunctiva
• Slow absorption via skin
• Bound in the plasma to a cortisol-binding globulin called transcortin
• Inactivated in the liver and kidneys before excretion in the urine and feces
Signs of Cushing's syndrome
• Diabetes
• Hypertension
• Hirsutism
• Moon facies
• Truncal obesity
• Muscle weakness

• Caused by excess of glucocorticoids from (a) adrenal adenoma, (b) anterior pituitary tumor, or (c) excessive exogenous hormones
Signs of Adrenocortical insufficiency
• Weakness
• Fatigue
• Diarrhea
• Hypotension
• Pigmented patches on buccal mucosa

• Causes:
1. Addison's disease (primary form)
• Genetic insufficiency or destruction of adrenal cortex via HIV, tuberculosis, a tumor, or autoimmune disease
2. Glucocorticoid therapy 2+ weeks (secondary form)
• Suppresses the hypothalamus-pituitary-adrenal axis
Synthetic forms of glucocorticoids
• Prednisone
• Prednisolone
• Methylprednisolone
• Dexamethasone
• Betamethasone
• Triamcinolone
• Beclametasone
When to use glucocorticosteroids in dentistry
• Topical - apthous ulcers, desquamative gingivitis, oral pemphigus, pulp capping
• Systemic - IV dexamethasone pre-operatively for 3rd molar extractions; ice pack and analgesics post-operatively
Synthetic forms of mineralocorticoids
• Fludocortisone
• Deoxycorticosterone
Dihydrotachysterol
• A synthetic form of Vitamin D
• Does not require 1-alpha-hydroxylase activation in the kidneys
• Used to treat disorders of calcium homeostasis
Teriparatide
• A recombinant form of PTH
• Has an anabolic effect on bone in low doses
• Used to treat disorders of calcium homeostasis
Inhibitors of osteoclast activity
• Calcitonin
• Estrogen
• Selective estrogen receptor modulators (non-steroidal ligands of estrogen receptors) - raloxifene
• First generation bisphosphonates - alendronate, etidronate
• Second generation bisphosphonates (less inhibition of osteoblasts) - zoledronate
• Oral bisphosphonates - ibandronate, risedronate
Mechanism of action of bisphosphonates
1. Bisphosphonates attach to Ca2+ in hydroxyapatite
2. Bisphosphonates are taken up by osteoclasts during bone resorption
3. Bisphosphonates replace bisphosphate in ATP, rendering them non-functional
4. Induces apoptosis of osteoclasts
5. Decreases osteoclastic activity (includes normal bone turnover)
How do you prevent osteonecrosis of the jaw?
• Have the patient discontinue the oral bisphosphonates for at least 3 months before the procedure (if possible)
• Do not go back on medication until healing of would side has occurred
• Examples: implant placement, perio surgery, periapical surgery, extraction
Albuterol
• Selectivee* Beta 2 adrenergic receptor agonists
• Bind to Beta 2 receptors to induce bronchodilationn*, decrease microvasculature permeability, and increase intracellular cAMP
• 10% of inhaled goes directly to lungs, other 90% goes to liver for first pass inactivation
• Used to treat acute asthma episodes & to help stop smoking
Formeterol
• Selectivee* Beta 2 adrenergic receptor agonist
• Bind to Beta 2 receptors to induce bronchodilation, decrease microvasculature permeability, and increase intracellular cAMP
• Administered orally or inhaled
• Used to treat acute asthma episodes & to help stop smoking
Epinephrine
• Non-selectivee* Beta 2 adrenergic receptor agonist
• Administered via epi pen (IM) or orally
• Used to treat anaphylactic reactionss* & to help stop smoking
Isoproterenol
• Non-selectivee* Beta 2 adrenergic receptor agonist
• Administered orally or via inhalation
• Used to treat anaphylactic reactionss* & to help stop smoking
Atropin
• A muscarinic receptor antagonist
• Muscarinic receptors are activated by acetylcholine (parasympathetic) and typically induce bronchoconstriction
• Muscarinic receptor blocker --> bronchodilation
• Used to treat acute asthma episodes & to help stop smoking
• Side effects: xerostomia
Ipratropium
• A muscarinic receptor antagonist
• Muscarinic receptors are activated by acetylcholine (parasympathetic) and typically induce bronchoconstriction
• Muscarinic receptor blocker --> bronchodilation
• Administered via inhalation
• Used to treat acute asthma episodes & to help stop smoking
• Side effects: xerostomia
Tiotropium
• A muscarinic receptor antagonist
• Muscarinic receptors are activated by acetylcholine (parasympathetic) and typically induce bronchoconstriction
• Muscarinic receptor blocker --> bronchodilation
• Administered via inhalation
• Used to treat acute asthma episodes & to help stop smoking
• Side effects: xerostomia
Theophyline
• A methylxanthine
• Reduces frequency of bronchospasms
• Increases intracellular cAMPP* -> inhibits phosphodiesterase
• Used to treat respiratory disorders
• Methylxanthines have a very small therapeutic window
• Side effects: GI upset caused by increase of gastric acid, CNS effects, cardiac dysrhythmias, life-threatening seizures
Antihistamines
• Block histamine release
• Only used to treat allergic rhinitis
Omalzumab
• An anti-IgE antibody
• Prevents degranulation of mast cells
• An anti-inflammatory drug used for longterm control of asthma symptoms
Cromolyn
• A cromone
• Increases the stability of the mast cell surface membrane -> inhibits degranulation
• An anti-inflammatory drug used for longterm control of asthma symptoms
Montelucast, Zafirlucast
• Leukotriene modulators
• Either (a) decrease leukotriene synthesis or (b) prevent leukotriene receptor activation
• An anti-inflammatory drug used to treat respiratory disorders
Beclomethasone, Budesonide, Prednisone, Predinisolone, Hydrocortisone
• Glucorticoids
• Control transcription of inflammatory mediator genes
• Controls edema, mucous production, and eosinophil infiltration
• Administered orally
• Used to treat acute asthma episodes
• Short term side effects: hypertension, elevated blood glucose, GI bleeding
• Long term side effects: osteoporosis, thinning of skin, aseptic necrosis of the head of the femur, diabetes, CNS disturbances, growth retardation in children, oral candidiasis
• Dose should be decreased after 7 days for the next 1-2 weeks to allow the adrenal gland to recover from its lowered function
Histology of Parkinson's Dz
• 70-80% loss of cells in the Substantia Nigra of the midbrain
• Lewy bodiess* made of alpha-synoclein protein form in the substantia nigra as well
Cardinal features of Parkinson's Disease
• Unsteady, short gait
• Rigidity in movement (very slow)
• Resting tremor
• Slouched back
• Arms out in front of body but do not swing
• Postural impairments - legs bent, stiff kneed and hips
• Mask-like face
Pathophysiology of Parkinson's Disease
• Nigrostriatal pathwayy* - the loop between the motor neurons and the motor cortex is damaged - motor cortex controls fine, coordinated movements
• Loss of dopaminergic neurons in the substantia nigra leads to the loss of motor control and permanent damages the basal ganglia
• As a result, there is increased cholinergic motor neuron activity, which is responsible for the tremor
Etiology of Parkinson's disease
• Infection (encephalitis lethargica)
• Genetic mutation (such as in the alpha-synoclein protein)
• Environmental toxins - manganese, MPTP, pesticides
• Oxidative stress (ROS from mitochondria)
• Parkinson-like symptoms from dopamine antagonists
Levodopa/L-dopa
• A dopamine agonist
• L-dopa is the immediate precursor of dopamine, which is metabolized by L-amino acid decarboxylase
• Reduces rigidity, tremors, and improves posture and gait
• Must be given in high doses if given alone
• Works for 2-3 years, but after that the therapeutic response declines; fluctuations in response and dyskinesias after 3-5 years of treatment
• Side effects - schizophrenia-like syndrome, confusion, slow-developing dyskinesia, on and off controlled motor movements in first couple of years
• Nausea, vomiting, anorexia, tachycardia, depression, anxiety, hallucinations, extra systole, and postural hypotension also possible
Carbidopa/Lodosyn
• Inhibits the aromatic L-amino acid decarboxylase in the PERIPHERYY* - that way more L-DOPA remains (is not turned into dopamine in periphery) and can be transported to the brain
• Used in adjunct therapy with L-Dopa
• Decreases dose of L-Dopa needed, thus reducing vomiting and nausea associated with L-Dopa
Carbidopa + L-Dopa
• Used as the first line treatment for Parkinson's disease
• Lower doses of L-Dopa required because Carbidopa permits greater fractions of L-Dopa to reach the brain
• Examples: Atamet, Parcopa, Sinemet
Apomorphine (Apokyn, Uprima)
• A dopamine receptor agonist - a derivative of morphine without the effects of a narcotic
• Also has some effect on alpha 1 or alpha 2 adrenoceptors
• Uses: diagnostic for receptiveness of Parkinson's patients to dopamine tx; treats episodes seen in severe idiopathic Parkinson's disease
• Side effects: significant vomitingg* (emetic), marked CNS depression, respiratory depression, hallucinations, impulsivity, sleepiness
Bromocriptine (Parlodel)
• A dopamine receptor agonist - a synthetic ergotamine
• Agonist for dopamine type 2 receptors and antagonist for dopamine type 1 receptors
• Used in conjunction with Levodopa in order to reduce the dosage of Levodopa by 40%
• Side effects: significant vomitingg* (emetic), marked CNS depression, respiratory depression, hallucinations, impulsivity, sleepiness
• Used to treat Parkinson's disease
Pramixpexole (Mirapex), Ropinirole (Requip), and Rotigotine (Neurpro)
• Dopamine agonists
• Clinically they are used as a monotherapy or in conjunction with L-dopa
• Can induce sudden attacks of sleeping during daytime activities
• Side effects: significant vomitingg* (emetic), marked CNS depression, respiratory depression, hallucinations, impulsivity, sleepiness
• Used to treat Parkinson's disease
Entacapone (Comtan)
• Selectively inhibits COMT in the periphery
• COMT is a substance that coverts L-dopa into 2-O-methyl-DOPA before elimination
• Decreases elimination of L-DOPA in order to increase the effects of L-DOPA
• Used in combination with Levodopa to decrease "off time" in severe Parkinson's
• Side effects: brown/orange urine
Tolcapone (Tasmar)
• Selectively inhibits COMT in the periphery and brain
• COMT is a substance that coverts L-dopa into 2-O-methyl-DOPA before elimination
• Decreases elimination of L-DOPA in order to increase the effects of L-DOPA
• Used in combination with Levodopa to decrease "off time" in severe Parkinson's
• Side effects: brown/orange urine, hepatoxicityy* that requires monitoring
Amantadine (Symmetrel)
• Enhances dopamine synthesis and release
• Weak antagonist for NMDA receptors
• Used to decrease the symptoms of bradykinesia (slow movement) and rigidity in Parkinson's disease
• Side effects: restlessness, agitation, confusion, hallucinations, orthostatic hypotension, livedo reticularis
Selegiline
• Selectively inhibits MAO-BB* (MAO-B metabolizes dopamine but not other catecholamines)
• Used as monotherapy in early Parkinson's disease and in combination with L-Dopa
• Side effects: can accentuate adverse motor and cognitive functions in late PDD*, anxiety, depression
Rasagiline
• Selectively inhibits MAO-BB* (MAO-B metabolizes dopamine but not other catecholamines)
• Used as monotherapy in early Parkinson's disease and in combination with L-Dopa
• Side effects: can accentuate adverse motor and cognitive functions in late PDD*, anxiety, depression
Trihexyphenidyl
• Anti-cholinergic drug -> an antagonist for muscarinic cholinergic receptors in the CNS and smooth muscle (to a lesser extent)
• Moderately decreases the tremor in early stage Parkinson's disease (only effective in 50-75% of patients)
• Side effects: xerostomia, confusion, urinary retention, blurred vision
Procyclidine
• Anti-cholinergic drug -> an antagonist for muscarinic cholinergic receptors in the CNS and smooth muscle (to a lesser extent)*
• Moderately decreases the tremor in early stage Parkinson's disease (only effective in 50-75% of patients)
• Side effects: xerostomia, confusion, urinary retention, blurred vision
Benzotropine
• Anti-cholinergic drug -> an antagonist for muscarinic cholinergic receptors in the CNS and smooth muscle (to a lesser extent)
• Moderately decreases the tremor in early stage Parkinson's disease (only effective in 50-75% of patients)
• Side effects: xerostomia, confusion, urinary retention, blurred vision
What is the most common cause of dementia?
Alzheimer's disease (60-70% of dementias)
• Lewy body dementia + Alzheimers (15-25%) and vascular dementia + Alzheimer's (10-20%) are also common
How do you confirm the diagnosis of Alzheimer's disease?
Post-mortem inspect of the brain
Diagnostic features of Alzheimer's
• Emotionally unstable
• Forgetful
• A loss of memory in an otherwise alert subject (senile dementia)
• Problems with language, attention, and perception
• Problems with calculations and problem-solving
• Signs typically develop in the 6th or 7th decade of life
Riskfactors for Alzheimer's disease
• Obesity
• Diabetes
• Hypertension
• Smoking
• Head injury
• Infection (such as AIDs)
• Tumors
• Vascular disease
• ApoE4 gene
Characteristics of Mild Alzheimer's
• Self-care, social skills, & neurofunction generally intact
• Difficulty with complex tasks
• Depressio and apathy
• Examples: repeating stories or questions, trouble operating appliances, less interest in hobbies, misplacing items
Characteristics of Moderate Alzheimer's
• Deterioration of the ability to think, reason, and communicate
• Behavioral symptoms begin
• Examples: unable to travel alone, restless, wanders, insomnia, difficulty using machinery and telling time
Characteristics of Severe Alzheimer's
• Completely dependent on others - no capacity for self-care
• Longterm care placement
• Examples: gait disturbance, incontinence, aggression, agitation, irritability, difficulty eating/bathing/drinking, etc
What are the two biomarkers for Alzheimer's disease and how do they work?
1. Florbetepir/Amyvid
2. Flutemetamol/Vizamyl
• Bind to amyloid plaquess* that can be picked up via a PET scan
Pathophysiology of Alzheimer's Disease
• General shrinkage in the brain matter that leads to a great loss of grey matter cells in the cortex
• Mediotemporal lobe lost - important for memory
• Laterotemporal lobe lost - important for language
• Ventricles enlarge because they fill in the space where brain matter has been lost
• Appearance of amyloid plaques and neurofibrillary tangles
• Neurofibrillary tangles are made of hyperphosphorylated Tau proteins
Which cholinergic brain pathways breakdown in Alzheimer's?
• Septo-hippocampal pathway (learning and memory)
• Basal forebrain to telencephalon
• Pontomesencephalic tegmental system (innervates spinal cord & brainstem)
• Cholinergic neurons in the limbic system and neocortex
Acetylcholinesterase inhibitors
• Inhibit acetylcholinesterase (which breaks down Ach into choline and acetate) in the CNS and periphery
• Thus, the medications elongate the effects of Ach transmission
• Clinically leads to a mild improvement in AD symptoms for 3-4 years
• Tacrinee* - not used any longer bc of hepatoxicity
• Donepezill* - longest half-life (70 hours) so can be taken daily, associated with rhinorrhea
• Galantaminee* - enhances Ach effects of nicotinic receptors in the brain
• Rivastigminee* - intermediate agent most specific for AchE in the heart and brain
Adverse effects of anti-cholinesterase inhibitors
• Blurred vision
• Increased salivation
• Decreased heart rate (potential problem for people with pre-existing heart conditions) - bradycardia
• Nausea
• Airway contraction
• Increase GI mobility (nausea, diarrhea, abdominal cramps, anorexia) - 1/3 of people have diarrhea
• Tremors
• Urinary incontinence
• Myalgia
• Caution on using on patients with asthma, COPD, or peptic ulcers
• Contraindicated in patient's with Parkinson's disease who take anti-cholinergic drugs for their tremor
Memantine & Namzaric
• N-Methyl-D-Aspartate (NMDA) receptor antagonist
• NMDA receptors are glutamate receptors in the brain that are implicated in learning and memory and excitotoxity - excessive activation of the receptors can lead to neurons dying
• Used to gain a moderate improvement in symptoms for moderate to severe Alzheimer's patients
• Side effects: agitation and headaches
What is the most common psychosis and when is its onset?
• Schizophrenia (affects 1% of population)
• Adolescent onset and persists for life
Diagnostic characteristics of schizophrenia
• Positive symptoms (psychotic episodes))*: hallucinations, delusions, disorganized speech, disorganized posture, catatonia (a state of immobility/stupor)
• Negative symptoms (non-psychotic episodes))*: reduced emotions, poverty of speech, apathy
• Prodromal (early) signss*: social isolation, neglect of personal hygiene
• Depression
• Mania
What puts a patient at risk for developing schizophrenia?
• Viral infections, autoimmunity, and maternal starvation (during fetal life)
• Certain susceptibility genes - brain-derived neurotrophic factor (BDNF), dysbindin, neuregin, DISC-11* - that lead to abnormal development in neuronal circuits, migration, synaptogenesis, myelination in brain development, etc
• Abnormal glutamate NMDA receptors (critical in synaptic plasticity, leanring, and memory)
Neurobiological findings in Schizophrenia patients
• Decreased blood flow to the frontal lobes
• Decreased blood flow the caudate nucleus
• Reduction in size of the hippocampus
• Enlarged ventricles
• DISC-1 mutation
• Cellular disarray in medial temporal lobes
What is the dopamine hypothesis of schizophrenia?
• Hyperactivity in mesolimbic dopamine pathways -> positive symptoms
• Hyperactivity in mesocortical dopamine pathways -> negative symptoms
• Blocking Dopamine 2 receptors have shown to act as an anti-psychotic
MOA of Classical Anti-psychotics
• Drug classes: phenothiazines, thioxanthines, hertocyclics
• Dopamine 1 and 2 receptor antagonistss* - blocking D2 receptors in the mesiolimbic system decreases hallucinations, delusions, and disordered thought (controls positive symptoms)
• Smaller effect on apathy, social isolation, etc
• Takes a few weeks to kick in
Atypical, Second Generation Anti-psychotics
• Weak Dopamine 2 antagonist; strong Dopamine 1, Dopamine 4, and 5HT2A receptors throughout the CNS
• Improves positive symptoms, apathy, and mood
• Can be effective in patients that are unresponsive to classical anti-psychotics
Side Effects of Classical Anti-psychotics
1. D2 blocking of Nigrostriatial System
• 25% of patients will develop Extra-pyramidal symptoms (EPS))* after 5 years of taking D2 blockers
• Extra-pyramidal symptoms: Parkinsonism, dystonia (uncontrolled muscle contraction that leads to twisting of area), akathisia (inner restlessness that creates a desire for constant motion), and Tardive dyskinesia (belated onset & hard to treat dyskinesia)
2. D2 blocking of Tuberoinfundibular system
• Gynecomastia - development of breasts in men
• Galactorrhoae - excessive or inappropriate production of milk
• Amenorrhoea - no period
• Infertility
3. Alpha adrenoreceptor block
• Leads to postural/orthostatic hypotension
4. Muscarinic receptor block
• Leads to dry mouth, blurred vision, urinary retention
5. Histamine H1 receptor block
• Sedation
• Weight gain
6. 5HT2C receptor block
• Weight gain
What is the mechanism of action of most abusive drugs?
• They modulate the mesiolimbic dopamine receptors
• This includes the ventricle tegmental area that sends signals to the nucleus accumbenss* that projects to the prefrontal cortex
• The VTA regulates responses to natural reinforcers such as food, sex, drink, friendship, family, social and professional interactions
Classifications of Drugs of Abuse
1. GPCR
• Act on G-protein coupled receptors
• Cannabinoids, opioidss*, gamma hydroxybutyrate (date rape drug)
2. LGIC
• Act on ligand-gated ion channels such as nicotinic Ach receptors or Gabba A receptors to induce euphoria
• Nicotine, alcohol, benzodiazepiness* (valium), dissociative anesthetics (ketamine), some inhalants
3. Monoamine transporters
• The most addictive drugs
• Induce the release of NTs, but the main effect is to block the reuptake of NTs back into the axon terminal
• Cocainee*, amphetamines, ecstasy
Marijuana
• Most common illicit drug in the U.S.
• Active chemical is THC
• Has hallucinogenic, psychedelic, and medicinal properties
• MOA: agonist to CB1 and CB2 GPC receptors
Opioids
• Heroin, codeine, morphine, oxycodone, hydrocodone, methadone, fentanyl
• MOA: act on mu, kappa, and delta GPC receptors all over the brainn* (spinal cord, brainstem, etc)
• All induce strong tolerance and dependence - have to take more + more to get the same psychological effects
• Withdrawal symptoms include intense dysphoria, nausea, vomiting, muscle aches, lacrimation, rhinorrhea, mydriasis, piloerection, sweating, diarrhea, insomnia, autonomic hyperactivity
• Relative risk for addition is 4
Hallucinogens
• LSD/Acid, mescaline, psilocybin
• MOA: act on serotonin type 2 receptors (5-HT2A) to increase glutamate release in the cortex
• Alter consciousness (shape, color, time perception); increase sense of wellbeing; and induce hallucinations
• Dizziness, paresthesia, and blurred vision are potential somatic effects
• Not highly addictive - dependence and tolerance do not develop
Benzodiazepines
• Diazepam, temazepam, lorazepam, etc
• MOA: potentiate GABA receptor function
• Induce a sense of euphoria, sedative-hypnotics, and anxiolytic actions
• Highly addictive - dependence and tolerance develop quickly
• Withdrawal symptoms include anxiety, seizures, irritability, and insomnia
Ketamine & Phencyclidine
• LGIC dissociative anesthetics (mostly used in vet medicine)
• Also known as Angel's dust and Special K
• MOA: blocks NMDA receptor ion channels, but does not affect the mesiolimbic system directly
• Effects: psychedelics, impaired memory function, visual changes, out of body experiences
• Relative risk for addiction is 1
Cocaine
• Cocaine HCl, Crack cocaine (free base cocaine)
• MOA: blocks Na channels in the PNS; blocks uptake of dopamine, serotonin, and noradrenaline in the CNS by inhibiting transporters
• The blockage of dopamine is what makes it so addictive
• Users get an instantaneous rush; they are hyperactive, sleep very little, and lose their appetite
• Increases risks of intracranial hemorrhage, ischemic stroke, MI, and seizures
• Relative risk for addiction is 5
Methamphetamine
• Major cause of severe dental decay
• MOA: indirect agonist of dopamine receptors by stimulating dopamine release
• Xerostomia, bruxism, sugary drinks, and poor dental hygiene contribute to the dental breakdown
• Xerostomia likely from constriction of salivary glands and decreased salivary flow from alpha-1 receptor activation by meth
• Bruxism likely from increased monoamines -> parafunctional habits
What are anti-spasmodic drugs used for?
• Muscle spasms related to neurological disorders and injury
• Examples: multiple sclerosis, cerebral palsy, stroke
Baclofen
• MOA: GABA agonist in the CNS - increases K conductance and decreases Ca flux at pre-synaptic sites
• This leads to hyper polarization and decreased excitatory glutamate NT release
• Used to treat MS-related spasms, facial tics, and spasticity from spinal cord injuries
• Side effects: drowsiness, fatigue, motor incoordination, impaired memory, and hypotension
Cyclobenzaprine & Metxalone
• MOA is unknown - relaxes skeletal muscle centrally to decrease motor nerve activity
• Adjunctive in physical therapy and muscle spasticity for rest
• Side effects: drowsiness, sedation, dry mouthh*, dizziness, headache
Dantrolene
• MOA: inhibits calcium release from the sarcoplasmic reticulum in muscle fibers -> uncouples nerve activity to decrease muscle contraction
• Used to treat spasticity from spinal cord injury, stroke, cerebral palsy
• Treats malignant hyperthermiaa* (a rapid increase in body temperature)
• Side effects: dizziness, drowsiness, seizures, diarrhea, and hepatoxity with chronic use
Methocarbamol
• Unknown MOA - an OTC drug
• Use as an adjunct to PT and for muscle spasticity associated with tetanus poisoning
• Side effects: sedation, dizziness, headache
Tizanidine
• A clonidine derivative
• MOA: an alpha-2 receptor agonist
• Decreases excitatory NT release at pre-synaptic sites in the spinal cord
• Used to treat muscle spasticity associated with MS, ALS, and spinal cord injuries
• Side effects: dizziness, sedation, dry mouth, orthostatic hypotension
Analgesia
The elimination or diminution of pain in a conscious patient
Local anesthesia
The elimination of sensation (esp pain) in one part of the body by topical application or regional injection of a drug
Conscious sedation
• Minimally depressed conscious state
• Achieved through non-pharmacological or pharmacological methods
• Able to independently maintain airway
• Responds to appropriate physical stimuli and commands
• Patient rendered free of fear, anxiety, and apprehension
Deep sedation
• A controlled, pharmacologically induced state of depressed consciousness
• Patient unaware of self + surroundings
• Patient is not easily aroused and may experience a partial loss of protective reflexes
• The includes the ability to maintain a patent airway independently and/or respond purposefully to physical stimulation or verbal command
• Administered through IV injectionn* of drugs (can be well regulated and titrated, short latency period)
• Must be able to maintain airway and oxygen saturation
General anesthesia
• Elimination of all sensation
• Loss of consciousness
• Absolute loss of airway/airway compromise - intubation required
Stage 1 of Anesthesia
• IV sedationn*, sleeping pills, nitrous oxide, lorazepam, alcohol, etc
• Respiration: normal
• Eye movements: normal
• Protective reflexes: intact
• Amnesia sometimes present
Stage 2 of Anesthesia
Stage of delirium
Stage 3 of Anesthesia
• Stage of surgical anesthesia, including GA (in plane III)
• Respiration: intercostal muscle paralysis (plane III) and eventual diaphragm paralysis (plane IV)
• Eye movements: cessation in phase I
• Protective reflexes:lost
Stage 4 of Anesthesia
Stage of respiratory paralysis
Advantages & Disadvantages of GA, deep sedation, conscious sedation
• GA and deep sedation: require more training/licensing and higher medical risk to patient; rapid onset of action, high reliability, high effectiveness
• Used in invasive surgical procedures, severely phobic dental patients, uncooperative pediatric patients, and some disabled patients
• Conscious sedation: high reliance on patient cooperation for tx to be successful
Light sedation
• A type of conscious sedation
• Patient is aware of himself/herself and their surroundings
• Sleepy
• Achieved through oral ingestion of medications
Moderate sedation
• A type of conscious sedation
• Patient is slight aware of himself/herself and their surroundings
• Somnolent but easily aroused with stimulation
• Airway is patent
• Most likely achieved through IV
What is the standard of care for moderate and deep sedation?
• Pulse-oximeter - measures saturation of oxygen
• Normal is 95%
• Abnormal is below 90%
• Delay of 20-90 seconds
• Reliability of +/- 3%
Sedation: Benzodiazepines
• Used for oral analgesics
• MOA: occupies GABA receptor in the brain (GABA is a major NT)
• Drugs provide sedation, amnesia, anxiolysis, and anticonvulsant properties
• Midazolam/Versedd* - 3 to 4x more potent than diazepam; hypotension, vomiting, decreased respiratory rate, and apnea are possible side effects
• Oxygen and nasal canula and pulse-oximetry are mandatory
• Diazepam/Valium
• Lorazepam
• Alprazolam/Xanaxx* - 8 to 10x more potent than diazepam
Sedation: Opioids
• Used as strong analgesics
• Examples: morphine, hydrocodone, oxycodone, etc
• Absorption via oral ingestion is not consistent
• Respiratory and cardiovascular depression may be noted
• Significant side effects such as nausea
Sedation: Fentanyl
• A dissociative anesthetic
• A narcotic opioid agonist
• Pain attentuation and some sedation
• Onset of action is ~1 minute and half-life is 30-60 minutes
Medications used when deep levels of anesthesia are performed
• Propofol - "milk of amenisia"; has no analgesic properities, but does produce sedation and amnesia
• Robinul
• Ketamine - "angel's dust"; can give hallucinations; always use after Versed

• Versed + Ketamine + Propofol are a typical combination in IV anesthetics
Reversal agents + Emergency drugs
1. Epinephrine
2. Naloxone
• An opioid antagonist that binds to CNS opioid receptors to displace opioid agonists
• Reverses respiratory depression and sedation
3. Flumazanil
• Binds to GABA receptors in the CNS to reverse effects of benzodiazepines
• Half-life of BZDs is 12 hours, flumazenil's is only ~45 mins
• Thus, pt. needs monitoring up to 1 hour after the last dose of flumazanil
4. Atropine
• An anti-cholinergic
• Treats significant bradycardia or asystole
5. Ephedrine
• Turns on beta and alpha adrenergic receptors
• Used for hypotension
Doctor requirements to administer IV sedation
• Proper training - ADA approve 50 hour course + ACLS + 30 cases ORR* residency training with anesthesia
• Knowledge of pharmacology
• Ongoing renewal of BLS and ACLS certification
• Ongoing CE
Office requirements to adminstered IV sedation
• Certificaton
• Pulse oximetry, EKG, BP, etc monitors
• Defibrillator and emergency cart
• Staff training
• Malpractice insurance
Physiology of neuromuscular blockage drugs
• Somatic nervous system sends neurons from the ventral horn of grey matter to effector organs (muscles)
• Main neurotransmitter is acetylcholine
• Nicotinic cholinergic receptors
• Activation of neuron -> depolarization of post-synaptic membrane
• Blockade of neuron -> prevents signal propagation along muscle fiber
What are possible targets for neuromuscular blockades?
1. Action potential in axon
2. Nerve terminal
3. Ach receptors in the neuromuscular junction
4. Acetylcholinesterase
5. End plate of muscle
D-Tubocurarine
• A non-depolarizing NM blockade
• An original protype for the newer drugs
• Not used much any longer due to excessive hypotension from blockade of autonomic ganglia and mast cell histamine release
Pancuronium
• A non-depolarizing NM blockade
• Causes a moderate increase in heart rate
• No mast cell histamine relese and no autonomic ganglion blockade to cause excessive hypotensionn* - how it is different from D-tubocurarine
• Excrted by the kidney with minimal hepatic metabolism
Vecuronium
• A non-depoloarzing NM blockade
• Causes very little vagolytic, histaminic, or ganglionic activity (aka very few side effects)
• Duration of activity is unpredictable in patients with renal or hepatic insufficiencyy* (relies on hepatic and renal excretion)
Atracurium
• A non-depolarizing NM blockade
• Causes histamine release
• Its ionomer - Nimbex - however, is more potent and does not cause histamine release
• Removed by Hoffaman elimination so the drug is unaffected by renal or hepatic impairment in patients
Mivacurium
• A non-depolarizing NM blockade
• Fast onset
• Causes histamine release
• No cardiac effects
• Elimination by plasma cholinesterases
Rocuronium
• A non-depolarzing NM blockade
• Fast onset (1.5-3 min), but less potent
• Caution in hepatic impairment patients as it is mainly excretion via liver
Primary adverse side effects from non-depolarizing NM blockade drugs
• Cardiovascular: hypotension from histamine release from mast cells and sometimes blockade of autonomic ganglia; tachycardia as compensation
• Respiratory: bronchospasm from histamine release; prolonged apnea
What are potential drug interactions of BM blockade drugs?
• Can be combined with inhalation anesthetics to increase neuromuscular blocking action of inhalation anesthetics
• Sugammadexx* - used to inhibit NM blockade "-curonium" drugs; reverses the block without interfering with systemic cholinesterase inhibition
• Effects reversed also by aceytlcholinesterase inhibitors (what the "-curonium" drugs do is break down Ach in the NM junction to prevent Ach from getting to the motor end plate)
Succinylcholine/Sucamenthonium chloride
• A depolarizing anesthetic
• Maintains an open state in the Na ion channel - this prevents repolorizaton of the muscle and subsequent contraction
• Not antagonized by acetylcholinesterases
Depolarizing event of Succinylcholine
• Phase I (30-60 s): initial depolarization results in muscle contractions; fasciculation
• This phase is followed by flaccid paralysis for 5-10 min
• Phase II: continued longterm exposure to drug (which is rare in clinical use) leads to slow repolarization with no further depolarization
Primary adverse side effects from depolarizing NM blockade drugs
• Bradycardia
• Hyperkalemiaa* (K stays in bloodstream as excessive Na enters the cell)
• Histamine release (leads to hypotention)
• Post-op muscle pain
• Malignant hyperthermiaa* (if you give dantrolene then you can inihbit the release of calcium, thus preventing overheating by excessive muscle contraction and metabolism - counteracts this side effect)
Botox/Botulinum toxin
• MOA: prevents release of acetylcholine into the neuromuscular junction
• Long-lasting blockade at the local site of injection
• Used to relieve wrinkles and correct ocular deviatoins in opthalmology
• Side effects: xerostomia and facial pain
What are the clinical uses of neuromusuclar blockers?
1. Relaxes muscles for intubation for general anesthesia
2. Inhibit acetylcholine receptors
• Non-depolarizing NM blockers: large molecules with variable onset, but medium to long duration
• Depolarizing NM blockers: rapid onset, but short duration
Common inhalation anesthetics
• Halothane
• Sevoflurane
• Desflurane
• Isoflurane
• Finflurane
• Sevoflurane - some toxic metabolism
• Methoxyflurane - some toxic metabolism
Ideal biologic properties of inhalation anesthetics
• Pleasant to inhale - non-irrtating, induces bronchodilation
• Low blood:gas solubility to induce fast onset
• High oil:water solubility to have high potency
• Minimal effects on other systems (such as cardiovascular, renal, hepatic, etc)
• No biotransformation - ideally excreted by the lungs unchanged
• Non-toxic to operating personnel
Minimum alveolar concentration (MAC)
• A measure of potency of an inhalation anesthetic
• MAC is the concentration of anesthetic needed to achieve NO RESPONSE to skin incision in 50% of subjects (at sea level)
• Thus, the lower the MAC, the greater the potency
• Examples: halothane has a very low MAC whereas nitrous oxide has a very high MAC
MOA of inhalant anesthetics
• Potency related to lipophilicity - can disrupt the membrane potential by incorporating themselves into the cell lipid membrane
• Activation of inhibitor GABA receptors
• Inhibitionof stimulatory receptors
Side effects of cholinomimetrics (i.e. AchE inhibitors) significant in dentistry
Tongue edema
Taste disturbances
Sialagogue effects (increased rate of salivation)
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