Pharm 2 Flashcards
Local anesthetics are made of what 3 components
Why is each important
Aromatic - lipophilic
Ester or amide linkage - amides are favored. Esters broken down faster
Amine - basic crosses membrane, acidic binds to Na channel
Esters vs amides:
Half life
Where hydrolyzed/metabolized
How to tell which is which by name
Esters have shorter 1/2 life
Esters hydrolyzed by PsChEsterase
Amides metabolized by P450 in liver
Amides have i in name before caine (lidocaine), Esters don’t
Which type of bond in local anest. Is more allergic
Esters
Local anesthetics effect in axon
Interact with open and inactivated channel, blocking Na conductance
Why are the acidic and basic forms of a local anesthetic important
Basic form crosses membrane
Acidic form blocks sodium channel
Local anesthetics produce more rapid nerve block on axons with a _ firing rate because _
Rapid
They bind to open form of Na channel
Which functions are more disrupted by LA
Functions served by B/C fibers more than A
CNS neurons are _ sensitive than PNS neurons to local an
More
Which local an is especially cardiotoxic
Bupivacaine
Most amides last longer than esters, except 2:
Prilocaine
Articaine
2 ways an operator can cause excessive local an conc in blood
3 possible effects of overdose
Intravascular injection
Excessive quantities
Convulsions
Respiratory arrest
Cardiovascular collapse
Ideal anesthetic (7)
BRAUMS’S
Smooth and Rapid
Unconsciousness
Amnesia
Maintain physiologic functions while blocking reflexes
Skeletal muscle relaxation, NOT resp. Muscles
Block sensory stimuli
Recovery with no lasting effects
5 types of drugs in a cocktail, what do they do
Antimuscarinics - minimize salivation Analgesics - Preop pain relief, sedation NOx / Opioids - reduce anest. Requirement Anti-nicotinics - paralyze sk. Muscle Antiemetics
Meyer Overton correlation:
Implication in body
Correlation b/t solubility in olive oil and anesthetic potency
Anesthesia begins when anesthetic reaches critical conc. In membrane lipids
What are 2 protein targets of general anesth.
Definitive target
Ligand activated ion channels
GABA receptors
No definitive target
Synaptic transmission is _ sensitive to anesthetics than action potentials
More
Which structures in the brain do anesthetics effect directly
Thalamus
Hippocampus
Limbic system
4 stages of general anesthesia
Analgesia
Excitement
Surgical anesthesia
Medullary paralysis
Blood : gas partition coefficient
Low vs high
Ratio of conc of anest. In blood phase to the conc. In gas phase when anesthetic is in equilibrium b/t two phases
Low - faster induction and recovery (NOx)
Higher - slower induction and recovery
MAC
What determines it
Minimum alveolar conc.
Olive oil solubility determines it
MAC and blood solubility of a good inhalation anesthetic agent
Low MAC
Low blood solubility
NOx has a low blood/gas and high MAC. What does this mean
Fast induction, recovery
Not potent, doesn’t produce full surgical anesthesia
3 common volatile anesthetics
General properties of the three?
Isoflurane
Desflurane
Sevoflurane
Low b/g (~0.5)
Single digit MAC
Barbiturates act as CNS depressants by doing what?
Binds to GABA
Activates chloride channels
Hyperpolarizes post synaptic membrane
Provides inhibitory influence on synaptic transmission
4 advantages of IV anesthetics like barbituates
Rapid distribution
Reduced cardiac depression
No risk of malignant hyperthermia
Eliminate risk of occupational exposure
3 barbituates used in dental settings
General qualities
Thiopental
Methoxhexital
Propofol
Fast acting, fast recovery (use with something else to keep them under)
Ketamine produces _ anesthesia.
What is it
Who gets it
Dissociative anesthesia
Anesthesia with analgesia and amnesia, minimal effect on respiratory funct.
Pt. Doesn’t seem anesthetized
Trauma patients, elderly pts
Pathway of pain receptors
Sensory receptor (body in DRG/T.G.) Dorsal root Synapse Cross spine Thalamus
Aδ fibers vs C fibers
Aδ: faster, myelinated, first response to mechanical stimuli
Sharp pain
C: slower, unmyelinated, thermal, mechanical, chemical
Dull, aching, burning pain
5x more than Aδ
5 inflammatory mediators that facilitate transmission of pain
Prostaglandins Substance P Tumor necrosis factor- α Interleukin 1β Ιnterleukin-6
Allodynia:
How?
Pain from normally painless stimuli
Tissue injury sensitizes pain response
3 places pain can be inhibited
Opioids affect which
Periphery
Signaling to CNS
CNS activity
Opioids do all 3
What affects whether a single neuron can initiate an action potential? 3 things
Number and types of post-synaptic receptors
Synchrony of signals
Frequency of signals
Cl, Na, K channels do what to let the ions pass?
Which way do they pass
Cl: channels that let in Cl HYPERpolarize
Na: channels that let in Na will DEpolarize
K: channels that let out K will HYPERpolarize
4 families of endogenous opioids
Pro-opiomelanocortin peptides
Pro-enkephalin peptides
Prodynorphin peptides
Endomorphins
Pro-OMC
Pro-EK
ProDynomorphin
Endomorphins
Three important opioid receptors
All 3 are _ receptors
They activate
μ
κ
δ
G-protein coupled receptors
Activate Gαi
_ is the natural agonist of the μ-opioid receptor
β-endorphin
2 natural agonists of δ opioid receptor
Met-enkephalin
Leu-enkephalins
Agonists of κ-opioid receptor
Dynorphin A/B
α/β Neo-endorphin
How do opioids affect GPCRs
Modulate nerve activity
Make it more difficult for nerve impulses to be conducted
Opioids can inhibit synaptic transmission on receptors where
Pre or post-synaptically
Majority of analgesic drugs act primarily at _ receptors
μ
μ receptors are found where
Peri aqueduct always gray Superficial dorsal horn of spinal cord Nucleus accumbens Amygdala Cerebral cortex
MOSTLY PRE-SYNAPTIC
What exactly do opioids inhibit? Why is this strange
They inhibit the inhibitor
Helping to activate the pathway that produces CNS mediated inhibition of pain
Clinical effects of opioids
Analgesia Respiratory depression Constipation GI spasm Physical dependence
Morphine is a strong _ agonist
μ
Which opioid has important effects on the motivational-affective component in limbic system
Morphine
Morphine is metabolized to what 2 molecules?
What’s the difference b/t the two
M-3-G - not active, doesn’t get to brain
M-6-G - more active than morphine, crosses BBB
Codeine metabolizes to what 2 things?
What are they like?
Morphine and codeine-6-glucuronide
They’re both active
Codeine is more effective than morphine when administered _
Orally
2 factors that make fentanyl more toxic and more therapeutic
- Fentanyl is more lipid soluble than morphine or heroin
2. Fentanyl binds tighter to μ opioid receptor than morphine or heroin
Therapeutic index of fentanyl
Why is it so dangerous
300 (morphine is 70)
People cutting it with other drugs
Prolonged respiratory depression
Harder to reverse tight binding
3 opioid antagonists that treat opioid toxicity
Naloxone
Naltrexone
Nalmefene
Opioids available for oral administration
Codeine
Hydrocodone
Oxycodone
Pentazocine
3 NSAIDS
Aspirin (acetylsalicylic acid)
Ibuprofen
Naproxen
Injured cells release _
Example
Alarmins
IL-33
How does histamine act
Through GPCR to produce local vasodilation and leaky capillaries
Histamine H1 receptor activity increases intracellular _
2 major effects from this
Ca++
- NO mediated relaxation of smooth muscle -> vasodilation
- MLCK mediated contraction of capillary endothelium
Anti-inflammatory drugs do what
- Attenuate inflammatory response
2. Attenuate pain
Which inflammatory mediator is the most important to attenuate
Prostaglandins
Pg is derived from _
4 main ones are
Arachidonic acid
PGE2
PGD2
PDF2
PGI2
2 enzymes that send arachidonic acid down the path toward pg
COX1
COX2
Inhibition of which COX is desirable/undesirable
inhibition of COX1 is bad
Inhibition of COX2 is desirable
Aspirin reduces what 4 things
Ibuprofen, naproxen?
Acetaminophen?
Pain
Fever
Inflammation
Thrombosis
Ibuprofen does 3 (not thrombosis)
Acetaminophen 2 (pain/fever only)
Only _ is effective at preventing thrombotic events
Low dose aspirin
Why do NSAIDS mess with the stomach
They block prostaglandins
Pgs stimulate mucus and bicarbonate secretion
2 most common arthritis
Osteoarthritis
Rheumatoid
Lupus erythematosus
Immune sys attacks healthy tissues, esp. joints
What is osteoarthritis
Breakdown of articular hyaline cartilage in synovial joints
Chondrocytes in inflamed vs healthy cartilage
Healthy - balanced b/t anabolic and catabolic
Inflamed - catabolic dominate, decreased collagen prod., increased prod. Of proteolytic enzymes
2 important inflammatory mediators in arthritis
IL-1β
TNF-α
Rheumatoid arthritis is _ mediated joint inflammation
Immunologically
Rheumatoid a. Affects _ joints. These are joints that _
Diarthrodial
Join two opposing bone surfaces covered by hyaline cartilage
Hyaline cartilage
Type of collagen?
Type II
Ra starts initially with inflammation in the _
Synovium
Synovitis leads to an overgrowth called the _.
What is it?
That leads to _ which leads to _
Pannus
Abnormal layer of fibrovcascular tiss or granulation tiss.
Fibrous ankylosis
Bony ankylosis
Immune cells, osteoclasts, and chondrocytes make what that destroy bone and cartilage?
3 things
MMP
Cathepsins - cysteine proteases
ROS
What causes rheumatoid arthritis
T-cell mediated response to immunological trigger
some alleles of MHC genes
What cells (other than wonky MHC) are heavily implicated in AI disorders like RA
Th17
Very important therapeutic target in AI disorders
TNFα
5 types of antibodies that are associated with RA
CKCPC
Anti collagen Anti cardiolipin Anti keratin Anti calpastatin Anti perinuclear factor
Important DIAGNOSTIC marker of RA
Rheumatoid factor
Antibodies directed against _ are frequently discovered in patients with RA.
Why else are they important?
Citrullinated proteins
Present in 80% of cases # CCPs correlates with disease severity Antibodies appear years before joints are affected
_ catalyzes citrullination of peptides
Peptidyl arginine deaminase
4 drugs to treat RA
NSAIDS
DMARDS (disease modifying anti rheumatic drugs)
Glucocorticoids
Pain meds (non-NSAIDS)
A common DMARD is _.
It acts as an _
Methotrexate
Immunosuppressant
How does methotrexate work
Potentiation of adenosine signaling as an immune modulator
7 DMARDS - method of action of each
THA CALM
- Methotrexate
- Leflunomide - inhibits dihydroorotate dehydrogenase
- Hydroxychloroquine - inhibits TLRs on dendritic cells
- Cyclosporin - inhibits cytokine gene expression
- Azathioprine - inhibits DNA replication
- Tofacitinib - JAK kinase inhibitor
- Adalimumab - interferes with TNFα
THACALM
TNF alpha results in what 5 changes
Increased: Inflammation Cell infiltration Angiogenesis CRP in serum
And articular cartilage degradation
TNFα is a _ that plays a major role in the _ response
Pleotropic cytokine
Immune/inflammatory response
How does adalimumab work
It’s an anti-TNF IgG
NTMs that act on GPCR will ultimately modify the activity of _
Synaptic proteins (pre or post)
Glutamate can either act as a _ or a _
Excitatory NTM (opens Na channel) Neuromodulator (activates GPCR)
Glycine receptors do what? What potentiates glycine receptors
Activate Cl- channels and produ e hyperpolarization
THC
Positive and negative symptoms of schizo are lined to _
Positive: linked to excess dopamine
Negative: linked to prefrontal pathologies
_ stimulation is the basis for hallucinatory effects of drugs
5-HT-receptor
Dopamine hypothesis of schizo
Positive symptoms of schizo involve over activity of brain dopaminergic synapses
-azine:
Phenothiazine-like antipsychotics
Schizo has an over activity of the _ pathway (positive symptoms)
And a dysfunction of the _ pathway (negative and cognitive systems)
Over of Mesolimbic pathway
Dys of mesocortical pathway
Two subtypes and 5 different dopamine receptors
What are the two subtypes linked to?
Antagonists of which are important drugs?
D1 like family (D1/D5)
-Linked to Gαs Inc. cAMP
D2 like family (D2, D3, D4)
- Linked to Gαi dec. cAMP
- antagonists are important
Extrapyramidal effects of anti-psychotics
Parkinson’s like symptoms
Why is antagonism of D2 and D4 receptors important
Important in producing therapeutic and adverse effects of anti-psychotics
T/F atypical anti-psychotics don’t have extrapyramidal activity
TRUE
Typical vs atypical antipsychotics
Typical: antagonists of D2, little activity on D4, varying on the rest
Atypical: antagonist of D4, stronger on 5-HT2, varying on H1, M1, α1
NTMs that are deficient in depression
NE and serotonin
Anti-depressants act in 3 ways:
Block transmitter reuptake
Inhibit MAO
Inhibit presynaptic autoreceptors
Two types of reuptake blockers
Tricyclic antidepressants are non-specific blockers of transmitter reuptake and also muscarinic receptor antagonists
SSRIs are specific for serotonergic systems
Side effects of SSRIs
First
- nausea
- anxiety
- agitation
- insomnia
Late
- weight gain
- weakness
- sexual dysfunction
- withdrawal syndrome
SNRI:
4 common ones
Serotonin and NE reuptake inhibitors
Duloxetine (cymbalta)
Venlafaxine (Effexor)
Nefazodone (serzone)
Desvenlafaxine (pristiq)
MAOs do what
Degrade dopamine etc
Why block presynaptic autoreceptor
It’s feedback inhibition, won’t stop the NTM from being released
3 serotonin receptor antagonists
Nefazodone
Trazodone
Mirtazapine
All are 5-HT2A receptor antagonists
Parkinson’s disease is what
Degeneration of dopaminergic neurons projecting from substantia nigra to striatum
What does L-DOPA do
Makes the remaining projections into the striatum provide more dopamine
_ crosses BBB, but _ does not
L-DOPA
Dopamine
L-DOPA treatment good for how long
3-4 years
L-DOPA is given with _ to prevent what
Carbidopa
Nausea and vomiting
In addition to LDOPA, Parkinson’s can be treated with _
Dopamine receptor agonists
Epilepsy is caused by what
Inherited biochemical defect
Previously healed brain injury
Ways to treat epilepsy (5)
- Phenytoin and others block high-frequency firing of action potentials
- Potentiate effects of GABA to dampen synaptic nerve impulses
- Blockade T-type Ca channels in thalamus
- Blockade of voltage-gated Ca channels
- Blockade of NMDA receptors
How to potentiate GABA?
- Inhibition of GABA transaminase
- metabolizes GABA - Inhibition of GABA uptake
- Facilitation of Cl channel opening (Benzodiazepines)
Dentists use _ to treat emergency seizures
Benzodiazepines
5 effects of barbiturates and benzodiazepines in treating anxiety
Anxiolysis Sedation Hypnosis Anesthesia Respiratory failure
Sedation vs hypnosis vs anesthesia
Sedation is without loss of consciousness
Hypnosis is with impaired sensory responsiveness
Anesthesia is without possibility of arousal
GABA A is a _
GABA B is a _
Ligand gated ion channel
G-protein coupled receptor
Barbituates and benzodiazepines act by facilitating GABA mediated conductance of _ receptors
GABA A
Barbituates increase _ of GABA mediated channel opening
Benzodiazepines increase _ of GABA mediated channel opening
This causes _ which eventually causes _
Duration
Frequency
Membrane hyperpolarization
CNS depression
Effect of benzodiazepines vs barbiturates
Benzodiazepines - anti anxiety at doses that don’t incapacitate
Barbiturates knock out everything
_ manages benzodiazepine overdoses
Flumazenil
Hypnotics vs. benzodiazepines
Hyps are diff. Structure, but bind to same site
Barbiturates are especially strong on _
The reticular formation
In dentistry:
Sedative-hypnotic drugs = _
Drugs to treat anxiety = _
Drugs to treat anesthetic induced seizures = _
SH = barbiturates
anxiety = benzodiazepines with local an.
Anesthetic induced seizures = benzodiazepines
3 things are used to treat bipolar
Anti-psychotic
Anti-convulsant
Anti-depression
Sequence of events leading to infiltration of eosinophils in lung
Allergen -> mast cell -> Th2 -> infiltration of eosinophils
Eosinophilic vs. non-eosinophilic asthma
E: eosinophils, basement membrane thickening, inhalation always corticosteroids
Non: new treatments
_ is associated with eosinophilic asthma, _ is associated with neutrophilic asthma
Th2
Th17
3 goals of asthma tx
Relieve bronchoconstriction
Inhibit airway inflammation
Prevent airway remodeling
asthma vs COPD
A: bronchoconstriction part of allergic response, tx works, eosinophil recruitment
C: bronchoconstriction from change in vagal tone, tx doesn’t always help, neutrophil recruitment
_ cells mediate inflammation and bronchoconstriction
Mast cells and their contents
4 ways asthma drugs work
Snuff allergic response
Diminish number of immune cells in lung
Alter production of bronchoconstrictors
Attenuate activities of bronchoconstrictors and mucus producers
β2 adrenergic receptor agonists do what
Produce relaxation of smooth muscle cells
Best short acting β agonist
Albuterol
Adverse effects of β2 agonists
Muscle tremor
Tachycardia
CNS problems (pain, restless, nervous)
3 main functions of cortisol
- Carb and protein metabolism
- Lipid redistribution
- Hypertension
- Increased breakdown of bone/skin
- CNS - mood elevation
- ANTI-INFLAMMATORY agent
Glucocorticoid inducible gene that plays an important role in attenuating inflammation
Annexin-A1
Lowers leukocytes
Glucocorticoid Receptors do what to NF κB
Inhibit NFκB mediated transcription
Glucocorticoids are used to mainly treat what two diseases
Chronic adrenal insufficiency
Suppress inflammation
2 pts that don’t respond to ICS tx
Non-eosinophilic asthma
Glucocorticoid resistance
In context of respiratory diseases, Anti-cholinergics refer to _
Antagonists of muscarinic acetylcholine receptors
_ is a classic muscarinic antagonist
Atropine
Blockade of M1 and M3 muscarinic receptor subtypes can lead to _
Bronchodilation
Anti-cholinergics effect on airway
Inhibits smooth muscle contraction
Decreases mucus secretion
_ is 1000x more potent bronchoconstrictor than histamine in the airway
Leukotriene
Leukotrienes are made from _
Arachidonic acid (like prostaglandins)
Singulair is a _
Leukotriene modifier
T/F leukotriene modifiers treat COPD well
FALSE
Xolair is what
Anti IgE
Antihistamines block _
Vasodilation
α1-adrenergic receptor agonists are _. They work by _
Decongestants
Constricting blood vessels
