Pharm Exam 4

Front 1

Chronic Anxiety Disorders

Back 1

-Panic Disorder (4%) - recurrent episodes of intense anxiety
-Generalized Anxiety Disorder (5%) --> chronic persistent anxiety
-Social Phobia (5-10%) --> intense fear of negative evaluation during social contact
-Post-Traumatic Stress Disorder (8%) --> intense fear, helplessness, nightmares, flashbacks for prolonged period after exposure to a traumatic event
Obsessive-Compulsive Disorder (6%) --> persistent, recurrent thoughts causing anxiety

Front 2

Drugs Used to Treat Anxiety

Back 2

Benzodiazepines
5-HT/NE Uptake Inhibitors (drug of choice)
Burpirone (5HT receptor partial agonist)

Front 3

Benzodiazepines for Anxiety

Back 3

-safe, effective anxiolytics
-anxiolysis occurs within 1-2 hours
-pharmacokinetics dictate use
-dependence with chronic use (part physical & part psychological)
-limited usefulness for chronic anxiety

Front 4

Benzodiazepines
(Length of Action)

Back 4

-Alprazolam (Xanax) - short acting
-Diazepam (Valium) - Intermediate acting
-Chlordiazepoxide - Intermediate acting
-Lorazepam (Ativan) - Long acting

Front 5

Benzodiazepines
(Pharmacokinetics)

Back 5

-Absorption is rapid for Alprazolam, Diazepam & Triazolam (1 hour to peak)
-Absorption is slower for Oxazepam, Lorazepam, Prazepam (2-3 hours to peak) - longer onset is better for helping pt sleep
-Biotransformation (main determinant of half-life) takes place in the Liver:
1. Microsomal oxidation to produce hydroxylated & N-desalkylated metabolites that have biological activity
2. Glucuronidation of 3-OH groups
-Pts with cirrhosis or the elderly have increased t1/2s & require decreased dose

Front 6

CNS

Back 6

-a small perturbationat one point can cause major, unanticipated changes at a distant point

Front 7

Cerebral cortex

Back 7

-consists of frontal, temporal, parietal and occipital lobes.
-divided by information processed:
-somatosensory, visual, auditory, and motor
-sensory and motor integration, vision, hearing and memory
-produces abstract thought, memory and consciousness
-integrating role for autonomic nervous system as well as somatic and vegtative functions of the CV and GI systems

Front 8

Limbic System

Back 8

-region of the brain composed of: hipposcampus, amygadaloid complex and septum
-regulation of emotion, the autonomic system and neuroendocrine function and short term memory

Front 9

Basal ganglia

Back 9

-contains caudate nucleus, putamen, globus pallidus and lentiform nucleus
-regulates segments of extrapyramidal motor system needed for motor control

Front 10

Thalamus

Back 10

-in the center of the brain below the cortex and basal ganglia and above hypothalamus.
-integrates sensory and motor functions

Front 11

hypothalus

Back 11

-below the thalamus and is main integrating region for entire autonomic system
-regulates body temp, water balance, blood pressure, adenohypophysis secretions, sleep and emotions

Front 12

Midbrain and Brain stem

Back 12

-connect the cerebral hemispheres and thalamus-hypothalamus to the spinal cord
-swallowing and vomiting CV and respiratory systems
-receptors for visceral afferent sensory information are here
-reticular activation system= sleep wakefulness, level of arousal and coordination of eye movements
-nuclei of cranial nerves are here as well as the major monoamine-containing neurons of the brain

Front 13

Cerebellum

Back 13

Standing upright and walking is controlled here. It also has a role in learning and memory

Front 14

Spinal Cord

Back 14

-spinal cord runs from the caudal end of the medulla oblongata to lower lumbar vertebrae
-dorsal horn, ventral horn and itermediolateral cell column
-sensory info comes into the dorsal portion
-motor stimuli and autonomic output exit via ventral horn

Front 15

Hierarchicial

Back 15

-sesnory perception and with motor control
glutamate = main transmitter for projection neurons
-long have a stimulatory effect

Front 16

Local circuit nuerons are shorter ones-transmitters are glycine and GABA

Back 16

-make branches that are very close to the cell body which have synapses on the cell body and dendrites of both the projecting neurons and other local
-local project on the long projecting (or can also work on each other)
-inhibitory effect on the long: can be either feedback or feed forwardI (will work ahead of the signal)

Front 17

Neuronal systems

Back 17

1. heirarchical
2. non-specific or diffuse

Front 18

Heirarchical system

Back 18

-characterized by long projection neurons- transmit over long distance
-local circuit neurons that are smaller whose axons branch immediate vicinity of cell body
-inhibitory = release glycine (spinal cord) or GABA (gamma amino butyric acid) (supraspinally)

Front 19

Non-specific or diffuse neuronal systems

Back 19

-uses monoamines, norepi, dopamine and 5-HT (serotonin, 5-hydroxytryptamine) as transmitter
-innervate several regions of brain don't work by specific synaptic connects work by diffuse release of transmitter so that response is governed more by receptor location
-employ metabotropic (G protein mediated) receptors, have a long-lasting effect and are involved in global functions such as sleeping and waking, attention, appetite and emotions

Front 20

Ionic Control of Transmission

Back 20

-presynaptically decreasing conductance or inward flow of Ca that is needed for fusion and release of neurotransmitter will decrease release of transmitter
-postsynaptically susceptibility to excitation may be reduced by causing hyperpolarization by either increasing outward flux of K or increasing inward flux of Cl
-decreasing outward of K will result in hypopolarizaiton which will increase excitability
-endogenous transmitters or drugs will increase this

Front 21

Neurotransmitter

Back 21

-substance that is released from a presynaptic nerve terminal into the synaptic cleft that alters the excitablity of neurons
-cause excitation by opening ion channels to allow net influx of positively charged ions that leads to depolarization or cause inhibition by selective opening of ion channels = hyper polarization

Front 22

channels

Back 22

a. ligand-gated channels = binding of neurotransmitter to the channel controls opening and closing of the channel
b. G protein-coupled receptors in which the G protein, activated by the neurotransmitter binding to the receptor, directly interacts with the ion channel
c. G protein-coupled receptors in which the G protein activates an enzyme such as phospholipase C and produces a diffusible second messenger that interacts with the ion channel
b and c are also called metabotropic receptors
-voltage gated ion channels that are opened or closed by changes in membrane voltage

Front 23

Neutral amino acids

Back 23

-glycne and GABA
-work thorugh cuasing hyperpolarization or inhibitory post synaptic potentials (IPSP) opening chloride channels

Front 24

GABA

Back 24

-receptors grouped as GABAa or GABAb
-GABAa work thorugh chloride channels
-GABAb coupled to G proteins that either inhibit calcium channels or activate potassium channels
-calcium channesl are presynaptic and inhibit transmitter release while the potassium channels when activated = hyperpolarization thereby inhibiting impulse transmission

Front 25

Amino acid neurotransmitter

Back 25

-glutamate and aspartate
-found in hih concentrations in many regions of the CNS
-effect is excitatory
-Glutamate receptors are either ligand-gated or G protein-coupled
glutamate excitatory
aspartate-inhibitory

Front 26

Acetylcholine

Back 26

-acts thorugh both nicotinic and muscarinic receptors
-mediated through G protein coupled receptors, either inhibiton through M2 receptors that open potassium channels or excitation through M1 receptors that decreases membrane potassium permeability
-more M1 than M2
-M1 will stimulate and cause decrese in K, M2 will be inhibitiory and cause increase in K

Front 27

Monoamines

Back 27

-dopamine, norepi, serotonin (5-HT)
-epinephrine containing neurons are also present but little is known about their function

Front 28

dopamine

Back 28

-dopamine containing neurons link substantia nigra to neostriatum and the ventral tegmetnal region to limbic structures (limbic cortex)
-regions involved in parkinson's diesease and psychosis
-dopamine receptors: D1-like and D2-like
-G-protein copuled receptors
-D1-like couple thorugh Gs to increase adenyl cyclase
- D2-like couple through Gi to inhibit adenyl cyclase

Front 29

locus ceruleus or lateral tegmental area of reticular formation

Back 29

location of most noradrenergic neurons

Front 30

noradrenergic receptors

Back 30

-alpha-1, alpha-2 and beta are G-protein coupled receptors
-norepinephrine increases potassium conductance to hyperpolarize neurons via alpha 2
-norepi can indirectly cause excitation by inhibiting inhibitiory neurons

Front 31

alpha-1

Back 31

- work thorugh Gq and stimulate phopholipase C
- cause deploarization by decreaseing potassium conductance

Front 32

beta

Back 32

-via increasing adenyl cyclase

Front 33

Serotonin-containing neurons

Back 33

-originate in the raphe or midline regions of pons and upper brain stem
-diffusely innervate most regions of CNS
-all except one of 5-HT receptors are G-protiein coupled
-hyperpolarization due to increased potassium permeability or conductance
-regulation of sleep, temp, apetite and neuroendocrine control, mood and anxiety
-5-HT3 receptor when stimulated leads to emesis and antinociceptive actions so that antagonists are used in managing cancer chemotherapy-induced nausea

Front 34

Histamine

Back 34

-in the ventral posterior hypothalamus project upwards and downwards to the whole CNS
-four receptor subtypes are thought to regulate arousal, body temp and vascular function throug hdecreased potassium conductance or increases in inositol tris-phosphate or diacylglycerol

Front 35

Peptides

Back 35

-opiid peptides (enkephalins and endorphins), neurotensin, substance P, somatostain, cholecytokinin, vasoactive intestinal peptide, neuropeptide Y and throtropin-releasing hormone.
-G protein coupled
-multiple subtypes
-opioid peptide have cell bodies at all levels of CNS with long and short connections
-involved in pain
-work through mu and kappa and delta receptors

Front 36

Other possible transmitters

Back 36

-purines, NO, and brain lipids act as endogenous cannabinoids such as anadamide and 2-arachidonyglycerol are possible neutransmiters through some such as purines and NO also are consdiered to be neuromodulators
-brain lipids listed interact with a cannabinoid receptor, CB1,
-CB1 binds delta-9-tetrahydrocannabinol, the primary psychoactive ingredient in cannabis

Front 37

Neuromodulators

Back 37

-originate from non-synpatic sites such as glia and influence the excitablity of nerve cells
-adenosine, and other purines, neurosteroids produced in the CNS, eicosanoids and NO may function as neuromodulators
-circulating steroids may also have neuroodulatory activity

Front 38

Benzodiazepines
(Contraindicates)

Back 38

-Avoid if mental alertness is required for daily functions (e.g. driving or operating machinery)
-Avoid in individuals with propensity for drug dependence (e.g. drinkers, 20% of the population). Potentially fatal if used with alcohol or other CNS depressants
-Avoid in pregnant women due to birth defects

Front 39

Benzodiazepines
(Other Therapeutic Actions)

Back 39

Sedation (higher doses)
Muscle relaxation
Anti-spastic
Anticonvulsant
Amnesia (during surgery)
Alcohol withdrawal
Anxiolytic at low doses

Front 40

Benzodiazepines
(Mechanism of Action)

Back 40

BZs increase neuronal inhibition via interactions at GABA-A receptors (Chloride ion channels - increase frequency of opening)
-Causes hyperpolarization and inhibits the firing rate, which slows everything (reduced excitability throughout the nervous system).
-Binding of Diazapam increases the affinity of GABA for its receptor

Front 41

Molecular Basis of Benzodiazepine Actions

Back 41

Alpha-1 subunit receptors mediate hypnosis/sedation
Alpha-2 & Alpha-5 receptors mediate anxiolysis
Alpha-3 receptors --> non-specific
Alpha-4 receptors --> insensitive to benzodiazepines
Alpha-6 receptors --> insensitive to benzodiazepines

Front 42

Benzodiazepine effect on GABA

Back 42

-Benzodiazepine on GABA-A receptors increaeses the affinity of the receptor for GABA.
-Benzodiazepines have no direct effect on GABA receptors, but increase the frequency of chloride channel opening to enhance the response to GABA.
-Benzodiazepines can't cause any more inhibition than the neurotransmitter itself.

Front 43

Benzodiazepines
(Adverse Effects)

Back 43

-very safe; overdose not fatal
-rebound anxiety, aggression, irritability
-synergistic with alcohol (can be fatal)
-memory/cognitive impairment
-psychomotor impairment (sedation, ataxia)

Front 44

Benzodiazepines
(Tolerance & Dependence)

Back 44

Pharmacodynamic tolerance:
-Little tolerance to anxiolytic effects (sedative/hypnotic > anticonvulsant > antispastic >> anxiolytic)
--> limited use to seizure disorders b/c it requires ongoing medication

Physical dependence:
-Withdrawal syndrome (mild to severe)
-Most difficult with short-acting benzodiazepines
-Taper dose gradually and/or substitute with a long-acting benzodiazepine

Front 45

Usefulness of benzodiazepines in anxiety disorders

Back 45

Panic - alprazolam, excellent efficacy; high dependence risk
GAD - reasonably effective, chronic use troublesome--last choice
Social Phobia - not useful
Acute Stress Disorder - very effective for acute anxiety
PTSD - not useful in chronic PTSD

Front 46

Use of 5-HT/NE Uptake Inhibitors in Anxiety Disorders

Back 46

Panic
-SSRIs; Paroxetine, Sertraline
-SNRIs; imipramine - 2nd choice

GAD (Generalized Anxiety Disorder)
-SNRIs; venlafaxine
-SSRIs; Paroxetine

Social phobia
-SSRIs; Paroxetine, Sertraline
-SNRIs; venlafaxine

PTSD
-SSRIs; Paroxetine, Sertraline

Front 47

5-HT/NE Uptake Inhibitors - SSRIs & SNRIs
(Adverse Effects)

Back 47

Temporary nervousness/activation
Insomnia
Prolonged incidence of tremor
GI disturbances
Decreased libido
Contraindicated in pregnancy

Front 48

Proposed cellular action of serotonergic drugs in the treatment of anxiety

Back 48

-Anxiety is mediated by excessive neuronal activity in the hippocampus
-Can reduce activity through the GABA or the serotonin receptors
-SSRIs increase serotonin, which in turns acts on 5-HT1A & inhibits activity
-Must be taken for a couple of weeks before therapeutic levels are obtained (Benzodiazepines for immediate, SSRIs for long-term)

Front 49

Buspirone

Back 49

-Full/Partial agonist at 5-HT1A receptors
-Anxiolytic efficacy questionable
-Does not act via GABA-A receptors
-No sedative, anticonvulsant or anti-spastic (muscle relaxing) activity
-No tolerance, dependence or rebound anxiety
BUT...
-Clinical improvement occurs only after days to weeks of therapy
-Useful only for chronic anxiety states, not for acute therapy

Front 50

Summary of Pharmacologic Treatment of Anxiety Disorders

Back 50

Front 51

Other therapeutic uses of SSRIs

Back 51

-Depression (higher doses)
-Pain management
-Premenstual dysphoric disorder
-Sleep apnea - increases respiratory drive (paroxetine)

Front 52

Insomnia

Back 52

Difficulty getting to sleep, awakening early or not being refreshed by sleep

Transient - very common, caused by stressful events

Chronic - may arise from disease or correctable behavior

Front 53

Insomnia
(Sedative vs Hypnotic)

Back 53

Sedative - a drug that produces calmness & relaxation & reduces arousal

Hypnotic - a drug that promotes sleep; facilitates onset & maintenance

All anxiolytic & sedative benzos have hyponotic properties if the dose is increased

Not useful for chronic

Front 54

Insomnia
(Treatment)

Back 54

Selective Type 1 Benzodiazepine Receptor Agonists
Sedating SSRIs or SNRIs
Non-selective Benzodiazepines

Ideal Drug to Treat Insomnia:
-Rapid onset, no residual effects (sedation, memory loss)
-No rebound insomnia

Front 55

Pharmacologic Treatment of Transient Insomnia

Back 55

Type 1 BZ receptor agonists:
-Zaleplon (Sonata; short-acting - 3 hours)
-Zolpidem (Ambien; 6 hrs duration, no hangover & little rebound insomnia)
-Eszopliclone (Lunesta; 8 hr duration, no hangover, no tolerance, little rebound insomnia)

Front 56

Pharmacologic Treatment of Chronic Insomnia

Back 56

-Associated with depression, anxiety or sleep apnea (SSRIs or SNRIs)
-Long acting - anxious patient (Flurazepam, diazepam)
-Intermediate acting - difficulty stay asleep (eszopiclone, temazepam)
-Short acting - must be alert in the morning (zolpidem)

Front 57

Problems with Non-Selective Benzodiazepines for Treatment of Insomnia

Back 57

-Next day sedation, memory loss, difficulty with concentration
-Development of tolerance
-Rebound insomnia w/ abrupt discontinuation
-Synergistic with alcohol

Front 58

Type 1 Benzo Receptor Agonists
(Ideal Hypnotics)

Back 58

-Rapid onset, short t1/2, minimal side effects
-Well tolerated by elderly
-Similar efficacy to BZs
-Little next day sedation
-No significant drug interactions
-Less rebound insomnia or withdrawal than BZs
-Additive with EtOH, not synergistic

Front 59

Schizophrenia
(Clinical Features)

Back 59

Positive Symptoms (distortion or excess of normal function)
-Disturbance of perception (hallucinations)
-Disturbance of thought content (delusions)
-Disorganization of thought, speech, & behavior
Negative Symptoms (a decrease or loss in normal function)
-Decreased expression of feelings; diminished emotional range
-Poverty of speech
-Decreased interests & diminished sense of purpose & social drive
Cognitive Domain
-Difficult setting priorities, multi-tasking
-Perseveration - failure to un-learn old patterns that don't work anymore

Front 60

Schizophrenia
(Course)

Back 60

-Typically begins in late adolescents & early adulthood, though symptoms may begin at any age
-Late onset form: affects post-menopausal women
-Males have earlier age of onset than females (males are more vulnerable to schizophrenia & often have a worse course of disease)
-Has genetic & environmental components (genetic component = 15-20% of the cause)
Most important environmental factors = exposure to toxins during prenatal development that may later result in schizophrenia

Front 61

Schizophrenia is Heterogeneous

Back 61

-Syndrome described by a variety of clinical symptoms
-Probably involves multiple etiologies that express themselves with a similar set of symptoms

Front 62

Schizophrenia
(Different Courses/Categories)

Back 62

-1/3 of pts respond well to antipsychotic drugs & can generally return to a fairly normal life style (relapses and then recovery)
-1/3 of pts do not respond as well, and show long-term decrements in function over many years (decline with each relapse of the disease)
-1/3 of pts tend to be least responsive & often require long-term intensive or custodial care for decades (continues to decline until they no longer function well)

Front 63

Chlorpromazine & the pharmacological revolution

Back 63

-Studied originally for usefulness as a SEDATIVE
-Delay and Deniker found in open trials that PSYCHOTIC SYMPTOMS WERE CONTROLLED & this effect was more prominent than sedation

Front 64

Clinical Efficacy of Phenothiazines

Back 64

Very subjective
Based on a physicians subjective impression of whether the pt has improved or not

These compounds are not a CURE for schizophrenia, but do have positive effects

Front 65

Mechanisms of Antipsychotic Action

Back 65

-Classical drugs appeared to be functional dopamine receptor antagonists
-1972: Antipsychotic drugs competitively blocked the increase in cAMP induced by dopamine
-1976: Haloperidol radiolabeled - receptors could be studied directly (excellent correlation found between haloperidol binding & antipsychotic efficacy; but not between DA-induced cAMP synthesis)
-1978-9: Concept of 2 dopamine receptors:
1. D1: linked to cAMP synthesis but not important behaviorally
2. D2: not linked to cAMP, but more important behaviorally
-1989-91: Cloning of dopamine receptors

Front 66

Dopamine & its Receptors

Back 66

D1-like:
-Increases cAMP
-Preferentially recognize 1-phenyl-tetrahydrobenzazepines
-Linked to stimulatory types of G-proteins

D2-like:
-Inhibits cAMP
-Inhibits GIRK (a potassium channel)
-Preferentially recognize substituted benzamides (e.g. Sulpiride) or spiperone
-Linked to inhibitory types of G-proteins

Front 67

Antipsychotic-Related Treatment Side Effects & the Role of Dopamine

Back 67

"Neuroleptic" (acute)
-Parkinsonian-like --> motor: muscle rigidity, shuffling gait, decreased facial expression, drooling
-Emotional: apathy, dysphoria
-Cognitive: impaired thinking
-Akathesia (involuntary hyperactivity): subjective & objective motor restlessness

Tardive Dyskinesia:
-Abnormal involuntary movements affecting major muscle groups, may be irreversible

Endocrine
-prolactin mediated (glactorrhea, sexual dysfunction, amenorrhea)

Front 68

Antipsychotic-Related Treatment Side Effects & the Role of Dopamine
(Mechanisms)

Back 68

"Neuroleptic" (acute)
-Motor side effects (dopamine receptors in basal ganglia)
-Emotional & cognitive (dopamine receptors in limbic system & cortex)

Tardive Dyskinesia:
-Abnormal involuntary movements affecting major muscle groups, may be irreversible
-Apparently involves decreased dopaminergic function - worsened by levodopa & reduced antipsychotic dose

Endocrine
-prolactin mediated - DA increases prolactin secretion (dopamine receptors in pituitary)

Front 69

Antimuscarinics work to treat APD-induced parkinsonism

Back 69

-Typical antipsychotics block inhibitory D2 receptors.
-Antimuscarinics block effects of increased amounts of ACh resulting from increased firing
-This increases firing of striatal cholinergic interneurons

If we combat excess firing with antimuscarinic drugs, then we can block a lot of the motor problems

Front 70

Antipsychotics
(Side Effects)

Back 70

Anticholinergic (antimuscarinic)
-dry mouth, urinary retention, constipation, blurred vision, sinus tachycardia, confusion, memory impairment

Antihistaminergic
-sedation, weight gain, confusion, disturbed concentration

Alpha1-Adrenergic antagonism:
-orthostatic hypotension, reflex tachycardia, sexual dysfunction, priapism

Front 71

"Old" Atypical Antipsychotics

Back 71

Risperidone (antagonist of seratonin receptors)
-Good with positive symptoms, but not as good for the negative symptoms as the newer atypicals.
-High affinity for Dopamine D2 & serotonin 5HT2 receptors.
-Lack of Parkinsonian side effects

Clozapine (binds to many receptors) = best antipsychotic
-Can cause agranulocytosis in 1-3% of population.
-Causes major weight gain
-Extremely toxic when first administered; most start slowly and gradually increase to therapeutic dose
-Causes profound sedation & anticholinergic effects

Front 72

"Newer" Atypical Antipsychotics
(Clozapine-like)

Back 72

-Alanzapine
-Sertindole
-Ziprasidone
-Quetiapine
-Aripiprazole (D2 - functionally selective or partial agonist)
-Asenapine

Front 73

Typical Antipsychotics

Back 73

-Chlorpromazine
-Haloperidol
-Thiothixene

-Provide better therapy for negative symptoms

Front 74

4 Most Commonly Used Antipsychotics
(Side Effects)

Back 74

Haloperidol --> weight gain & severe Extrapyrmideal side effects - EPS (Parkinsonian-like symptoms)
Risperidone - rare EPS, doesn't work well for negative symptoms
Olanzapine - rare EPS, does NOT cause Agranulocytosis
Clozapine - causes agranulocytosis, rare EPS, severe sedation, major weight gane

Front 75

Human Imaging Studies
(Antipsychotics)

Back 75

-D2 receptor occupancy predicts antipsychotic potency
-Only 60% receptor occupancy is required for therapeutic effects
-Antipsychotic doses can be titrated to reduce side effects without loss of therapeutic efficacy
-Dopamine D2 receptor hypothesis of the etiology of schizophrenia has MERIT.

Front 76

Ideal Antipsychotic Drug
("Atypical Antipsychotic Drug")

Back 76

-Decrease in positive & negative symptoms
-Improved cognitive performance
-No extrapyramidal side effects
-No tardive dyskinesia
-No endocrine side effects

Front 77

Recent Strategies for the search for new "atypical" antipsychotics

Back 77

Selectivity for single dopamine receptor isoform
-D4 selective antagonists (failed in clinical trials)
-D1 selective antagonists (failed in clinical trials)

Concomitant occupation of dopamine & other receptors
-muscarinic
-alpha-adrenergic
-serotonergic

Selective targeting of other receptors
-Serotonergic (5-HT2A failed in clinical trials)
-glutamatergic (NMDA?)

Front 78

Pharmacology of Antipsychotic Drugs

Back 78

Interaction with receptors occurs rapidly as drug distributes
Direct receptor-mediated drug side-effects are seen immediately
-Antimuscarinic effects
-Autonomic effects (e.g. via alpha1 adrenoreceptor blockage)
-Acute neurological effects (EPS) or typical APDs
Maximal therapeutic benefit is temporally delayed (by several weeks)
-Tardive dyskinesia (typical APDs) also temporally delayed (by years)

Front 79

New drugs target cognitive function in schizophrenia

Back 79

Cognitive deficits --> including impairments in areas such as memory, attention, & executive function --> are a major determinant & predictor of long-term disability in schizophrenia. Unfortunately, available antipsychotic medications are relatively ineffective in improving cognition. Scientific discoveries during the past decade suggest that there may be opportunities for developing medications that will be effective for improving cognition in schizophrenia.

Front 80

Alcohol
(Dosage - in a 70kg person)

Back 80

Beer: 3-6% by volume (12oz)
Wine: 5 oz
Liquor: 45% by volume (1.5 oz)

This will give you a BAC of 0.03% (loss of a little fine motor coordination)

Front 81

Alcohol
(Absorption & Distribution)

Back 81

-Absorbed by passive diffusion from the stomach (25%) & the small intestine (75%)
-More rapid absorption in the small intestine
-Food in the stomach delays absorption because it delays gastric emptying into the small intestine
-The rate of distribution to a particular tissue is proportional to the blood supply of the tissue (brain has large blood supply, so it will rapidly accumulate ethanol that is absorbed)

Front 82

Alcohol
(Elimination)

Back 82

Ethanol is eliminated from the blood at the rate of 8-10g/hour for a 70 kg person
1-3% of a dose is excreted via the lungs
2-4% excreted via the urine

-Takes 60-90 minutes to get rid of 1 standard drink
-Blood alcohol is decreased by about 0.015%/hour

Front 83

Disulfiram
(Effect when drinking Alcohol)

Back 83

-Causes flushing of the face, neck shoulders, & chest
-Get palpitations, difficulty breathing, become nauseous & eventualy BP goes down
-This can occur with as little as 1/2 a drink

Front 84

Alcohol
(Effects on the Liver)

Back 84

Causes:
-Hepatitis (loss of appetite, fever, jaundice, pain)
-Hypermetabolism (may be associated with thyroid hormones being produced more)
-Fatty liver (fat from adipose tissue is mobilized and will collect in the liver; may be related to an effect of the adrenal cortex - cortisol mobilizes fats)
-Cirrhosis that can be fatal (results in scarring of the liver; liver becomes harder & smaller, get varicose veins in the liver, eventually the veins may rupture & death will result)

Front 85

Alcohol
(Effects on the GI tract)

Back 85

Increases:
-Acid secretion (HCl production increases)
-Irritation
-Pancreatitis

Front 86

Alcohol
(Effects on the Kidneys)

Back 86

Diuresis

Front 87

Alcohol
(Effects on the CV system)

Back 87

-Small increases in heart rate & cardiac output (heart myopathy)
-Increased incidence of Hypertension

-Moderate consumption seems to be beneficial

Front 88

Alcohol
(Effects on the Endocrine system)

Back 88

-Glucocorticoids increase (may be associated with fatty liver)
-Inhibition of testosterone synthesis (feminization in males)
-Altered estrogen metabolism
-Decreased release of posterior pituitary hormones (ADH --> greater urine volume; Oxytocin --> may help relieve menstrual cramps)
-Infertility

Front 89

Alcohol
(Effects on the Fetal Alcohol Syndrome)

Back 89

Congenital malformations & Retardation

Front 90

Alcohol-Drug Interactions
(Drugs with Disulfiram-like Activity)

Back 90

-3rd generation Cephalosporins
-Metranidazole
-oral sulfonylurea hypoglycemics
-quinacrine

If prescribed, must warn pt not to have ANY alcohol

Front 91

Alcohol-Drug Interactions
(Drugs with CNS Depressing Activity)

Back 91

-Barbiturates (interact synergistically with alcohol)
-1st generation Antihistamines
-Phenothiazines (add to the alcohol effect)
-Benzodiazepines (through the same receptors as alcohol)

-Ethanol & these drugs further depress the CNS
-Chronic ethanol may cause tolerance to general anesthetics

Front 92

Alcohol-Drug Interactions
(Other Drugs at Non-CNS sites)

Back 92

Aspirin --> can cause GI irritation (additive effect with alcohol)

Isoniazid --> used for treating TB; can cause liver damage; increased risk of hepatitis (additive effect with alcohol)

Salicylates - increased GI irritation

Front 93

Alcohol-Drug Interactions
(Acute Ethanol & Metabolism)

Back 93

Ethanol competes with other drugs for metabolism by the P450 enzymes.
Thus, it PROLONGS the effects of the 2nd drug

Front 94

Alcohol-Drug Interactions
(Chronic Ethanol & Metabolism)

Back 94

-The P450 enzymes are increased which may lead to more rapid metabolism of the 2nd drug (concentration will decrease with the usual dose; decreased therapeutic ability)
-These drugs include: barbiturates, anticoagulants, oral hypoglycemics & ACETAMINOPHEN, which becomes possibly more TOXIC to the liver by the metabolic mechanism involving CYP2E1 and the toxic product N-acetyl-p-benzoquinone - imine & glutathione

-Ethanol not only increases CYP2E1 to increase production of the toxic compound, but also reduces the amount of the protective reduced glutathione in the liver.

Front 95

Alcohol
(Lecture Pearls)

Back 95

-Liver cirrhosis resulting from alcohol is the 9th leading cause of death in the US
-Alcohol has a very low therapeutic index
-If blood alcohol is between 0.03 & 0.08, then you are 2x more likely to be in a car accident
-If BAC 0.1%, then you are 6x more likely to be in a car accident
-If more than 0.4%, then you will be dead
-If you have 3 standard drinks, then BAC will be about 0.067-0.092% on an empty stomach & 0.05% with a meal

Front 96

Alcohol
(Genetics)

Back 96

-If your parents were alcoholics, but you are raised by non-alcoholics, then you will STILL have a greater than average chance of alcoholism

-If you are a child of non-alcoholic parents, but are raised by people who are alcoholics, then the chance of being an alcoholic is no greater than the general population.

Front 97

Alcoholics
(2 Types)

Back 97

Type 1: seen with males & females (generally starts at >25 years old)
-Must have a genetic component & an environmental component

Type 2: mainly seen with men (onset at ~18 years of age)
-Associated with inappropriate aggressive behavior

Front 98

Alcohol
(Zero Order Kinetics)

Back 98

-The Km for alcohol dehydrogenase = 2mM
-When you have 0.08% BAC, it's equal to 16mM (well beyond the Km for the enzyme and it is working maximally)

Supply of NAD:
-6 strong drinks use up 2 moles of NAD (2 moles of NAD in the liver = 1.5kg)
-Therefore, turnover is dependent upon continually generating NAD to maintain metabolism

Front 99

Alcohol
(CYP2E1)

Back 99

-CYP2E1 uses NADPH to produce caetaldehyde & NADP+ from alcohol
-It can metabolize up to 10% of a dose of alcohol
-This is MOST important when talking about drug interactions
-Can get rid of 10mL of 100% ethanol/hour
-1 standard drink has 15-20 mL of alcohol

Front 100

Pain
(3 Categories)

Back 100

1. Pathological pain --> pain associated with inflammation or trauma
2. Acute pain --> results from brief/transient high intensity stimulation (i.e. cutting yourself). This activates the nociceptors, which results in perceiving pain (this can lead to tissue damage).
3. Neuropathic pain --> chronic and persistent pain resulting from either damage to peripheral nerves (nerve endings) or CNS lesions (i.e. stepping on a tack)

Acute pain which is not promptly treated can lead to chronic pain that is more difficult to treat

Front 101

Opioid vs. Non-opioid analgesics

Back 101

Opioid Analgesics --> act in the CNS to blunt the perception of pain

Non-opioid Analgesics --> act in the periphery where the pain signal originates (generally works by reducing the inflammation that causes the pain)

Glucocorticoids have anti-inflammatory activity, and by this means will reduce pain

Front 102

Pain Fibers

Back 102

Thinly myelinated A-delta fibers and unmyelinated C fibers (more common)

A nerve pain fiber with nociceptors has its cell bodies in the dorsal root or trigeminal ganglion of the face. A central axon synapses on a second order neuron in the dorsal root ganglion where the noxious stimulus is detected. The action potential is carried to the CNS where it is perceived as pain.
-Nociceptors respond to chemical (acid), temperature (heat, and mechanical (sticking & cutting) stimulation
-There are various ion channels, which are on the nerve terminal. Through these ion channels, the stimulus is perceived.

Front 103

Pain Ion Channels

Back 103

TRPV1 (the non-selective Calcium & Sodium Ion Channel)
-Responds to temperature. Stimulus propagating the signal has a threshold of ~40 degree Celsius

Peripheral Sensitization --> injury and/or inflammation result in the production of many substances that sensitize the nociceptor by changing its threshold for firing impulses. Sensitization allows low-intensity stimuli to cause pain through the nociceptors.

Front 104

Inflammatory "Soup" that alters Nociceptors

Back 104

-Macrophages --> release Interleukins
-Mast cells --> release PGE2, bradykinin, & histamine
-Damaged tissue --> releases protons, ATP & adenosine
-Platelets --> release ATP

-These all contribute to the inflammatory response, which goes into pain & sensitizes you to more pain
-Decreased synthesis of PGE2 reduces inflammation & thus pain due to sensitization of nociceptors. Although this action is of therapeutic benefit, it may cause a possible problem relative to ulcers & GI bleeding (PGE2 has a protective action in the GI tract)

Front 105

NSAIDS
(2 Main Toxicities)

Back 105

1. GI irritation (to the point of ulceration)
2. CV problems (which cause clotting & infarcts)

Front 106

NSAIDS
(2 Groups)

Back 106

1. Non-selective --> Inhibits both COX1 & COX 2

2. Selective --> selectively inhibit COX 2
-Only 1 group of selective NSAIDS = Celecoxib - "coxibs"

Front 107

NSAIDS
(COX Inhibitors)

Back 107

-In the GI tract, the main COX enzyme is COX1, which produces PGE2 --> which has a protective effect against erosion, irritation, & ulceration
-Platelets only have COX1. The COX1 will produce Thromboxane A2, which leads to aggregation of the platelets & clotting. If you inhibit synthesis of thromboxane A2, you will decrease platelet aggregation & DECREASE clotting.
-Endothelial cells in the blood vessels --> COX1, leads to synthesis of thromboxane A2, which promotes clotting
-Selective inhibition of COX2 leads to less prostaglandin synthesis to balance against thromboxane A2 = anti-clotting
-In inflamed tissues, we get the induction of COX2

Front 108

Non-Opioid Analgesics
(Basis of Toxicity)

Back 108

-Non-selective COX2 inhibitors also inhibit COX1. This will decrease synthesis of PGE2, which helps protect the GI tract.
-Therefore, continued use of non-selective COX inhibitors will cause GI problems/irritation/ulceration.
-Selectively inhibiting COX2 will not cause the same GI problems. However, COX inhibitors (like Celebrex) change the balance between thromboxane A2 and PGE2. TBX A2 favors clotting, while PGE2 opposes clotting. Selective COX2 inhibitors FAVOR CLOTTING, thus they favor formation of infarcts.
-Non-selective COX inhibitors can cause CV clots, but the risk is decreased. Similarly, Celecoxibs can cause GI irritation, but risk is decreased.

Front 109

NSAIDS
(Aspirin)

Back 109

Aspirin (acetylsalicylic acid) is unique because its inhibition of COX is IRREVERSIBLE because its acetyl group is trnsferred to & irreversibly acetylates COX.
-In the body, the half-left for aspirin = ~15 minutes (very rapidly converted)

Front 110

Aspirin
(Uses)

Back 110

-Low dose aspirin prevents infarcts & clots
-Platelets, which make PGE2 from COX1, have the COX1 inhibited. Platelets do not have nuclei, so they do not have the capacity ot replace inactivated COX (permanent inhibition of COX)
-The effect of aspirin on platelets lasts 8-10 days (life span of platelets = 8-10 days and then new platelets are made).
-Aspirin has relatively little effect on the COX activity in other cells where new enzymes are synthesized in ~8 hours.

Front 111

Aspirin
(Toxicities)

Back 111

Too much aspirin, can cause salicylate intoxication (a possibly lethal effect)

Salicylism is characterized by: headaches, dizziness, mental confusion & tinnitus (ringing of the ears)

-Aspirin & salicylic acid are eliminated through the kidneys. One way to increase elimination is to treat with sodium bicarbonate to alkalinize the urine, which keeps aspirin in the alkylated form so that more will be eliminated.

Front 112

Ibuprofen & Naproxen
(Non-Selective NSAIDs)

Back 112

-Ibuprofen has a t1/2 = 2 hours
-Naproxen has a t1/2 = 15 hours

Both have similar toxicities characteristic for the NSAIDS (GI & CV problems)

Front 113

Major depression

Back 113

-if you have five or more of symptoms of depression and have them for at least 2 weeks or more
-primary: arising from reasons we do not know; idiopathic
-subsequent to med s
-also part of bipolar disease

Front 114

Bipolar disease

Back 114

-people swing from depression to mania
-2 categories: Bipolar I and Bipolar II

Front 115

Bipolar I

Back 115

-depression plus mania
-behave in manic way: boundless energy, boundless ambition, try to do everything

Front 116

Bipolar II

Back 116

-depression lesser amount of mania (hypomania)
-still have extra energy ambition etc
-not quite as bad as mania

Front 117

Disthymic depression

Back 117

-if you have 2 or more and you have it for lesser frequency (moderate-dysthymic)

Front 118

Minor depression

Back 118

-even fewer symptoms at a fewer times is minor

Front 119

Monoamine Hypothesis

Back 119

-earliest that is still around
-based on three observations
1. reserpine
2. isoniazid, iproniazid
3. drugs used today to treat depression increase monoamines

Front 120

Reserpine

Back 120

-blocks uptake of NE (dopamine, serotoning)
-diminishes the monoamine that are in nerve terminals in the CNS + PNS
-taking reserpine leads to depression

Front 121

Isoniazid, Iproniazid

Back 121

-were experimental drugs which were being tested to treat people with TB (isoniazid used for this now)
-people treated with these drugs began to feel happiness
-year later psychiatrist decided to try these on depressed patients and he found that their modd improved
-we know that these are MAO inhibitors (inhibit monamine oxidase you increase amount of neurotransmitter in brain an dother parts of the body)
-increase in monoamine

Front 122

Current drugs today to treat depression...

Back 122

-increase monoamines
-monamines are related to depression and a decrease in monoamines makes you depressed and increasing them will treat depression
-1-2 days will increase monoamines- can be a problem; it takes 2-3 or more weeks before people feel relief from depression

Front 123

Two hypothesis together

Back 123

-if we give a drug---> monoamines increasing--> happens in a day or two--> this somehow leads to an increase in BDNF--> increases volume/size of particular regions of the brain
-this idea would explain why it takes 2-3 weeks to see an effect from increase in monoamines (you have to have new neurons made, new proteins, etc)

Front 124

Drugs to treat depression

Back 124

-may be effective on treating depression (maybe emphasized)
-choice on which class to use is largely based on which type of drug will be effective with the fewest adverse/toxic effects

Front 125

Toxicities of SSRIs

Back 125

-jittery, restless, agitated, headache, diarrhea, nausea
-some of these go away after about a week or so

Front 126

SNRIs

Back 126

-next if SSRIs aren't working
-not only inhibit reuptake of serotonin, but also inhibit reuptake of NE
-venotaxine, desnotaxine, duloxetine

Front 127

Toxicities of SNRIs

Back 127

-similar to SSRIs
-sweating, dizziness, agitation
-if people have liver disease, these can cause liver failure
DO NOT USE WITH PEOPLE WITH LIVER DS
-cause hypertension and cardiac prolems
-more adverse effectsthan the SRRIs

Front 128

MAO inhibitors

Back 128

-phenelzine (isoniazide and other above are not used)
-tranycipramine, selegeline
-all work by mechanism of increasing monoamines in the terminal thus more can be released
-one of the problems with inhibiting MAO is that you hav eto watch the foods that you eat that contain tyramine

Front 129

Bupropion

Back 129

-reuptake inhibitor of NE and dopamine
-used in combination with SSRI

Front 130

Lithium therapeutic window

Back 130

-.5-1.25 mM- Rx (therapeutic)
-1.25-2 mM you get nausea vominting, abdominal pain, tremor, CV problesm
-exceed 2mM -cardiac arrhythmias, convulsions, coma and death

Front 131

all drugs for depression

Back 131

-work for major but for mild or moderate it is arguable whether they have any better effect than placebo
-orginal studies done by drug companies get them approved but results of independent studies show poorer results
-people get relief from taking placebo and then shortly after finding out it is placebo become depressed again
-getting the right drug is trial and error
-on average people try 2-3 different drugs until they hit the right one that helps them

Front 132

Talk therapy

Back 132

-go for seven or more week s
-talking about depression with someone qualified
-receive as much improvement as you will taking the drugs
-do both (drugs and therapy) then have more improvement (combination better- studies shown)

Front 133

2 other drugs

Back 133

1. Aripiprazole (abilify)
2. Quetiapine (seroquel)
-these drugs cause tardive dyskinesia: irreversible effect wher eyou can't help making faces, you glucose goes up akathenia (felling of inner restlessness)
-anripiprazole: show some improvement in 25% of people treated
-placebo: 15%
-incidence of akathenia in people taking placebo: 4%
-"" for apipripazole: 25% (1 out of 4)
-cost of drugs are 25 times price of other drugs

Front 134

Antimicrobials

Back 134

Unique - curative rather than palliative

Relatively common Rx: 15-20% of prescriptions

One of the most misused classes of drugs

Front 135

Bacteristatic & Bactericidal
(Definition)

Back 135

Bacteristatic antibiotics --> inhibits bacterial replication, but the inhibition is reversed upon drug removal

Bactericidal antibiotics --> the drug has an irreversible lethal effect on the bacteria

Front 136

Bacteristatic & Bactericidal
(Mechanism)

Back 136

-Bacteristatic antibiotics, if given long enough, will eventually result in the bacteria dying
-Bactericidal antibiotics, if not given in a large enough dose, then it may end up not killing the bacteria.
-Most antibiotics that are bactericidal generally only affect growing microbes
-Combining bactericidal & bacteristatic antibiotics may decrease the effect of the bactericidal antibiotic because you stop replication, which is required for bactericidal antibiotics (a bacteristatic antibiotic that blocks bacterial growth may prevent the action of a bactericidal drug)

Front 137

Antibiotics
(Immune System Considerations)

Back 137

-It's important for a person to have an intact immune system (phagocytes) because the immune system aids the effects of the antibiotic

Limitations:
-If pt has HIV & is taking glucocorticoids, certain anti-cancer drugs or if cancer pt is being treated with radiation --> then it decreases the immune response.
-If pt has Diabetes & glucose concentrations are up, then it inhibits macrophages & supplies energy for bacteria.

Front 138

Superinfection

Back 138

A second infection on top of a preexisting infection. Can occur in 2 ways:
1. Get another infecting bacteria from outside
2. Outgrowth of normal bacteria that are normally kept in check due to an ecological balance between many types (>400 bacteria in person's GI tract)

-When you overuse broader-spectrum antibiotics & kill multiple kinds of bacteria, you are more likely to get a superinfection

Front 139

Antibiotic vs Antimicrobial
(Definition)

Back 139

Antibiotic --> a substance made by a living organisms that kills or gets rid of another living organism

Antimicrobial --> often not made by a living organism (may be chemically made in the laboratory)

Front 140

Antibiotics
(2 Important Considerations)

Back 140

1. Selectivity --> selective to kill the bacteria & not the patient

2. Resistance --> bacteria are becoming resistant to antibiotics.

The greater the selectivity of the antimicrobial, the more possible it will be to overcome resistance. If bacteria are resistance or have a very selective drug, then we can give a lot more (higher dose) of that antimicrobial & possibly overcome the resistance.

Front 141

Drug Resistance

Back 141

-Generally genotypic changes in the infecting microorganism, which persist during further growth in the absence of the drug.

Drug resistance arises by:
1. Mutation & Selection
2. Plasmid Infection (more prevalent)

Front 142

Drug Resistance
(Mutation & Selection)

Back 142

If we have a bacterial infection & we have 10^6 population of bacteria, then 1 bacterium may be resistant by virtue of a mutation to the particular antibiotic that you are using. The antibiotic will eliminate 10^6 - 1. The 1 that is resistant is not selected for and that 1 bacteria will quickly become a million bacteria all of which are resistant to the antibiotic

Front 143

Drug Resistance
(Plasmid Infection)

Back 143

Plasmids --> small circular pieces of DNA that can exist in bacteria & have multiple genes. It is possible for each of these genes to make a protein that encodes resistance to a particular kind of antibiotic (ex: penicillin resistance, sulfonamide resistance, tetracycline resistance, etc on different genes).
-If you treat someone wiht penicillin and those bacteria have penicillin resistance, then they will NOT be affected by penicillin & will grow. Additionally, you are generating a population of bacteria that can be resistant to tetracycline & sulfonamide, as well. Now you have multiple-resistance. You cannot treat this population with any of these drugs.

Front 144

Sulfonamide Structure

Back 144

Para-amino (N4) benzene group
Sulfide
Amide

Front 145

Sulfonamides
(History)

Back 145

-Synthesized in 1908
-A group of drugs that were tried & found to be successful, but were successful for the wrong (not initial) reason that they tried.
-Used in the war industry as a dye for wool (have a great affinity for protein in the wool)
-A drug, Prontosil, was synthesized & used. It turns out that Prontosil is broken down to make Sulfonamide

Front 146

PABA
(Structure)

Back 146

An endogenous substance in bacteria

The form of the molecule with O- resembles the naturally occurring PABA in the bacteria --> this accounts for the antibacterial activity of the sulfonamides because they all work in the same way.

Front 147

Sulfonamides
(Pharmacology)

Back 147

-Oral administration (can also be taken topically) --> short-acting (4-8 hours), intermediate-acting (10-25 hours), long-acting (35 hours)
-Sulfonamides & bilirubin are bound at the same sites on albumin (compete for binding; in newborn infants, bilirubin can pass the BBB & cause Kernicterus --> encephalopathy, binds to basal ganglia & subthalamic nuclei)
-Can cross the BBB & placental barrier (do not give to pregnancy or nursing women)

Front 148

Sulfonamides
(Metabolism & Excretion)

Back 148

Metabolism:
-N4-acetylated in liver

Excretion:
-Eliminated via kidneys
-Advantage --> in the tubules, the concentration of sulfonamides is higher than the blood (higher - more effective concentration to fight off bacteria)
-Disadvantage --> many sulfonamides are NOT SOLUBLE. Therefore, there is risk of Crystaluria (formation of crystals in kidneys that can damage the tubules). Must use Sulfisoxazole (relatively soluble sulfonamide; short-acting - 4-8 hours)

Front 149

Sulfonamides
(Toxicity)

Back 149

-Hypersensitivity reactions (Stevens-Johnson syndrome --> a rare but serious condition where you have severe bleeding, lesions erupting all over the body, sloughing of the mucosal membranes & eventually death. It is reversible if you catch it early enough; if not caught early, then pt can die)
-GI disturbances
-Blood dyscrasias
-Hemolytic anemias
-Deficiency in Glucose-6-phosphate dehydrogenase

Front 150

Sulfonamides
(Uses)

Back 150

-Acute urinary tract infections caused by Gram- bacteria (E. coli, proteus, etc)
-Nocardiosis (Cerebral & pulmonary abscesses caused by bacteria)

Alternative Treatment:
-Trachoma (cause of blindness)
-Infections (has been superseded by a combination of 2 drugs --> Sulfamethoxazole-trimethoprim)

Front 151

Sulfonamides
(Combination of 2 drugs)

Back 151

1. Trimethoprim --> dihydrofolate reductase (FH2 --> FH4)
-This reaction occurs in bacteria AND humans
-Selectivity? Trimethoprim is needed in much higher doses (5 order of magnitude more) to inhibit the Human FH2 reductase by 50% than to inhibit the Bacterial FH2 reductase by 50% (concentrations do not effect human enzymes)
2. Sulfamethoxazole (aka Bactrim & Septra)
-Trimethoprim & Sulfamethoxazole act synergistically for killing bacteria.
-Combination is used for the same things that you use sulfonamides for, but is also good for CHRONIC urinary tract infections.

Front 152

Sites of Inhibition
(Nucleic Acid Synthesis)

Back 152

Sulfonamides
Trimethoprim
Rifampin
Fluoroquinolones

Front 153

Sites of Inhibition
(Cell Wall Synthesis)

Back 153

Penicillin
Cephalosporins
Vancomycin
Isoiazid
Bacitracin

Front 154

Sites of Inhibition
(Protein Synthesis)

Back 154

Aminoglycosides
Erythromycin
Tetracyclines
Clindamycin
Chloramphenicol

Front 155

Sites of Inhibition
(Cell Membrane)

Back 155

Amphotericin B
Miconazole
Fluconazole

Front 156

Penicillin
(Basics)

Back 156

-Route of elimination = Kidneys
-Penicillin is NOT metabolized
-Drug is dosed in units (1 unit = 0.6 micrograms)
-Have beta lactam ring

Front 157

Bacterial Cell Wall Structure

Back 157

-Bacteria are HYPERtonic relative to the environment, so the cell wall prevents water from coming end (prevents lysis)
-Beta lactams prevent the proper synthesis of bacterial cell walls & cause lysis
-Cell wall = peptidoglycan (longitudinal strands with vertical strands connecting them)
-->made up of peptides & sugar molecules (N-acetylmuramic acid & N-acetylglucosamine)
-->alternating MurNAc & GlcNAc strands
--> attached to N-AcMur = peptide chain with 4 AAs (L-Ala, D-Glu, L-Lys, D-Ala); Attached to L-Lys is 5 Glycines, which form a peptide bond (glycine bridge) with D-Ala on the other vertical strand

Front 158

Bacterial Cell Wall Synthesis
(Stage 1 Cytoplasm)

Back 158

-Begin with N-Acetylglucosamine-1-P, which reacts with UTP to release Pyrophosphate to make --> UDP-GlcNAc
-UDP-GlcNAc reacts with Phosphoenolpyruvate, which adds to the GluNAc to make --> UDP-MurNAc
-UDP-MurNAc undergoes 3 separate reactions to add L-Ala, D-Glu, & L-Lys
-At the same time, L-Ala is acted on by Alanine Racemase, which changes L-Ala to D-Ala. D-alanyl synthetase links 2 D-Ala together to yield a dipeptide
-Finally, D-Ala-D-Ala is added to the end of the tripeptide chain to make --> UDP-MurNAc-pentapeptide

Front 159

Bacterial Cell Wall Synthesis
(Stage 1 Cytoplasm - INHIBITION)

Back 159

The 2 steps (below) are inhibited by Cycloserine.
Cycloserine looks like D-Ala & thus, inhibits these reactions (2nd line treatment for TB)


(UDP-MurNAc undergoes 3 separate reactions to add L-Ala, D-Glu, & L-Lys
At the same time, L-Ala is acted on by Alanine Racemase, which changes L-Ala to D-Ala. D-alanyl synthetase links 2 D-Ala together to yield a dipeptide)

Front 160

Penicillin G
(Salt Toxicities)

Back 160

Depends on the salt that is given
-If pt is taking a digitalis glycoside or a drug for congestive heart failure, then a lot of K+ will counter the effects of the glycoside & will DECREASE effectiveness
-If pt has renal problems & you give a lot of penicillin G as a K+ salt, then you will get HYPERKALEMIA
-If using the sodium salt & the pt has hypertension, then you will increase the pt's sodium levels.

Front 161

Penicillin G
(Elimination)

Back 161

-90% of Penicillin that is injected IM will be excreted through the kidneys unchanged. Of the 90% that goes out, only ~10% is by filtration & the other 90% is by tubular secretion (Elimination is almost completely tubular)

Probenecid inhibits tubular secretion & increases the concentration & length of time that Penicillin is in the circulation (2nd line for treating gout - prevents reabsorption of uric acid)

Front 162

Penicillin G
(Distribution)

Back 162

Penicillin G is widely distributed.

It enters interstitial fluid, gets into bone, synovial fluid & will cross the placenta.
Normally, it will NOT get into CSF (does not readily cross the BBB). If the meninges are inflamed, then they will allow the passage of Penicillin G

Front 163

Penicillin G
(Uses)

Back 163

Aerobes:
-Streptococcus infections (A, B, C & G strains)
-Strep. pneumoniae (resistant) --> accounts for 35% of middle ear infections (otitis media)
-Neisseria gonorrhea & Neisseria meningitidis (resistant)
-Treponema pallidum (syphilis) --> spirochete; VERY sensitive to Penicillin G
-Borrelia burgdorferi (Lyme Disease) --> spirochete
-Bacillus anthracas (antrax)
Anaerobes:
-Gram+ Glostridium perfringens & tetani (CANNOT be used for Clostridium difficile)
-Gram- Bacteroides - Oropharyngeal infections (NOT used for Bacteroides fragilis)

Front 164

Penicillin G & Staph infections

Back 164

Most Staph infections are resistant to Penicillin (hospital acquired infections = Nosocomial infections)

Front 165

Problem with Pts taking antibiotics

Back 165

-many antibiotics are given for 7-10 days, after a few days patients begin to feel better and stop taking them, this allows for the infection to come back and cause resistance

Front 166

Macrolide Types

Back 166

-Erythromycin
-Clarithromycin
-Azithromycin
-Telithromycin

Front 167

Macrolides

Back 167

-own their antibiotic activity bc they selectivity inhibit protein synthesis since it is so different from the protein synthesis in humans and doesn't interfere

Front 168

Erythromycin

Back 168

-half life is 1.5 hours
-macrolide, inhibits protein synthesis

Front 169

Clarithromycin

Back 169

-half life of 6 hours
-macrolide, inhibits protein synthesis

Front 170

Azithromycin

Back 170

-half life 3 days
-part of the benefit is that it is highly concentrated in the tissues and then it slowly released
-used differently bc of its long half life, usually given a loading dose and then once a day for 7-10 days

Front 171

Telithromycin

Back 171

-liver toxicity
-doesnt work on pts with myasthenia gravis
-was used a lot but bc it is believed to work better than other drugs

Front 172

Uses of Macrolides

Back 172

-mycoplasma pneumonia
-strep infections in which the person is hypersensitive to penicillin and its derivatives
-treponema
-legionella (legionares disease)
-helicobacter pylori- usually causes ulcers, antibiotic treatment is now given to treat ulcers
-used for mycoplasmid avium complex (found in pts with AIDS)
-chlamydia

Front 173

Erythromycin Problems

Back 173

-along with clarithromycin can inhibit P450 metabolism of certain drugs
-Increases theophylline (too much causes convulsions)and increased warfarin (causes bleeding disorders) and carbamazepine (antiepileptic that now in higher concentration causes seizures)
-GI distress (cramping, diarrhea
-causes Torsades de pointe

Front 174

Torsades de pointe

Back 174

- twisting points
-with standard EKG you have the standard points QRS and T,
-the macrolides have the ability to block the efflux of potassium in the ventricles and make the Q-->T interval longer, causing sudden cardiac death,
-2 fold higher in people taking erythromycin (all macrolides but mainly erythromycin, but also clarithromycin) .
- If you combine another drug with erythromycin that inhibits the metabolism of erythromycin there is a 5 fold increase in sudden cardiac death.

Front 175

Modes of Resistance of Gram Positive Bacteria

Back 175

1. Can make beta-lactamases (or penicillinase)
2. Mutated form of the PBPs (no longer inhibited by penicillin G)
3. Inability to activate Autolysins (enzymes that break down the cell wall)

Front 176

Modes of Resistance of Gram Negative Bacteria

Back 176

1. Mutations in Porins (prevents beta lactams from getting across the outer membrane to inhibit PBPs)
2. Can make beta-lactamases (or penicillinase)
3. Some bacteria (ex: Neisseria) have a pump that pumps the penicillin & other beta lactams out of the bacteria

Front 177

Broader Spectrum Antibiotics
(Uses)

Back 177

Will treat all the same things as Penicillin G, but only 1/2 as effective

Treats a range of Gram Negative bacteria that Penicillin G will not treat:
-E. coli, Proteus, Shigella, & Typhus

Will work aginst Klebsiella & Pseudomonas

Front 178

Carbapenems

Back 178

Imipenem (combined with Cilastatin)
-Has a 2nd beta lactam ring
-Renal dipeptidase will break down imipenem, so Cilastatin inhibits the renal dipeptidase & allows imipenem to last longer.

Meropenem --> resistant to dipeptidase

Reserved for Serious Multi-Drug Resistant bacteria (DO NOT work against MRSA)

Front 179

Cephalosporins

Back 179

Can confer resistance
Divided into generations:
1st generation:
-Similar in activity to Penicillin G
-Mainly treats Gram+ infections
2nd generation:
-More like Amoxicillin & Ampicillin
-Can treat Gram+ & Gram- infections
3rd generation:
-Mainly treat Gram- infections
4th generation:
-Cefepime --> more Beta lactamase resistant
2nd & 3rd generations have a Disulfiram-like effect (must warn pt NOT to drink ALCOHOL)

Front 180

Clindamycin

Back 180

-can be given orally and inhibits protein synthesis, eliminated by the liver through the bile and through the feces

Front 181

Clindamycin uses

Back 181

-bacteroides (gram - infections)
-clostridium perfringes (anaerobe gram +)
-alternative strep infections

Front 182

Pseudomembranous Colitis

Back 182

-sloughing of the intestinal mucous membrane
-clindamycin allows the outgrowth of clostridium difficile which secretes a toxin that attacks the mucous membrane of the intestinal tract causing the sloughing, now you have to get rid of the C. difficile
-this is done by vancomycin

Front 183

Vancomycin toxicity

Back 183

-ototox (damaging ear)
-nephrotox (kidney damage)
-elimination of vancomycin is through the kidney and normal half life is 6 hours, but with reduced kidney function it is 250 hours.
-must be careful about pairing drugs with similar toxicities

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Vancomycin Uses

Back 184

-C. difficile (must be given orally bc this is an intestinal infection)
-MRSA, (first choice, however sometimes it will not be responsive)
-Alternative Strep infections due to penicillin allergy
-Enterococcus faecium
-Enterococcus facaelis

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Dolfupristin/Quinupristin

Back 185

-together are called Synercid
-only good for enterococcus faecium and used if linezolid fails
-administered by IV

Front 186

Linezolid

Back 186

-if pt is alreads taking an SSRI or an SNRI, Linezolid is an MAO inhibitor (MAO-A metabolizes serotonin) causing a serotonin syndrome which involves possible convulsions , dizziness and confusion, this should only be used if it is a life threatening infection if pt is on SSRI SNRI.

Front 187

Linezolid uses

Back 187

-MRSA
-Enterococcus faecium
-Enterococcus facelis

Front 188

Aminoglycosides

Back 188

-streptomycin
-gentamycin
-tobramycin
-amikacin
-neomycin

Front 189

Streptomycin

Back 189

-first used of the aminoglycosides

Front 190

Gentamycin

Back 190

-most frequently used,
-resistance can develop

Front 191

Tobramycin

Back 191

-most frequently used
- resistance can develop

Front 192

Amikacin

Back 192

-developed to get around resistance to gentamycin and tobamycin, bc they metabolize the antibiotic, these sites were modified so that the sites with inactivation cannot be inactivate

Front 193

Aminoglycosides

Back 193

For severe infections aminoglycosides may be combined with one of the penicillins, these are given IV, a caution when this is done you can mix both in the same syringe or back because they react with one another and precipitate out and must be injected separately
-work at the site of the 30s ribosome

Front 194

Gram negative bacteria

Back 194

-have and outer membrane and cytoplasmic membrane and have a two step process for the amninoglycoside to get into the bacteria
-antibiotic must go through porins
-once in periplasmic space must be transported by and O2 dependent transporter, consequence is that aminoglycosidesare used only for Aerobic gram - bacteria

Front 195

Ways bacteria create resistance

Back 195

-mutation of porins
-metabolize antibiotic, modify and inactivate
-Mutation at 30s ribosome
-transporter actively pumps out antibiotic

Front 196

Aminoglycoside toxicity

Back 196

-ototoxicty
-nephrotoxicity
-reserved for moderate to severe gram - infections

Front 197

Metronidazole

Back 197

-believed to work by inhibits anaerobic energy production or inhibit DNA synthesis. Used only for ANAEROBES, gram + or gram -

Front 198

Metronidazole uses

Back 198

-Bacteroides
-Clostridium difficile
- Helicobacter
- Vincent's ginvivostomatitis
- ANUG

Front 199

Metronidazole toxicities

Back 199

- Nausea
- Heart burn
- Can produce a disulfur like effect, have to caution them to not have alcohol
- Carcinogenic and mutagenic and shouldn’t be used in pregnant women

Front 200

Tetracycline

Back 200

- inhibit protein synthesis, mainly eliminated through the bile via the feces,
-varying half life (6-15hrs) can use them orally and IV,

Front 201

Tetracycline cautions

Back 201

-cautions include: they are chelators (compund that is a claw like molecule that can bond to di or trivalent cations such as calcium magnesium and aluminum,
-when it does this they become insoluble and are not absobed well. For this reason you have to tell them to be careful to not drink milk or dairy products and cant be taking antacids because these all prevent the absorption of tetracyclines)

Front 202

Tetracycline Toxicities

Back 202

-GI irritation (more frequent)
-photo sensitivity
-overdose can cause liver toxicity
-can get into bone and teeth due to chelating agent
-should not be prescribed to children who are under 8 years old, pr pregnant women
-can be toxic to kidneys but not frequent
-taking outdated tetracycline causes fanconi-like syndrome (kidney damage)

Front 203

Tetracycline Types

Back 203

-tetracycline
-doxycycline
-demecloncycline
-minocycline

Front 204

Minocycline

Back 204

-has a derivative called tigecycline
-accumulates in gingival fluid to a higher concentration than the plasma
-useful in dental infections
-used in microspheres to be used in perio disease

Front 205

Tetracycline Uses

Back 205

-mycoplasma pneumonia
-rocky mountain spotted fever
-chlamydia
-helicobacter
-anthrax
-can be combined with metronidazole and bismuth subsalycilate (pepto bismol)

Front 206

Choramphenicol

Back 206

-infrequently used
-effective for serious gram + and gram - and for Rocky mountain spotted fever
- Not used much anymore because if caused complete shut down of bone marrow

Front 207

Fluorquinolones

Back 207

-metabolized and eliminated through the kidneys.
-Acts on DNA gyrase

Front 208

Fluorquinolone Problems

Back 208

-cause arthropathy (condition of the joints where there is an erosion of cartilage, not used in children or pregnant women)
-can effect tendons in geriatric pts and they can snap,
-nausea and vomting. (most common problem)

Front 209

Fluorquinolone Types

Back 209

-Ciprofloxacin
-Norfloxacin

Front 210

DNA gyrase activity

Back 210

-prevents DNA from tangling up when it is being uncoiled during synthesis

Front 211

Fluroquinolone uses

Back 211

-aerobic gram + and - infections, particularly for recurrent urinary infections and Rocky Mountain Spotted fever
-used for serious infections with pts with cystic fibrosis.

Front 212

Topical Antibiotics

Back 212

-frequently used in combo
-bacitracin (gram +)
-Polymixin B (gram -, detergent breaks up bacteria)
-Neomycin (aminoglycoside, gram + and - infections)
-Neosprorin: (gram -, too toxic to take internally

Front 213

Antibiotics that inhibit protein synthesis

Back 213

-macrolides
-tetracycline
-clindamycin
-chroamphenachol
-Linezolid
-quinupristin/dolfupristin

Front 214

Antifungal Drug Types

Back 214

-Amphotericin B
-Azole
-Echinocandins
-Caspofungin

Front 215

Amphotericin B

Back 215

-toxic to kidneys and heart on occasion, comes in many diff forms , least toxic is most expensive and vice versa, reserved for serious system fungal infections,
-selectivity is not great
- Forms channels in the membrane and allows contents of the cells to leak out and the fungus dies, creates channels next to ergosterol (equivalent in human cells is cholesterol, ergosterol is in fungal membranes and binds better to this than cholesterol) used for pts with HIV candidiasis infections

Front 216

Azole

Back 216

-used for oropharyngeal candidiasis , interferes with the synthesis of ergosterol via a 14 alpha demethylase

Front 217

Azole types

Back 217

-Fluconazole
-Itraconizole
-Clotrimazole :
-Miconazole:

Front 218

Miconazole

Back 218

used for vaginal yeast infections

Front 219

Clotrimazole

Back 219

used for athletes foot

Front 220

Echinocandins

Back 220

- used for various fungal infections, thought to replace amphotericin B.
-Caspofungin

Front 221

Pre-Med patients for dental work

Back 221

-Pts with artificial heart valves
-Previous endocarditis
- Enlarged heart
- Transplant heart pts
-For treatment that will involve bleeding (does not include injection of local anesthetic

Front 222

Oral Amoxicillin

Back 222

- drug of choice 1 hour before the procedure, give IM then 30 min before

Front 223

Pt cannot take oral medication

Back 223

nject amoxicillin or cephalosporin

Front 224

Pt has allergy to penicillins

Back 224

-give clindamycin or azithromycin, can give a cephalosporin if not rxn to penicillin

Front 225

Pt cannot take oral meds and allergy to penicillin

Back 225

-give clindamycin parenterally or cephalosporin

Front 226

Tuberculosis

Back 226

-About 3 million ppl in the world die from TB and about a billion ppl are infected with it . In non HIV pts it is the most frequent cause of infectious disease death in the world.
-If you test and find that the mycobacterium tuberculosis (infecting organism) is sensitive to Isoniazid & Rifampin, then you can use them BOTH in combination. If you use both, then you will treat for at least 4 months

Front 227

First Line TB drugs

Back 227

-Isoniazid
-Rafampin
-ethambutol
-Pyrizinamide

Front 228

3 categories of Depression

Back 228

1. Major depression
2. disthymic depression
3. Minor depression

Front 229

TB difficult to treat

Back 229

-HIV pts are immunocompromised & are more likely to keep having the infection
-Generally starting out with 10^8 to 10^9 bacteria (very large number to treat)
-Mycobacteria grow intracellularly, as well as extracellularly (drug must penetrate cells)
-TB goes to the brain, so it must cross the BBB
-Mycobacteria form CASEOUS lesions (cheesy)

Front 230

Lithium

Back 230

(used to treat bipolar ds)
-given as lithium bicarbonate Li2CO3
-various effects not sure which one effects bipolar disease
-while drug is effective must be carefully MONITORED
-lithium likes sodium: lithium will go into sodium channels as well as sodium can, but lithium, unlike sodium, is not as efficiently pumped out (accumulates in cell), concentration of intracellular potassium goes down and leads to hyperpolarization and is perhaps part of the problems or problems that are seen if you get to high a concentration of lithium in the blood
-the only way to treat the toxicities (after stopping lithium) is dialysis to try and get rid of the lithium

Front 231

SSRIs

Back 231

-Fluoxetine, Citalopram, Escitalopram (s-isomer of citalopram, unlike Prilosec (omeprazole), isomers work better because one isomer counters the effect of the s-isomer), Paroxitene, Sertraline
-Selectively inhibit reuptake of serotonin from serotoneric neurons in the brain
-all bind to the transporter for serotonin reuptake and allostericly change the transporter so that it no longer takes up serotonin as well
-drugs are usually taken long term
-people taking this long term stop taking it on their won because these cause sexual problems; in women: anorgasmia (not being able to achieve orgasm); in men- increase latency to ejaculation; 5-10% of peple on one of these drugs there is significant weight gain

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Symptoms of Depression

Back 232

1. Emotions -general feeling of depression, use interest and lack of pleasure
2. Ideation- feeling of worthlessness, guilt, thoughts about death or attempting suicide
3. Somatic Symptoms
-insomnia, hypersomnia (all you want to do is sleep), lose apetite, eat all the time, don't want to move around, sense of agitation, having trouble concentrating

Front 233

Alcohol
(Metabolism)

Back 233

-90-95% of ethanol is oxidized to acetaldehyde (CH3CHO) in the liver by alcohol dehydrogenase (CH3CH2OH + NAD+ --> CH3CHO + CADH + H+)
-Metabolism follows Zero Order Kinetics (a constant amount per unit time)
-Alcohol dehydrogenase is also in the gastric mucosa, but women have ~1/2 that of men
-A small percentage of ethanol is metabolized by P450 (Ethanol may increase P450 enzymes that also metabolize other drugs or it may compete with other drugs for metabolism by P450).
-Acetaldehyde is TOXIC and is converted to Acetate by aldehyde dehydrogenase (CH3CHO + NAD+ --> CH3COO- + NADH + H+)
-Disulfiram inhibits aldehyde dehydrogenase. Thus, it has been employed to discourage drinking in alcoholics by resulting in unpleasant effects. Disulfiram also affects P450 metabolism of some drugs: (i.e. phenytoin)

Front 234

Penicillin G
(Toxicities)

Back 234

Main toxicity = Hypersensitivity (1-10%)
2 Types:
1. Immediate (within 1 hour)
-Involve Anaphylaxis & IgE
-0.002% chance of an immediate hypersensitivity reaction
-Characterized by: swelling, rashes, flushing, itching, drop in BP, difficulty breathing & can be fatal if not treated rapidly
-Treatment = Epinephrine
2. Non-Immediate (>>1 hour)
-Characterized by: rashes & itching
-NOT treated with epi (local corticosteroid or an antihistamine)
-Do not try to substitute another beta-lactam drug if pt is allergic to Penicillin G

Other toxicity: Neurotoxicity -Occurs when given HIGH doses of Penicillin G (>20-60 million units)
-More likely in neonates, elderly, & pts with preexisting brain injuries

Front 235

Penicillin G
(Carbonyl Group)

Back 235

The carbonyl group can be matched to a K+ or Na+ salt.

-It can make a salt with Procaine or Benzathine (positively charged).
-Procaine & Benzathine are NOT SOLUBLE because they are given IM. When you inject them IM, you form a depot, which allows the Penicillin to be slowly released into the general circulation.

Procaine --> Inject 1x/day
Benzocaine --> Inject 1x/week

-Cannot achieve high plasma concentrations of Penicillin G intramuscularly, so the bacteria must be very sensitive to it (can't be used for bacteria requiring high concentration of Penicillin G)
-IM procaine stays for 1-2 days & benzathine stays for 1+ weeks, so if you run into a toxic effect, then you are SOL

Front 236

Typical Antipsychotic Drugs

Back 236

Chlorpromazine, Haloperidol, Thiothixene
• Resolution of hallucinations, delusions, & disorganized thought processes (positive effects)
• Loss of initiative, loss of interest in the environment & more limited range of affect (little display of emotion) --> poor compliance because it makes them feel bad; more likely to relapse
• Drowsiness & slowness to respond to external stimuli (zombie phenomenon - not totally there; lack of interest), although subjects are easily aroused with intact intellectual functions (no ataxia or incoordination)
• Antiemetic actions against non-GI-induced emesis (given to prevent emesis caused by general anesthesia)
• Maximal therapeutic benefit is delayed (Takes a few weeks to get full antipsychotic effects)

Front 237

Broader Spectrum Antibiotics

Back 237

Broader spectrum penicillin derivatives are can treat more types of bacteria. Involves changes to Penicillin G:
-Ampicillin (add an amino group --> benzene-CH(NH2)C(=O)...
-Amoxicillin (add hydroxyl group to benzene)
These derivatives are more HYDROPHILIC than Penicillin G & are able to go into porins; thus, effective on Gram Negative bacteria
These derivations are NOT penicillinase resistant & are often combined with another drug (sole purpose of the 2nd drug is to inhibit penicillinase):
•Ampicillin + Sulbactam = Unasyn
•Amoxicillin + Clavulanic acid = Augmentin (only ORAL)
•Ticarcillin + Calvulanic acid = Timentin
•Piperacillin + Tazobactam = Zosyn
•All are acid Stable --> (Amoxicillin>Ampicillin)
•Associated with GI problems:
-->Ampicillin = 8-10%
-->Amoxicillin = 3%

Front 238

Dopamine Pathways & Their Interactions

Back 238

-Neurons located in the substantia nigra project to different parts of the brain. Axons terminate & impulses synapse on cholinergic neurons in the striatum (caudate-putamen), which functions in fine motor control.
-The D2 receptors on the cholinergic target neurons are inhibitory; when occupied by D2 dopamine antagonists, the inhibitory effects of dopamine are blocked & the cholinergic neurons become disinhibited. Results in increased firing & release of more ACh, which activates muscarinic receptors = antipsychotic-induced parkinsonism. These side effects can be treated by coadmin. of appropriate antimuscarinic drugs.
•Pre-frontal cortex (imp. for cognitive impairing effects)
•Nucleus Accumbens - thought to be important for drug abuse/addition mechanisms that involve dopamine (many schizophrenics have problems with abuse of alcohol, nicotine, etc)
•Dopamine released from the pituitary into the hypothalamic-pituitary portal system regulates (inhibits) release of prolactin.

Front 239

Mechanism of Pain Reduction by Non-Opioid Analgesics

Back 239

-Membrane of cells have Phosphatidylcholine (carbond backbone with a phosphate & choline, fatty acid, & arachidonic acid-AA)
-AA is cleaved from the phosphatidylcholine by Phospholipase A2.
-This initial step is inhibited by glucocorticoids that induce the synthesis of lipocortin that binds to & inhibits the phospholipase A2, thus inhibiting formation of AA.
-AA can be worked on by lipooxygenases to make leukotrienes or can be metabolized by COX 1 or 2. COX 2 is induced by a painful stimulus & inflammation. COX enzyme converts AA to PGH1. PGH1 can form Thromboxanes and/or Prostaglandins.
-Non-opioid analgesics (aka NSAIDS) work by inhibiting COX 1 & 2. They block conversion of AA to form PGE2 and thromboxanes.

Front 240

Acetaminophen
(Non-Selective NSAIDs)

Back 240

-Acetaminophen DOES HAVE anti-inflammatory properties AND is a Selective COX Inhibitor (as previously thought)
-Does not appear to have GI disturbances, but has the potential to cause serious liver toxicity that can be irreversible & lethal (especially with alcohol consumption)
-It is metabolized in the liver where it produces benign metabolites & a non-benign metabolite: N-acetyl benzoquinone via the P450 enzyme (normally not a problem)
-A small amount of N-acteyl benzoquinone can react with Glutathione to produce a glutathione N-acetyl benzoquinone, which can be eliminated.
-If combined with alcohol, it can be deadly because:
1. Alcohol induces p450 enzyme that makes N-acetyl benzoquinone. So N-acteyl benzoquinone is produced.
2. Alcohol consumption (damaging to the liver), will decrease the amount of glutathione that is available to inactivate the toxic metabolite (N-acetyl benzoquinone builds up & reacts with various molecules/proteins/DNA & lead to lethal liver damage)

Front 241

Neurotrophic Hypothesis

Back 241

-Based upon substance brain derived neurotrophic factor (BDNF)
-made in brain
-plays role in plasticity (ability of brain) to change the number of neurons; it affects neurogenesis (making of more nerves)
-BDNF can lead to increase in volume/size in certain parts of the brain
-people who are depressed have a decreased volume/size of particular areas of the brain
-In animal studies: if BDNF infused into animal brains ---> if they are depressed, they seem to be less depressed
-in humans who are depressed: BDNF are decreased
-drugs that are used--->lead to increase in BDNF--> treats depression

Front 242

Tricyclic antidepressants

Back 242

-Core of the molecules are 3 ring structures
-Inhibit reuptake of serotonin & NE
-Imipramine, Desmipramine (metabolite of imipramine), Amytryptiline, Noramytryptiline(metabolite of amytryptiline)
-Parent drug & metabolite have activity: part of the longer activity is the formation of the metabolite which also has activity (so parent drugs should last longer)
-Only used if no results from SSRis or SNRI
-Not 1st choice because they effect other receptors
-Block muscarinic, H1 receptors & alpha 1 receptors
-Muscarinic receptors blocked --> dry mouth & constipation
-H1: result = sleepiness, sedation
-alpha 1: cause orthostatic hypotension

Front 243

Antibiotics
(Suppurative Abscess)

Back 243

Abscess --> a suppurative (pus forming) infection that derives from dead & dying cells in the area of infection, which will lead to poor circulation. This has a consequences:
-Effective antibiotic concentration is difficult to achieve at the site of infection
-Supply of antibodies, phagocytes, oxygen and nutrients decrease & waste products (including CO2) increase:
-->This causes bacteria to stop replicating & sometimes lyse (thus, bactericidal drugs will not work)
-Leukocytes, which can fight infections, will go down
- Lysis of host cells may release previously unavailable intracellular metabolites that the bacteria may now utilize to bypass the block created by the antibiotic
-When you come across an abscess in a pt:
--> Drain the pus for optimal antibiotic action

Front 244

Staph Treatment
(Penicillinase-Resistant Penicillins)

Back 244

-Some beta-lactamases are more selective for penicillin molecules (penicillinases) & others are more selective for cephalosporin molecules (cephalosporinases)
-Staph is resistant because they produce a penicillinase that inactivates the penicillin. Thus we must modify Penicillin G:
-->Methicillin
-->Nafcillin (most used - unique b/c it's eliminated through the liver by bile)
-->Oxacillin (most used)
-->Cloxacillin
-->Dicloxacillin
-These are ONLY used when bacteria are penicillin-resistant (If not resistant, then Penicillin G is more effective)
-Some staph are resistant to all alternative --> Methicillin Resistant Staph aureus (MRSA)

Front 245

Monobactams

Back 245

Aztreonam (only available drug)

ONLY has the beta lactam ring (no 2nd ring)
-->Anaphylactic reactions occur by a reaction to the 2nd ring...so Monobactams do NOT have anaphylactic reactions

Uses: SERIOUS AEROBIC infections
-Septicemia
-Serious pneumonia
-Osteomyelitis
-UTIs
-Pseudomonas aerogenosa

For serious Gram Negative infections there is an alternative:
-Combination of a broader spectrum penicillin + an Aminoglycoside

Front 246

Alcohol
(Effects on the CNS)

Back 246

Acute Effects:
-Behavioral depression
-Depression of respiration (main cause of death)
-Altered temperature regulation with heat loss (actually getting colder due to vasodilation)
-Arteriole & capillary dilation in the skin & GI tract
Chronic Effects:
-Tolerance --> decreased sensitivity to intoxication, reduced CNS depression (brain learns to counter the effects of alcohol with a stimulatory effect) by induction of metabolizing enzymes & learned behavioral compensation - when you feel terrible in the morning, it's because the depressive effects have left with the alcohol and the overcompensated stimulatory effect is still there.
-Physical Dependence: withdrawal reaction when consumption is stopped --> characterized by tremors (delerium tremens), sweating, nausea, hallucinations, delirium, convulsions. Withdrawal can be life-threatening. Often treated with Benzodiazepines.

Front 247

Antipyresis
(NSAIDs)

Back 247

NSAIDs can reduce Fever (different from Hyperthermia)
-Hyperthermia is an increase in body temperature (occurs when the body produces more heat than it can eliminate; i.e. vigorous exercise)
-Fever occurs due to a change in the "setpoint" for body temperature (like a thermostat); the body has decided to maintain the temperature higher.
•Fever is produced by exogenous or endogenous pyrogens:
-Some cytokines produce endotoxin (i.e. Gram- bacteria). These substances stimulate endothelial cells in the hypothalamus, ventricles & brain to get an increase in COX2. PGE2 synthesis increases & PGE2 is released & interacts with the PGE2 receptor EP-3 on glial cells to release cAMP, which causes the elevation of the thermoregulatory setpoint (through the action of the hypothalamus).
•Anti-pyretics (acetominophen, ibufrofen, aspirin, etc) inhibit COX2 & prevent the increase of PGE2, thus allowing the temperature set point to remain at "normal"

Front 248

Bacterial Cell Wall Synthesis
(Stage 2 Cell Membrane)

Back 248

-UDP-MurNAc-pentapeptide reacts with Lipid-P to make --> Lipid-P-P-MurNAc-UDP-pentapeptide
-This product reacts with UDP-GlcNAc to yield --> Lipid-P-P-MurNAc-pentapeptide-GlcNAc
-Glycyl-tRNA is then used to add the 5 Glycines onto L-Lys on Lipid-P-P-MurNAc-pentapeptide-GlcNAc
[NONE of the above steps are inhibited by Penicillins]
-The Lipid-P-P-MurNAc-peptapeptide(5 glycine)-GlcNAc is added onto the growing end of the cell wall (Peptidoglycan) and Lipid-P-P remains.
--> This step is inhibited by Vancomycin (binds to D-Ala-D-Ala)
--> Bacteria resistant to Vancomycin change D-Ala-D-Ala to D-Ala-D-Lactate (binding affinity is reduced 1000 fold, so the usual dose of Vancomycin will not inhibit this step)
-Lipid-P-P reacts with phosphatase to give Lipid-P, which goes through the cycle again
--> This step is inhibited by Bacitracin (a topical antibiotic)

Front 249

Bacterial Cell Wall Synthesis
(Stage 3 Cell Wall)

Back 249

The 5 glycines on Peptidoglycan-MurNAc-pentapeptide(L-Lys)-GlcNAc form a bond with the next to last D-Ala & the last D-Ala is removed.
--> This reaction is catalyzed by a Transpeptidase, which yield MurNAc-GlcNAc-4AAs + 5 glycines
--> This step is inhibited by ALL Beta-Lactams
Penicillin resembles the last 2 D-Alanines. Penicillin- Binding-Proteins (PBPs), such as transpeptidases, react with penicillin. So the transpeptidase reacts with penicillin & opens the beta-lactam ring = IRREVERSIBLE & the transpeptidase can no longer function to link the 2 strands
•Penicillin Resistance --> Bacteria may produce a Beta-lactamASE that reacts with the beta lactam bond instead of transpeptidase. It binds reversibly & causes a hydrolysis reaction. The beta-lactamase comes off active & inactivates penicillin
•Beta lactamases are made from a genome of a bacterium & are frequently carried on plasmids

Front 250

Penicillin G
(Administration & Absorption)

Back 250

•Orally, IM, or IV administration
-Orally, only 1/5-1/3 of what is given is absorbed since Penicillin G is acid-labile (beta-lactam bond cleaved by HCl)
-->Orally, take at least 1 hour before eating or at least 2 hours after eating (will minimize the problems of absorption & given better adsorption into systemic circulation)
--> Takes 30-60 minutes to be in plasma
-IM, 1/2 of penicillin gets absorbed
--> Takes 30 minutes to be in plasma
To combat acid-lability, you can give a variant of Penicillin G --> Penicillin V (has an oxygen in the structure that makes it acid stable).
Unlike Penicillin G, Penicillin V will NOT absorb the food in the GI tract
•Generally dose Penicillin G ~every 4 hours (we do not see a plateau concentration, but it's ok b/c it binds irreversibly so the effect stays the same)
•Penicillin G is very selective because Cell wall synthesis does not exist in human cells

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Sulfonamides
(Mechanism)

Back 251

-Bacteria make 6-pyrophosphoryl-methyl-7,8-dihydropteroin, which reacts with PABA & is catalyzed by dihydropteroate synthetase to make dihydropteroate. Dihydropteroate has a glutamate molecule added onto the end, which forms dihydrofolate (FH2). FH2 is then converted to tetrahydrofolate (FH4) by dihydrofolate reductase.
-TH4 (important in bacterial & human cells) transfers carbons to molecules, such as dUMP (deoxyuridylic acid). dUMP is catalyzed by N-5,10-methylene FH4 to dTMP (deoxythymidylic acid). The methylene group is put onto dUMP to convert it to dTMP.
-Folate (taken up in the diet) can be converted to dihydrofolate (FH2). Since sulfonamides look like PABA, they will block formation of folate compounds (FH2 & FH4) competitively inhibiting dihydropteroate synthetase. It also inhibits making dTMP (thymidine), purines & methionine.

Front 252

Sulfonamides
(Mechanism - DNA synthesis inhibition)

Back 252

-It is possible for humans & bacteria to get preformed purines & methionine. However, there is not enough thymidine that can be converted to dTMP. If purines, methionine, & thymidine are very low, then we inhibit DNA, RNA, and protein synthesis = bacteristatic
-If enough purines & methionine are present, but low levels of thymidine, then only dTMP synthesis is inhibited = bactericidal
-The block in folate synthesis leads to inhibition of DNA, RNA, & protein synthesis & the sulfonamides are bacteristatis. Under conditions where only DNA synthesis is inhibited "thymineless death" occurs (i.e. the sulfonamides are bactericidal)
-The selectively of sulfonamides for bacterial synthesis is due to the fact that humans can make FH2 & FH4 from Folate in the diet, whereas bacteria cannot & rely on the synthesis using dihydropteroate synthase (humans do not have or use this enzyme)