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Pharm Exam #2 (Part II)

Pharm Exam #2 (Part Ii)

by muzicfreak2k3, Mar. 2014

Subjects: Pharmacology

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	Pain	“an unpleasant sensory or emotional experience associated with actual or potential tissue damage or described in terms of such damage” --> Pain is what a patient perceives it to be and is highly subjective
	Nociceptive Pain	Important adaptation for survival Pathophysiology of acute pain - Stimulation - Transmission - Perception - Modulation Nociceptors found in somatic and visceral structures --> Adelta myelinated short fibers and C demyelinated long fibers
	Nociception --> Stimulation	Activation of nociceptors at nerve root endings Noxious stimuli such as bradykinin, potassium, substance P, prostaglandins, histamine, leukotrienes, serotonin and others Transmission of action potential along nerve to spinal cord
	Nociception --> Transmission	Occurs within spinal cord, neurotransmitters relay to visceral and somatic structures Substance P, glutamate, and others Different types of nerve fibers produce different types of pain --> Sharp/localized (A-delta) vs dull/aching (C)
	Nociception --> Perception	Conscious awareness of pain in cerebral cortex Subjective Focus of non-pharmacologic therapies (meditation, visualization of non-pain state, distractions – commonly for chronic pain or peds pts)
	Nociception --> Modulation	Endogenous pain relief - Endorphins, enkephalins, dynorphins - NMDA receptor activation in dorsal horn - GABA, serotonin, norepinephrine release from brain Target for many pharmacologic therapies
	Neuropathic Pain	Abnormal processing of sensory input - Often from repeated or constant stimulation over time Different from nociceptive pain and difficult to treat Causes include - HIV associated pain - Cancer pain - Post-herpetic neuralgia (due to Herpes zoster infection) - Diabetic neuropathy (poor perfusion or glucose toxicity to nerves) - Trigeminal neuralgia - Other nerve injury (i.e. trauma to the face or surgery)
	Clinical Assessment of Pain
	PQRST	Palliative/provocative factors Quality Radiation Severity Temporal factors
	The most important tools to diagnose pain	History and physical
	Analgesia	The loss of ability to feel pain without a loss of consciousness
	Targets of Analgesia
	target of analgesia --> stimulation
	target of analgesia --> modulation
	target of analgesia --> transmission
	Approach to Pain Management	- Determine nature and severity of pain - Determine expected duration of pain - Set goals for pain management with patient - Evaluate patient specific risk factors - Evaluate potential adverse effects - Choose analgesic regimen --> Scheduled pain medications – we want to PREVENT pain, not treat it when it comes --> Breakthrough treatments – pain management if scheduled pain management is not enough --> Adjunctive medications
	Co-Morbidities
	Co-Morbidities --> renal dysfunction
	Co-Morbidities --> hepatic dysfunction
	Co-Morbidities --> hematologic disorder
	Co-Morbidities --> cardiac disoder
	Co-Morbidities --> elderly
	drug allergies
	drug allergies -> NSAIDs
	drug allergies --> local anesthetics
	drug allergies --> acetaminophen
	Chronic Pain	Chronic opiate users can develop tolerance or hyperalgesia Opiate requirements will be higher than opiate naïve patients Will require acute, short acting medications in addition to chronic pain treatment May consider NMDA receptor antagonists such as ketamine or methadone – shown to increase sensitivity to opiates in chronic pts
	evaluation of adverse effects of drugs
	evaluation of adverse effects of NSAIDs
	evaluation of adverse effects of opiates
	Adjunctive Therapies	Important to include with analgesics Explain potential adverse effects to patient so they know what to expect Often over the counter and easy to obtain Also counsel on medications to avoid
	Designing Analgesic Regimens
	Mild Pain vs. Moderate Pain vs. Severe Pain
	Multi-modal Pain Management	Analgesia from multiple mechanisms Target different steps in nociception Decrease adverse effects of analgesics - Smaller doses of each agent - NSAIDS and acetaminophen decrease opiate requirements – impt as opiates have the most side effects - Avoid tolerance Includes pharmacologic and non-pharmacologic components – i.e. ice, positioning
	Dosage Forms	Oral tablets - Sublingual - Immediate release - Extended release - should NOT be used for acute pain Oral liquids - Preferred for pediatric patients or any pt that have difficulty swallowing or cannot open mouth as wide Topical
	Red Flags in Pain Management
	Changing Analgesic Regimens	When red flags are ruled out several options exist: - “Stepping up” in pain ladder – i.e. use combination product - Adding adjunctive medications - Increasing dose of analgesics - Non-pharmacologic management – may not be helpful for someone who has severe pain Before adding medications ensure patient is taking analgesics as prescribed - Clarify around the clock dosing - Discuss PRN analgesic use - Determine if dose or duration needs alteration
	When red flags are ruled out several options exist:	When red flags are ruled out several options exist: - “Stepping up” in pain ladder – i.e. use combination product - Adding adjunctive medications - Increasing dose of analgesics - Non-pharmacologic management – may not be helpful for someone who has severe pain Before adding medications ensure patient is taking analgesics as prescribed - Clarify around the clock dosing - Discuss PRN analgesic use - Determine if dose or duration needs alteration
	Maximum Doses of Analgesics
	max dose of aetaminophen
	max dose of ibuprofen
	max dose of opiates
	Tolerance	The need for escalating doses over time - Common from opiates Chronic opiate users but can develop in several weeks Develops to analgesic as well as some adverse effects – i.e. tolerance can develop against side effects (except constipation) Hard to distinguish from hyperalgesia - Escalating dose should be trialed to determine tolerance vs hyperalgesia
	Outpatient Therapy	Generally limited to oral and topical analgesics - Oral tablet - Oral liquid - Topical (patch) Patients are not monitored - Limited options - Generally conservative approach Patients are stable - Do not need to consider hemodynamics -End organ function is stabl
	Inpatient Therapy	Involves selection of dosage form - Oral tablet/liquid - Continuous intravenous administration - Intermittent intravenous administration - Patient controlled analgesia Patient factors - Mechanical ventilation (ICU setting – resp failure) - Sedation - Clinical status --> End organ function, sepsis, hemodynamic stability (i.e. lower BP)
	Pain and Sedation	Pain, agitation, and delirium guidelines for intensive care unit (ICU) patients - Always treat pain first - Add sedation as needed Fentanyl, morphine, and hydromorphone are opiates available as continuous infusions Daily assessment of need for sedation “daily wake-up” Pain should be treated based on a scale/patient assessment
	Patient Controlled Analgesia	i.e. IV opiates that can be given at a continuous low rate and pt can push the button to deliver more dose when they are in pain Continuous and bolus dose components - Continuous only indicated in opioid tolerant Decreases use of pain medications - Self-limiting respiratory depression and sedation Increases patient satisfaction Offers a quantifiable measure of pain throughout the day
	Utility of Local Anesthetics	When given during a procedure can decrease post-operative pain When given in combination with opioids decrease opioid requirements and side effects Delivery systems for outpatient epidural, subcutaneous, and intramuscular administration (i.e. pumps) - Ropivacaine and bupivacaine
	Orofacial Pain Syndromes	- Generally chronic pain pathophysiology --> Not responsive to traditional analgesics - Traumatic neuralgia - Trigeminal neuralgia - Musculoskeletal pain and spasm - Migraine
	Neuropathic Pain	Pathophysiology differs from nociceptive pain Due to nerve damage - Inappropriate transmission - Crossed pathways – can lead to tingling, burning, cold or hot sensation other than pain (i.e. phantom limb pain) - Excess stimulation Presents as burning, tingling, numbness, or electric shock sensation Can be acute or chronic - May have a role in 3% of acute pain syndromes
	Adjunctive medications
	Adjunctive medications for trigeminal neuralgia
	Adjunctive medications for neuropathic pain
	adjunctive medicine --> Capsaicin
	adjunctive medicine --> Clonidine
	adjunctive medicine --> Ketamine dextromethorphan
	General anesthesia	A global but reversible state where there is no response to external stimuli - A condition to allow the performance of surgery or another procedure Desired effects include - Amnesia – we don’t want them to remember - Analgesia- no pain - Immobility - Attenuation of autonomic response - Unconsciousness
	Principles of General Anesthesia	Most agents can successfully put a patient under anesthesia The development of new agents is directed at: - Minimizing adverse effects (such as hallucination) - Maintaining physiologic homeostasis - Decreasing post-operative effects The practice of anesthesia is neither diagnostic nor therapeutic - Maintaining the patient in the state of general anesthesia in order to preform surgical procedure which is diagnostic and therapeutic itself
	Routes of Administration of Anesthesia	Endotracheal/inhalation - Blood volume completely passes through the lungs --> Thus ideal for agents that needs to be equilibrate quickly - Re-breathing is facilitated by the carbon dioxide absorber Intravenous - Continuous and bolus dosing - Route for supportive medications - Not going to eliminated through our lungs but metabolism through other organs Oral - Pre-operative for pediatric patients - Oral agents to sedate the patient before placing intravenous lines
	Routes of Administration of Anesthesia --> Endotracheal/inhalation	Endotracheal/inhalation - Blood volume completely passes through the lungs --> Thus ideal for agents that needs to be equilibrate quickly - Re-breathing is facilitated by the carbon dioxide absorber Intravenous - Continuous and bolus dosing - Route for supportive medications - Not going to eliminated through our lungs but metabolism through other organs Oral - Pre-operative for pediatric patients - Oral agents to sedate the patient before placing intravenous lines
	Routes of Administration of Anesthesia --> Intravenous	Endotracheal/inhalation - Blood volume completely passes through the lungs --> Thus ideal for agents that needs to be equilibrate quickly - Re-breathing is facilitated by the carbon dioxide absorber Intravenous - Continuous and bolus dosing - Route for supportive medications - Not going to eliminated through our lungs but metabolism through other organs Oral - Pre-operative for pediatric patients - Oral agents to sedate the patient before placing intravenous lines
	Routes of Administration of Anesthesia -->Oral	Endotracheal/inhalation - Blood volume completely passes through the lungs --> Thus ideal for agents that needs to be equilibrate quickly - Re-breathing is facilitated by the carbon dioxide absorber Intravenous - Continuous and bolus dosing - Route for supportive medications - Not going to eliminated through our lungs but metabolism through other organs Oral - Pre-operative for pediatric patients - Oral agents to sedate the patient before placing intravenous lines
	therapeutic monitoring for anesthesia	End tidal anesthetic concentration Bispectral index Level of sedation - Richmond agitation and sedation scale - Ramsey’s scale Level of paralysis - Train of four --> ex. 4/4 is not paralyzed, 2-3/4 is ideal paralyzed state; you do not want complete paralysis 0/4
	Monitoring Toxic Effects of Anesthesia	Vital signs - Blood pressure (low), heart rate and rhythm, temperature (hyperthermia), oxygen saturation (decrease) Laboratory - Blood gas arterial - Blood gas venous - Ex) pH; maintaining CO2 causing acidosis of blood
	Agents Used for General Anesthesia
	barbituates used for gen anesthesia
	opiods used for general anesthesia
	benzodiazapenes used for gen anesthesia
	Inhalation Anesthetics	- Dentist TG Morton was consulted to administer the first anesthetic for surgery in 1846 - Ether was used routinely until through the 1920s - Halogenated gases appeared in the 1950s
	Mechanisms of Action for inhalation anesthetics	1) Blocking N-methyl D-aspartate (NMDA) receptors to decrease binding and action of glutamate, the main excitatory neurotransmitter 2) Agonist for Glycine and Blocking Nicotinic acetylcholine receptors to reduce the response to noxious stimuli
	Mechanisms of Action for inhalation anesthetics	Two-pore-domain K+ channels in the neuronal cell membrane can be disrupted leading to impaired transmission Potentiation of GABAA Enhance inhibitory effects and decrease neuronal transmission
	MAC	minimum alveolar concentration needed to produce anesthesia in 50% of surgical patients
	Blood:gas	ratio of concentration in blood to that in inhaled gas, the lower the number the quicker equilibrium is reached. Poor solubility in blood allows less anesthetic to be removed from the sight of action to other tissues.
	Induction	Induction - the act of producing a state of anesthesia Maintenance - ongoing provision of anesthesia Recovery - loss of anesthetic state and return to normal function
	Recovery	Induction - the act of producing a state of anesthesia Maintenance - ongoing provision of anesthesia Recovery - loss of anesthetic state and return to normal function
	Maintenance	Induction - the act of producing a state of anesthesia Maintenance - ongoing provision of anesthesia Recovery - loss of anesthetic state and return to normal function
	Ether	Produces a state of amnesia, analgesia, immobility, and sedation Due to a high blood:gas concentration it takes long to induce and recover from anesthesia A flammable, explosive, and irritating liquid --> Not safe Strong odor - Induces airway secretions due to irritation --> Risk of aspiration inhibition - Potent emetic properties --> Not desirable recovery
	why does it take a long time to recover from ether?	Produces a state of amnesia, analgesia, immobility, and sedation Due to a high blood:gas concentration it takes long to induce and recover from anesthesia A flammable, explosive, and irritating liquid --> Not safe Strong odor - Induces airway secretions due to irritation --> Risk of aspiration inhibition - Potent emetic properties --> Not desirable recovery
	Nitrous Oxide	Produces sedation and analgesia (at subanesthetic dose) - NMDA receptor antagonism and hyperpolarization of neurons via activation of two-pore-domain K+ channels - Concentrations between 20-50% - still induce desirable effect for relatively less invasive procedures Poor solubility in blood and other tissues leads to quick equilibration - Rapid induction and rapid emergence Low potency leads to little utility as a sole anesthetic - Can be combined with other gases to quicken induction - MAC of 105% --> Minimum alveolar concentration higher than 100% to produce anesthesia in 50% of population --> Only way to reach this level is to put patient in a hyperbaric chamber = Not ideal
	why does nitrous oxide equilibrate quickly?	Produces sedation and analgesia (at subanesthetic dose) - NMDA receptor antagonism and hyperpolarization of neurons via activation of two-pore-domain K+ channels - Concentrations between 20-50% - still induce desirable effect for relatively less invasive procedures Poor solubility in blood and other tissues leads to quick equilibration - Rapid induction and rapid emergence Low potency leads to little utility as a sole anesthetic - Can be combined with other gases to quicken induction - MAC of 105% --> Minimum alveolar concentration higher than 100% to produce anesthesia in 50% of population --> Only way to reach this level is to put patient in a hyperbaric chamber = Not ideal
	main utility of Nitrous Oxide	Main utility is in outpatient dental procedures - Analgesia and Sedation rather than Anesthesia Adverse effects (only in Anesthesia does) - Augmented by co-administered anesthetics --> Since NO itself is not for general anesthetic - Increased pulmonary and peripheral vascular resistance - Will displace N2 in air-filled areas in the body and can worsen states such as air embolus, pneumothorax, intracranial or intraocular air, etc. --> Expanding with NO kicking in - Concentrations cannot exceed 80% without risk of hypoxia --> Remember NO requires 105% in order to reach GA effect = therefore it is not ideal General Anesthesia agent
	adverse effects of Nitrous Oxide	Main utility is in outpatient dental procedures - Analgesia and Sedation rather than Anesthesia Adverse effects (only in Anesthesia does) - Augmented by co-administered anesthetics --> Since NO itself is not for general anesthetic - Increased pulmonary and peripheral vascular resistance - Will displace N2 in air-filled areas in the body and can worsen states such as air embolus, pneumothorax, intracranial or intraocular air, etc. --> Expanding with NO kicking in - Concentrations cannot exceed 80% without risk of hypoxia --> Remember NO requires 105% in order to reach GA effect = therefore it is not ideal General Anesthesia agent
	Halogenated Gases	Share similar mechanisms of action Generally produce anesthesia, amnesia, analgesia, and immobility Differ in MAC, blood:gas, and side effect profiles - Different rates of induction and recovery All can be combined with nitrous oxide to facilitate quicker induction
	Halothane	Slow induction and slow recovery, high blood:gas and high fat solubility - Even after exhaling all, ones that dissolved in adipose tissue must eliminated = Longer time of recovery Some metabolism by the liver, may cause oxidative stress and potential hepatic necrosis Lowest cost of halogenated gases Cardiac effects - Direct myocardial depressant --> Predictable decrease in arterial blood pressure of 20-25 mmHg --> Not due to decrease peripheral resistance as others --> Not ideal for patient with cardiac problems - Decreases auto-regulation in end organs, decreased perfusion to gut, liver, and kidneys (and subsequently other end organs) Bronchodilator - May be used in resistant status asthmaticus (especially pediatrics – their cardiac function is usually healthy and not at risk)
	Isoflurane	Low blood:gas, quick induction and quick reversal of anesthesia - Due to pungent odor rarely used for induction but can be used for maintenance Cardiac effects - Decreased systemic vascular resistance leading to decreased blood pressure (unlike halothane; direct effect caused) --> But this does not last long; transient effect - Dilation of coronary and cerebral vessels --> Preferable to those with decreased coronary perfusion - Decreased perfusion of kidneys and liver with minimal adverse effects - Increased heart rate due to sympathetic stimulation --> Not preferable to those cardiac problem Respiratory (problem with most of the halogenated agents) Decreases normal response to hypercarbia and hypoxia - Decreases ventilation, concentration-dependant --> Monitoring is important due to this; risk of acidosis, hypoxia, etc May be preferred in cardiac or neurosurgery - Since it increases perfusion rate
	cardiac effects of isoflurane	Low blood:gas, quick induction and quick reversal of anesthesia - Due to pungent odor rarely used for induction but can be used for maintenance Cardiac effects - Decreased systemic vascular resistance leading to decreased blood pressure (unlike halothane; direct effect caused) --> But this does not last long; transient effect - Dilation of coronary and cerebral vessels --> Preferable to those with decreased coronary perfusion - Decreased perfusion of kidneys and liver with minimal adverse effects - Increased heart rate due to sympathetic stimulation --> Not preferable to those cardiac problem Respiratory (problem with most of the halogenated agents) Decreases normal response to hypercarbia and hypoxia - Decreases ventilation, concentration-dependant --> Monitoring is important due to this; risk of acidosis, hypoxia, etc May be preferred in cardiac or neurosurgery - Since it increases perfusion rate
	respiratory problem with isoflurane	Low blood:gas, quick induction and quick reversal of anesthesia - Due to pungent odor rarely used for induction but can be used for maintenance Cardiac effects - Decreased systemic vascular resistance leading to decreased blood pressure (unlike halothane; direct effect caused) --> But this does not last long; transient effect - Dilation of coronary and cerebral vessels --> Preferable to those with decreased coronary perfusion - Decreased perfusion of kidneys and liver with minimal adverse effects - Increased heart rate due to sympathetic stimulation --> Not preferable to those cardiac problem Respiratory (problem with most of the halogenated agents) Decreases normal response to hypercarbia and hypoxia - Decreases ventilation, concentration-dependant --> Monitoring is important due to this; risk of acidosis, hypoxia, etc May be preferred in cardiac or neurosurgery - Since it increases perfusion rate
	inductibility of halothane	Slow induction and slow recovery, high blood:gas and high fat solubility - Even after exhaling all, ones that dissolved in adipose tissue must eliminated = Longer time of recovery Some metabolism by the liver, may cause oxidative stress and potential hepatic necrosis Lowest cost of halogenated gases Cardiac effects - Direct myocardial depressant --> Predictable decrease in arterial blood pressure of 20-25 mmHg --> Not due to decrease peripheral resistance as others --> Not ideal for patient with cardiac problems - Decreases auto-regulation in end organs, decreased perfusion to gut, liver, and kidneys (and subsequently other end organs) Bronchodilator - May be used in resistant status asthmaticus (especially pediatrics – their cardiac function is usually healthy and not at risk)
	cardiac effects of halothane	Slow induction and slow recovery, high blood:gas and high fat solubility - Even after exhaling all, ones that dissolved in adipose tissue must eliminated = Longer time of recovery Some metabolism by the liver, may cause oxidative stress and potential hepatic necrosis Lowest cost of halogenated gases Cardiac effects - Direct myocardial depressant --> Predictable decrease in arterial blood pressure of 20-25 mmHg --> Not due to decrease peripheral resistance as others --> Not ideal for patient with cardiac problems - Decreases auto-regulation in end organs, decreased perfusion to gut, liver, and kidneys (and subsequently other end organs) Bronchodilator - May be used in resistant status asthmaticus (especially pediatrics – their cardiac function is usually healthy and not at risk)
	Desflurane	Very rapid induction and recovery Low concentrations in blood or tissues - Irritating to airway so not often used for induction - Does not have redistribution effect Cardiac effects - Decreased blood pressure due to decreased systemic vascular resistance - Does not subside with duration of anesthesia (unlike isoflurane) - Increased heart rate due to sympathetic stimulation Respiratory effects - Decreased ventilation, increased carbon dioxide retention, potential laryngospasm (due to irritating effect) Other effects - No effects on kidney or liver function
	induction of desflurane	Very rapid induction and recovery Low concentrations in blood or tissues - Irritating to airway so not often used for induction - Does not have redistribution effect Cardiac effects - Decreased blood pressure due to decreased systemic vascular resistance - Does not subside with duration of anesthesia (unlike isoflurane) - Increased heart rate due to sympathetic stimulation Respiratory effects - Decreased ventilation, increased carbon dioxide retention, potential laryngospasm (due to irritating effect) Other effects - No effects on kidney or liver function
	difference between desflurane & isoflurane	Desflurane, have cardiac effects that DO NOT SUBSIDE with duration of anesthesia, unlike isoflurane
	Sevoflurane	Rapid induction and rapid recovery from anesthesia Some metabolism by the liver - No hepatotoxicity though Some interaction with carbon dioxide absorber soda lime - Produces compound A which is speculated to increase nephrotoxicity (need to monitored) Cardiac effects - Decreased blood pressure due to decreased systemic vascular resistance - Does NOT increase heart rate (no sympathetic response) --> Preferable with cardiac patients with arrythmia Respiratory effects - Decreased ventilation - Bronchodilation (most potent of all halogenated gases) and not irritating so suitable for induction
	Which is the most potent of all halogenated gases ?	Sevoflurane !!! Rapid induction and rapid recovery from anesthesia Some metabolism by the liver - No hepatotoxicity though Some interaction with carbon dioxide absorber soda lime - Produces compound A which is speculated to increase nephrotoxicity (need to monitored) Cardiac effects - Decreased blood pressure due to decreased systemic vascular resistance - Does NOT increase heart rate (no sympathetic response) --> Preferable with cardiac patients with arrythmia Respiratory effects - Decreased ventilation - Bronchodilation (most potent of all halogenated gases) and not irritating so suitable for induction
	metabolism of sevoflurane	Rapid induction and rapid recovery from anesthesia Some metabolism by the liver - No hepatotoxicity though Some interaction with carbon dioxide absorber soda lime - Produces compound A which is speculated to increase nephrotoxicity (need to monitored) Cardiac effects - Decreased blood pressure due to decreased systemic vascular resistance - Does NOT increase heart rate (no sympathetic response) --> Preferable with cardiac patients with arrythmia Respiratory effects - Decreased ventilation - Bronchodilation (most potent of all halogenated gases) and not irritating so suitable for induction
	compound A	Sevoflurane !!! Rapid induction and rapid recovery from anesthesia Some metabolism by the liver - No hepatotoxicity though Some interaction with carbon dioxide absorber soda lime - Produces compound A which is speculated to increase nephrotoxicity (need to monitored) Cardiac effects - Decreased blood pressure due to decreased systemic vascular resistance - Does NOT increase heart rate (no sympathetic response) --> Preferable with cardiac patients with arrythmia Respiratory effects - Decreased ventilation - Bronchodilation (most potent of all halogenated gases) and not irritating so suitable for induction
	when is sevoflurane preferable to use?	Rapid induction and rapid recovery from anesthesia Some metabolism by the liver - No hepatotoxicity though Some interaction with carbon dioxide absorber soda lime - Produces compound A which is speculated to increase nephrotoxicity (need to monitored) Cardiac effects - Decreased blood pressure due to decreased systemic vascular resistance - Does NOT increase heart rate (no sympathetic response) --> Preferable with cardiac patients with arrythmia Respiratory effects - Decreased ventilation - Bronchodilation (most potent of all halogenated gases) and not irritating so suitable for induction
	Comparison of Inhalation Anesthetics
		Comparison of Inhalation Anesthetics
	highest MAC among inhalation anesthetics	Nitrous oxide --> desflurane also pretty high though
	highest blood_gas ratio among inhalation ansthetics	halothane
	respiratory problems with inhalation anesthetics
	cardiac problems with inhalation anesthetics
	CNS problems with inhalation anesthetics
	which inhalation anesthetic causes myocardial depression as a side effect?	Halothane
	which inhalation anesthetic causes increased pulmonary pressure?
	which inhalation anesthetic(s) causes depressed EEG?
	which inhalation anesthetic(s) D NOT cause depressed EEG?	nitrous oxide
	which inhalation anesthetic(s) provide muscle relaxation?	desflurane & isoflurane
	which inhalation anesthetic(s) is associated with hepatic toxicty?	halothane
	Malignant Hyperthermia	Can be induced by all halogenated gases - Due to genetic predisposition - Can also be induced by non-depolarizing neuromuscular blockers (ex. Succinylcholine) A condition of severe muscle contraction that is fatal if left untreated - Hyper-metabolic state that depletes adenosine triphosphate (ATP) Discontinuation of the anesthetic and administration of dantrolene are the life-saving treatments - Dantrolene – decrease Calcium release inhibiting contraction
	dantrolene	Malignant Hyperthermia can be induced by all halogenated gases - Due to genetic predisposition - Can also be induced by non-depolarizing neuromuscular blockers (ex. Succinylcholine) A condition of severe muscle contraction that is fatal if left untreated - Hyper-metabolic state that depletes adenosine triphosphate (ATP) Discontinuation of the anesthetic and administration of dantrolene are the life-saving treatments - Dantrolene – decrease Calcium release inhibiting contraction
	treatment to malignant hyperthermia	Can be induced by all halogenated gases - Due to genetic predisposition - Can also be induced by non-depolarizing neuromuscular blockers (ex. Succinylcholine) A condition of severe muscle contraction that is fatal if left untreated - Hyper-metabolic state that depletes adenosine triphosphate (ATP) Discontinuation of the anesthetic and administration of dantrolene are the life-saving treatments - Dantrolene – decrease Calcium release inhibiting contraction
	Intravenous Anesthetics	Given in conjunction with inhaled agents Can be given without inhalation agents Used for moderate sedation - Endotracheal intubation not necessary - Not as high monitoring required as inhalation anesthesia Used to facilitate one or more desired outcomes of anesthesia - Analgesia, amnesia, sedation, or immobility May be given in place of inhalation anesthetics in high risk patients or for induction
	Barbiturates (in terms of GA)	Work on a GABA receptor and potentiate the inhibitory effects of GABA (All the agents have different binding sites = not competitive binding)
	Thiopental	barbituate... for induction ONLY.. and NOT for continuous infusion !!!! Anesthetic effect in 30 seconds, lasting 5-8 minutes Duration of action increases with prolonged use - Can accumulate when given by continuous infusion (not recommended) - Half-life about 11 hours (long) --> Not exhaled out but only hepatic and renal metabolic elimination Use limited to induction - May cause transient hypotension and tachycardia Lethal injection
	Methohexital	barbituate... for induction ONLY.. and NOT for continuous infusion !!!! Similar onset and duration to thiopental Shorter half-life of 4 hours - Less risk of accumulation Injection site pain Potential for excitatory reactions - Hiccoughs, movements, seizures - Limits utility
	which barbituate is used in lethal injection?	Thiopental
	Thiopental vs. Methohexital	halflife of Thiopental is about 11 hours (long) methohexital Shorter half-life of 4 hours Less risk of accumulation
	Benzodiazepines
	benzodiazapenes
	diazepam
	midazolam
	lorazepam
	quickest onset for a benzodiazepine	diazepam
	longest duration for a benzodiazepin	lorazepam
	longest half-life for a benzodiazepine	diazepam
	which benzodiazepin is associated with toxicity?	lorazepam
	which benzodiazepine has a prolonged half-life in liver disease,
	Opioids (synthetic) for G.A. use	Not at risk for Respiratory depression (relatively from other opioids) -Because these are short acting agents No histamine release leads to favorable cardiovascular effects (hypotension and low BP) I DEAL for CONTINUOUS INFUSION Very appropriate analgesia
	shortest acting synthetic opioid used in GA	Remifentanil is the shortest acting and preferable for those with renal and hepatic impairment who cannot metabolize other options as quickly
	Propofol	The most commonly used IV anesthetic Formulated in a lipid emulsion that contains soy and egg - Allergy risk Rapid onset and short duration Potentiates GABA, NMDA antagonist
	most commonly usd IV anesthetic	Propofol Formulated in a lipid emulsion that contains soy and egg - Allergy risk Rapid onset and short duration Potentiates GABA, NMDA antagonist
	advantages of propofol	Quick onset and short duration - Re-dose possible and therefore easy to titrate Predictable patient response and pharmacokinetics - Not dependents on end organs Decreases intracranial pressure (Oxygen requirement) - Desired for neurosurgery Little to no post-operative nausea and vomiting Generally well tolerated
	disadvantages of propofol	Hypotension - Direct myocardial depressant - Decreased peripheral vascular resistance - Against Cardiac problem Apnea - Intubation is a must accompanying procedure that has to be present No analgesic properties - With opioids Allergies Lipid formulation - Hypertriglyceridemia - High risk of contamination Infusion syndrome - For children with prolong infusion
	Ketamine	NMDA receptor antagonist, opioid mu receptor Causes amnesia, analgesia, and catalepsy Disassociative anesthesia - Sympathetic stimulation - Increased peripheral and pulmonary vascular resistance --> Not for pulmonary hypertension - Increased heart rate - Can produce hallucinations (pre-medicate with benzodiazepine) No respiratory depression -Onset within 1 minute -Duration 10-15 minutes -Half-life about 2 hours -Most utility in children --> Less susceptible to hallucinogenic and emergence effects --> Or patients with conditions like hypotension who are not suitable candidate for other agents like propofol
	onset & duration of ketamine	NMDA receptor antagonist, opioid mu receptor Causes amnesia, analgesia, and catalepsy Disassociative anesthesia - Sympathetic stimulation - Increased peripheral and pulmonary vascular resistance --> Not for pulmonary hypertension - Increased heart rate - Can produce hallucinations (pre-medicate with benzodiazepine) No respiratory depression -Onset within 1 minute -Duration 10-15 minutes -Half-life about 2 hours -Most utility in children --> Less susceptible to hallucinogenic and emergence effects --> Or patients with conditions like hypotension who are not suitable candidate for other agents like propofol
	utility of ketamine	NMDA receptor antagonist, opioid mu receptor Causes amnesia, analgesia, and catalepsy Disassociative anesthesia - Sympathetic stimulation - Increased peripheral and pulmonary vascular resistance --> Not for pulmonary hypertension - Increased heart rate - Can produce hallucinations (pre-medicate with benzodiazepine) No respiratory depression -Onset within 1 minute -Duration 10-15 minutes -Half-life about 2 hours -Most utility in children --> Less susceptible to hallucinogenic and emergence effects --> Or patients with conditions like hypotension who are not suitable candidate for other agents like propofol
	how is ketamine uniique?	Ketamine is different in that Disassociative Anesthesis can cause hypertention, and tachycardia in contrast with other agents with hypotension, etc
	Etomidate	- Modulation of GABA - Quick onset and short duration Adrenal insufficiency through prolonged infusion - May be observed after a single dose Well tolerated and a preferred agent for induction or intubation - Little respiratory depression - Favorable cardiac effects
	problem with etomidate	- Modulation of GABA - Quick onset and short duration Adrenal insufficiency through prolonged infusion - May be observed after a single dose Well tolerated and a preferred agent for induction or intubation - Little respiratory depression - Favorable cardiac effects
	preferred agent for intubatio	- Modulation of GABA - Quick onset and short duration Adrenal insufficiency through prolonged infusion - May be observed after a single dose Well tolerated and a preferred agent for induction or intubation - Little respiratory depression - Favorable cardiac effects
	Dexmedetomidine	Central alpha 2 receptor agonist - Specific for the alpha 2a receptor producing more sedation than cardiovascular effects - Decreased norepinephrine release from central nervous system Sedation with ease of wakening with stimulation - Not intended for deep sedation No respiratory depression - Not ideal within operating room but during recovery stage without monitoring setting Bradycardia and hypotension are most common side effects Structurally related to etomidate, questionable potential for adrenal suppression but not reported clinically
	Dexmedetomidine is an agonist of what receptor	Central alpha 2 receptor agonist - Specific for the alpha 2a receptor producing more sedation than cardiovascular effects - Decreased norepinephrine release from central nervous system Sedation with ease of wakening with stimulation - Not intended for deep sedation No respiratory depression - Not ideal within operating room but during recovery stage without monitoring setting Bradycardia and hypotension are most common side effects Structurally related to etomidate, questionable potential for adrenal suppression but not reported clinically
	side effects of Dexmedetomidine	Central alpha 2 receptor agonist - Specific for the alpha 2a receptor producing more sedation than cardiovascular effects - Decreased norepinephrine release from central nervous system Sedation with ease of wakening with stimulation - Not intended for deep sedation No respiratory depression - Not ideal within operating room but during recovery stage without monitoring setting Bradycardia and hypotension are most common side effects Structurally related to etomidate, questionable potential for adrenal suppression but not reported clinically
	Adjunctive Agents --> Anti-emetics	Anti-emetics - Given peri-operatively to prevent post-operative nausea and vomiting Anti-inflammatory agents (control post-operative pain) - NSAIDS such as ketorolac - Acetaminophen Peripheral vasoconstrictors - To mitigate the peripheral vasodilation from anesthetics - And maintain adequate BP throughout Anti-histamines - Decrease histamine release from anesthetic agents - Augment sedation - Decrease anxiety Anti-muscarinic agents - Decrease respiratory secretions (ex. Desflurane) - Mitigate cardiovascular effects (prevent bradycardia) Neuromuscular blocking agents -To immobilize the patient - Adequate sedation and analgesia are necessary BEFORE administration --> What if you awake and cannot move? Higher risk of malignant hyperthermia if depolarizing agents used with halogenated gases --> Such as succinylcholine
	Adjunctive Agents --> Anti-inflammatory agents (control post-operative pain)	Anti-emetics - Given peri-operatively to prevent post-operative nausea and vomiting Anti-inflammatory agents (control post-operative pain) - NSAIDS such as ketorolac - Acetaminophen Peripheral vasoconstrictors - To mitigate the peripheral vasodilation from anesthetics - And maintain adequate BP throughout Anti-histamines - Decrease histamine release from anesthetic agents - Augment sedation - Decrease anxiety Anti-muscarinic agents - Decrease respiratory secretions (ex. Desflurane) - Mitigate cardiovascular effects (prevent bradycardia) Neuromuscular blocking agents -To immobilize the patient - Adequate sedation and analgesia are necessary BEFORE administration --> What if you awake and cannot move? Higher risk of malignant hyperthermia if depolarizing agents used with halogenated gases --> Such as succinylcholine
	Adjunctive Agents --> Peripheral vasoconstrictors	Anti-emetics - Given peri-operatively to prevent post-operative nausea and vomiting Anti-inflammatory agents (control post-operative pain) - NSAIDS such as ketorolac - Acetaminophen Peripheral vasoconstrictors - To mitigate the peripheral vasodilation from anesthetics - And maintain adequate BP throughout Anti-histamines - Decrease histamine release from anesthetic agents - Augment sedation - Decrease anxiety Anti-muscarinic agents - Decrease respiratory secretions (ex. Desflurane) - Mitigate cardiovascular effects (prevent bradycardia) Neuromuscular blocking agents -To immobilize the patient - Adequate sedation and analgesia are necessary BEFORE administration --> What if you awake and cannot move? Higher risk of malignant hyperthermia if depolarizing agents used with halogenated gases --> Such as succinylcholine
	Adjunctive Agents --> anti-histamines	Anti-emetics - Given peri-operatively to prevent post-operative nausea and vomiting Anti-inflammatory agents (control post-operative pain) - NSAIDS such as ketorolac - Acetaminophen Peripheral vasoconstrictors - To mitigate the peripheral vasodilation from anesthetics - And maintain adequate BP throughout Anti-histamines - Decrease histamine release from anesthetic agents - Augment sedation - Decrease anxiety Anti-muscarinic agents - Decrease respiratory secretions (ex. Desflurane) - Mitigate cardiovascular effects (prevent bradycardia) Neuromuscular blocking agents -To immobilize the patient - Adequate sedation and analgesia are necessary BEFORE administration --> What if you awake and cannot move? Higher risk of malignant hyperthermia if depolarizing agents used with halogenated gases --> Such as succinylcholine
	Adjunctive Agents --> Anti-muscarinic agents	Anti-emetics - Given peri-operatively to prevent post-operative nausea and vomiting Anti-inflammatory agents (control post-operative pain) - NSAIDS such as ketorolac - Acetaminophen Peripheral vasoconstrictors - To mitigate the peripheral vasodilation from anesthetics - And maintain adequate BP throughout Anti-histamines - Decrease histamine release from anesthetic agents - Augment sedation - Decrease anxiety Anti-muscarinic agents - Decrease respiratory secretions (ex. Desflurane) - Mitigate cardiovascular effects (prevent bradycardia) Neuromuscular blocking agents -To immobilize the patient - Adequate sedation and analgesia are necessary BEFORE administration --> What if you awake and cannot move? Higher risk of malignant hyperthermia if depolarizing agents used with halogenated gases --> Such as succinylcholine
	Adjunctive Agents --> Neuromuscular blocking agents	Anti-emetics - Given peri-operatively to prevent post-operative nausea and vomiting Anti-inflammatory agents (control post-operative pain) - NSAIDS such as ketorolac - Acetaminophen Peripheral vasoconstrictors - To mitigate the peripheral vasodilation from anesthetics - And maintain adequate BP throughout Anti-histamines - Decrease histamine release from anesthetic agents - Augment sedation - Decrease anxiety Anti-muscarinic agents - Decrease respiratory secretions (ex. Desflurane) - Mitigate cardiovascular effects (prevent bradycardia) Neuromuscular blocking agents -To immobilize the patient - Adequate sedation and analgesia are necessary BEFORE administration --> What if you awake and cannot move? Higher risk of malignant hyperthermia if depolarizing agents used with halogenated gases --> Such as succinylcholine
	The ideal anesthetic should produce	The ideal anesthetic should produce sedation, amnesia, analgesia, immobility, and quick recovery
		Steroids Hydrophobic molecules - therefore, they have to circulate in the plasma with a binding protein - small fraction of them will exist in soluble form (not with the binding protein) --> this form is what is capable of freely crossing the plasma membrane --> they also easily cross nuclear membrane to enter nucleus --> they bind to specific receptor (this receptor may be located in the cytoplasm. However, the ultimate end point is nucleus. Therefore, they all translocate to nucleus) --> upon binding, there is a conformation change --> ultimately this becomes a transcription factor --> interaction with steroid response element in the DNA -> transcription --> protein translation --> physiological effects Thyroid hormone behaves the same way their receptors are all in the same family - Vitamin D also behaves the same way
	precursor for ALL of the steroid hormones	Progesterone: precursor for ALL of the steroid hormones - not just sex steroids but also the aldosterone and cortisol - progestone has more carbon bonds than other steroid hormones
	what is a precursor for estradiol	testosterone
	how is estadiol structurally diffeent from testosterone?	Estradiol: aromatized ring (major difference from testosterone)
	Estrogens, Progestins and Related Drugs Drug List	PROTOTYPE DRUGS: -Estrogen - ethinyl estradiol -Mestranol -Progestin - levonorgestrel (L-norgestrel) -SERMs (Selective Estrogen Receptor Modulator) – clomiphene, tamoxifen, raloxifene -Aromatase inhibitor – letrozole -5-alpha-reductase inhibitor - finasteride -Androgen receptor antagonist - flutamide
	reproductive hormone signaling	Pituitary sends go signal to gonad Gonad makes germ cells and signals Gonad sends stop signal back to pituitary Gonad sends go signals to breast, uterus, bone, skin, etc Target organ such as breast goes in man or woman if signal is there
	describe production of FSH & LH	Hypothalamus produces GnRH, in a pulse frequency, which STIMULATES the production of FSH and LH from the pituitary
	what produces estradiol?	Granulosa cells in the ovaries produce estradiol, which feeds back to the brain, binds to estrogen receptors, and INHIBITS the production of GnRH which causes INHIBITION of FSH and LH (MORE FSH is inhibited than LH) *This is how oral contraceptives function --> INCREASED levels of estradiol INHIBIT FSH production --> NO follicle released
	what happens when estradiol is produced?	Granulosa cells in the ovaries produce estradiol, which feeds back to the brain, binds to estrogen receptors, and INHIBITS the production of GnRH which causes INHIBITION of FSH and LH (MORE FSH is inhibited than LH) *This is how oral contraceptives function --> INCREASED levels of estradiol INHIBIT FSH production --> NO follicle released
	basic premise of how contraceptives work	Granulosa cells in the ovaries produce estradiol, which feeds back to the brain, binds to estrogen receptors, and INHIBITS the production of GnRH which causes INHIBITION of FSH and LH (MORE FSH is inhibited than LH) *This is how oral contraceptives function --> INCREASED levels of estradiol INHIBIT FSH production --> NO follicle released
	what cells produce testosterone ?	Leydig cells (of testes) produce testosterone is converted to estradiol in the brain, which INHIBITS the GnRH produce
	FSH and LH are made where?	anterior pituitary
	what does progesterone do?	it inhibits LH greater than FSH (as opposed to estradiol, which inhibits more FSH than LH)
	when are there elevated levels of progesterone?	- During the luteal phase of the menstrual cycle, corpus luteum makes elevated levels of progesterone - This feeds back to the brain and acts on the progesterone receptor - GnRH pulse frequency shut down - Predominantly LH shut down, FSH minorly - also in progesterone contraceptives... and During pregnancy, placenta makes elevated levels of progesterone which ultimately results in the same effect
	During the luteal phase of the menstrual cycle, corpus luteum makes elevated levels of _______	- During the luteal phase of the menstrual cycle, corpus luteum makes elevated levels of progesterone - This feeds back to the brain and acts on the progesterone receptor - GnRH pulse frequency shut down - Predominantly LH shut down, FSH minorly
	progesterone contraceptives	progesterone contraceptives also act on the uterus: thickening of the cervical mucous and down-regulation of uterine progestrone receptor During pregnancy, placenta makes elevated levels of progesterone which ultimately results in the same effect
	Therapeutic Uses of Gonadotropins	Used in infertile men to promote spermatogenesis, in male children to stimulate Leydig cells to treat undescended testicles Used as adjunct in in vitro fertilization programs GnRH agonists-used to treat prostate cancer (Leuprolide) and menopausal syndromes
	Leuprolide	*Therapeutic Uses of Gonadotropins Used in infertile men to promote spermatogenesis, in male children to stimulate Leydig cells to treat undescended testicles Used as adjunct in in vitro fertilization programs GnRH agonists-used to treat prostate cancer (Leuprolide) and menopausal syndromes
	estrogens	Orally administered estrogens are among the most widely prescribed drugs For contraception Hormone replacement therapy
	Metabolism and Pharmacokinetics of estrogens	Principal naturally occurring estrogen is 17β-estradiol Formed from androstenedione or testosterone Produced primarily in ovaries and placenta Small amts. secreted from testes, adrenals, and fat
	Pharmacokinetics of estrogens	67% of circulating estrogens are bound to beta-globulin circulating estradiol is converted to estrone (and estriol) mainly in the liver liver metabolism of natural estrogens involves conjugation with sulfonic acid and urinary excretion
	__% of circulating estrogens are bound to beta-globulin	67% of circulating estrogens are bound to beta-globulin circulating estradiol is converted to estrone (and estriol) mainly in the liver liver metabolism of natural estrogens involves conjugation with sulfonic acid and urinary excretion
	circulating estradiol is converted to estrone (and estriol) mainly in ____________	67% of circulating estrogens are bound to beta-globulin circulating estradiol is converted to estrone (and estriol) mainly in the liver liver metabolism of natural estrogens involves conjugation with sulfonic acid and urinary excretion
	how is estradiol metabolized?	67% of circulating estrogens are bound to beta-globulin circulating estradiol is converted to estrone (and estriol) mainly in the liver liver metabolism of natural estrogens involves conjugation with sulfonic acid and urinary excretion
	Effects of estrogen on women
		Effects of estrogen on women
	miscellaneous effects of estrogens	influences sexual drive causes edema (sodium and water retention) modulates sympathetic control of smooth muscles
	Therapeutic uses of estrogens	Besides 17β-estradiol, orally-active synthetic and non-steroidal estrogens are also used --> ethinyl estradiol (synthetic steroid) is most potent estrogen available --> mestranol
	Clinical Uses of estrogens	Hypogonadism With progestin to prevent endometrial carcinoma *Menopause; effective for osteoporosis Atrophic vaginitis, local therapy **Contraception-inhibit production of gonadotropins and GnRH thus preventing ovulation Less frequent - dysmenorrhea --> painful menstrual periods relieved by estrogen/progestin treatment
	MAJOR uses for estrogen	Hypogonadism With progestin to prevent endometrial carcinoma *Menopause; effective for osteoporosis Atrophic vaginitis, local therapy **Contraception-inhibit production of gonadotropins and GnRH thus preventing ovulation Less frequent - dysmenorrhea --> painful menstrual periods relieved by estrogen/progestin treatment
	Relief from menopause	Generally, small doses of conjugated estrogens or ethinyl estradiol are adequate Adverse effect: possible risk of endometrial cancer if only estrogen taken - in combination with a progestin reduces risk Decreases hot flashes Vaginal dryness Osteoporosis
	Advantages of hormone patch	**Transdermal route bypasses liver and gut Delivers continuous dose of estradiol Dose can be 1/10th of oral dose Patch does not raise level of C-reactive protein and may not have same risks for heart attack
	Combination Hormone Replacement Therapy for Menopause	Addition of Progestin to Equine Estrogen Mixture, Premarin, results in combination drug, PremPro Progestin added to suppress estrogen activity on the postmenopausal uterus Studies raise possibility of increased risk for breast cancer without improvement in cardiovascular health
	PremPro	Addition of Progestin to Equine Estrogen Mixture, Premarin, results in combination drug, PremPro Progestin added to suppress estrogen activity on the postmenopausal uterus Studies raise possibility of increased risk for breast cancer without improvement in cardiovascular health
	Adverse effects and toxicity of estrogens	Common effects - nausea - endometrial hyperplasia (during chronic unopposed therapy) --> Major concern for post-menopausal women - vaginal bleeding (esp. postmenopausal) - breast tenderness - weight gain (due to fluid retention)
	Other adverse effects and toxicities of estrogens	estrogens may cause or potentiate - hypertension - migraine headaches - hyperpigmentation - thromboembolic disease (clotting problem) - gall bladder disease - breast cancer
	Dental Implications of estrogen drugs	- gingivitis - predispose to gingival bleeding - gingival hyperplasia - increase radio-opacity of - greater risk of dry socket (alveolar osteitis) --> third molar extractions --> do surgery several days after last estrogen dose
	Contraindications to estrogen therapy	known or suspected pregnancy estrogen-dependent breast or uterine cancer undiagnosed abnormal genital bleeding history/active thrombophlebitis or thromboembolic disorders
	Therapeutic uses of progestins	most often used in conjunction with --postmenopausal symptoms -- oral contraception progesterone and hydroxyprogesterone caproate used to suppress ovarian function - stop uterine bleeding, dysmenorrhea - endometriosis; continuous application - hirsutism
	progestins are most often used in conjunction with_____	most often used in conjunction with --postmenopausal symptoms -- oral contraception progesterone and hydroxyprogesterone caproate used to suppress ovarian function - stop uterine bleeding, dysmenorrhea - endometriosis; continuous application - hirsutism
	Pharmacokinetics of synthetic progestins	orally active (bc hydrophobic) modified progesterones - hydroxyprogesterone caproate; - medroxyprogesterone acetate (MPA) norethindrone; norgestrel prolonged plasma half-lives - norethindrone (7 h); norgestrel (16 h); MPA (24 h)
	modified progesterones	orally active (bc hydrophobic) modified progesterones - hydroxyprogesterone caproate; - medroxyprogesterone acetate (MPA) norethindrone; norgestrel prolonged plasma half-lives - norethindrone (7 h); norgestrel (16 h); MPA (24 h)
	Toxicity of progestins	- increased blood pressure - reduced plasma HDL - weight gain - depression ***Opposite effect compared to estrogen - Estrogen stimulates HDL and decreases LDL - Progestin reduces plasma HDL, so they are not good in terms of lipid profile - They stimulate weight gain eventually leading to depression
	toxicity of estrogen vs. progesterone	- increased blood pressure - reduced plasma HDL - weight gain - depression ***Opposite effect compared to estrogen - Estrogen stimulates HDL and decreases LDL - Progestin reduces plasma HDL, so they are not good in terms of lipid profile - They stimulate weight gain eventually leading to depression
	Mechanism of contraception for combination preps	main mechanism of action is continuous negative feedback suppression of gonadotropins - molecular mechanism unclear - no midcycle surge of FSH and LH - follicles rarely develop; ovaries atrophy exogenous hormones affect endometrium --> “Pill”-small amount of synthetic estrogen - ethinyl estradiol or mestranol - together with a progestin - withdrawal bleeding upon discontinuation
	positive or negative feedback control loop for contraception ?	main mechanism of action is continuous negative feedback suppression of gonadotropins - molecular mechanism unclear - no midcycle surge of FSH and LH - follicles rarely develop; ovaries atrophy exogenous hormones affect endometrium --> “Pill”-small amount of synthetic estrogen - ethinyl estradiol or mestranol - together with a progestin - withdrawal bleeding upon discontinuation
	Minipill	This mode of contraception involves exposure to a continuous low dose of a progestin Ovulation is prevented 70-80% of the time Other mechanisms on tubular peristalsis and cervical mucus Considered >95% effective
	Safety of OCPs	Decrease risk of endometrial cancer because progestin component inhibits endometrial proliferation Risk of blood clot formation is increased (but small risk) except for women who smoke Women over 35 recommended not to take OCPs because of the risk of cardiovascular complications Breast Cancer –controversial, but OCP use per se is not associated with increased risk of developing breast cancer.
	cancer and oral contraceptives	Decrease risk of endometrial cancer because progestin component inhibits endometrial proliferation Risk of blood clot formation is increased (but small risk) except for women who smoke Women over 35 recommended not to take OCPs because of the risk of cardiovascular complications Breast Cancer –controversial, but OCP use per se is not associated with increased risk of developing breast cancer.
	cardiovascular and blood clots and oral contraceptives	Decrease risk of endometrial cancer because progestin component inhibits endometrial proliferation Risk of blood clot formation is increased (but small risk) except for women who smoke Women over 35 recommended not to take OCPs because of the risk of cardiovascular complications Breast Cancer –controversial, but OCP use per se is not associated with increased risk of developing breast cancer.
	Injected and implanted contraceptives	Lunelle - monthly injections - medroxyprogesterone acetate with estradiol cyprionate Depo-Provera - every 3 months - 150 mg medroxyprogesterone acetate may take up to a year after going off to get pregnant Norplant system - up to every 5 years -implanted silicone rubber capsules containing levonorgesterol - less effective in overweight women (<5 years)
	lunelle	Lunelle - monthly injections - medroxyprogesterone acetate with estradiol cyprionate Depo-Provera - every 3 months - 150 mg medroxyprogesterone acetate may take up to a year after going off to get pregnant Norplant system - up to every 5 years -implanted silicone rubber capsules containing levonorgesterol - less effective in overweight women (<5 years)
	depo-provera	Lunelle - monthly injections - medroxyprogesterone acetate with estradiol cyprionate Depo-Provera - every 3 months - 150 mg medroxyprogesterone acetate may take up to a year after going off to get pregnant Norplant system - up to every 5 years -implanted silicone rubber capsules containing levonorgesterol - less effective in overweight women (<5 years)
	norplant system	Lunelle - monthly injections - medroxyprogesterone acetate with estradiol cyprionate Depo-Provera - every 3 months - 150 mg medroxyprogesterone acetate may take up to a year after going off to get pregnant Norplant system - up to every 5 years -implanted silicone rubber capsules containing levonorgesterol - less effective in overweight women (<5 years)
	Drug interactions involving contraceptives	ampicillin & penicillin V & maybe other antibiotics more than 10-14 days ******decreases estrogenic activity possibly due to reduced enterohepatic circulation
	Contraindications of oral contraceptives	- thromboembolic disease - women over 35 years of age - obese, hypertensive, subject to migraines, or a cigarette smoker - liver disease - breast or genital cancer - young girls before epiphyseal closure - pregnancy - nursing mothers (minipill OK)
	Postcoital Contraceptives	“morning after pill” -Administration of 2 doses of estrogen alone or in combination with progestins within 72 hours after coitus will induce menstruation 99% of the time ---Preven® Plan B® - Progestin only (0.75 mg L-norgestrel) (1 pill, 2 doses 12 hr apart) Prevents ovulation Sperm penetration
	Selective Estrogen Receptor Modulators (SERMs)	clomiphene citrate - orally active non-steroidal anti-estrogen --> now classified as SERM -first-line drug for infertility treatment --> enhances gonadotropin secretion to cause ovulation --> antagonizes estrogen-induced feedback suppression of GnRH is a weak agonist in selected ER-containing tissues (hence SERM designation)
	clomiphene citrate	clomiphene citrate - orally active non-steroidal anti-estrogen --> now classified as SERM -first-line drug for infertility treatment --> enhances gonadotropin secretion to cause ovulation --> antagonizes estrogen-induced feedback suppression of GnRH is a weak agonist in selected ER-containing tissues (hence SERM designation)
	Side effects of clomiphene (a SERM)	- increased risk of ovarian hyperstimulation syndrome (OHSS) at higher doses - ovarian cyst formation - abdominal discomfort - abnormal uterine bleeding - ovarian enlargement  ovulation  increased level of estrogen - breast tenderness - blurring of vision
	Tamoxifen citrate	orally-active non-steroidal SERM used for palliative treatment of metastatic breast cancer in postmenopausal women with ER-positive tumors competitive ER antagonist in breast tissue, estrogen agonist in bone tissue, uterus and on lipid metabolism can induce ovulation like clomiphene adverse effects: hot flashes, uterine carcinomas, thromboembolic events
	adverse effects of Tamoxifen citrate	orally-active non-steroidal SERM used for palliative treatment of metastatic breast cancer in postmenopausal women with ER-positive tumors competitive ER antagonist in breast tissue, estrogen agonist in bone tissue, uterus and on lipid metabolism can induce ovulation like clomiphene adverse effects: hot flashes, uterine carcinomas, thromboembolic events
	used for palliative treatment of metastatic breast cancer in postmenopausal women with ER-positive tumors	Tamoxifen citrate orally-active non-steroidal SERM used for palliative treatment of metastatic breast cancer in postmenopausal women with ER-positive tumors competitive ER antagonist in breast tissue, estrogen agonist in bone tissue, uterus and on lipid metabolism can induce ovulation like clomiphene adverse effects: hot flashes, uterine carcinomas, thromboembolic events
	Raloxifene	orally-active non-steroidal SERM for treatment and prophylaxis of osteoporosis in postmenopausal women estrogen agonist in bone tissue and on lipid metabolism, but estrogen antagonist in uterine tissue prevention of invasive breast cancer adverse effects: hot flashes, abdominal pain, infertility, peripheral edema, teratogenesis, thromoembolism, weight gain
	adverse effects of Raloxifene	orally-active non-steroidal SERM for treatment and prophylaxis of osteoporosis in postmenopausal women estrogen agonist in bone tissue and on lipid metabolism, but estrogen antagonist in uterine tissue prevention of invasive breast cancer adverse effects: hot flashes, abdominal pain, infertility, peripheral edema, teratogenesis, thromoembolism, weight gain
	what is special about Raloxifene	Used for osteoporosis Estrogen agonist in bone and liver Estrogen antagonist in the uterus --> no problem regarding uterine cancer Estrogen antagonist in the breast --> prevents breast cancer Estrogen antagonist in the brain --> causes hot flashes
	Aromatase Inhibitors	Type I: steroidal, bind irreversibly e.g., Exemestane Type II: non-steroidal, bind reversibly e.g., Letrozole --> will inhibit locally synthesized estrogen as well a. Now a first line treatment for breast cancer b. Shown to improve disease-free survival after tamoxifen c. As effective as tamoxifen, but does not increase uterine cancer d. Side effects- hot flashes, joint pain, weakness, nausea, osteoporosis e. Contraindications- premenopausal, pregnant, breastfeeding, male
	First line treatment today for breast cancer	Aromatase Inhibitors Type I: steroidal, bind irreversibly e.g., Exemestane Type II: non-steroidal, bind reversibly e.g., Letrozole --> will inhibit locally synthesized estrogen as well a. Now a first line treatment for breast cancer b. Shown to improve disease-free survival after tamoxifen c. As effective as tamoxifen, but does not increase uterine cancer d. Side effects- hot flashes, joint pain, weakness, nausea, osteoporosis e. Contraindications- premenopausal, pregnant, breastfeeding, male
	for aromatases.... which type (1 or II) binds irreversibly?	Aromatase Inhibitors Type I: steroidal, bind irreversibly e.g., Exemestane Type II: non-steroidal, bind reversibly e.g., Letrozole --> will inhibit locally synthesized estrogen as well a. Now a first line treatment for breast cancer b. Shown to improve disease-free survival after tamoxifen c. As effective as tamoxifen, but does not increase uterine cancer d. Side effects- hot flashes, joint pain, weakness, nausea, osteoporosis e. Contraindications- premenopausal, pregnant, breastfeeding, male
	for aromatases.... which type (1 or II) binds reversibly?	Aromatase Inhibitors Type I: steroidal, bind irreversibly e.g., Exemestane Type II: non-steroidal, bind reversibly e.g., Letrozole --> will inhibit locally synthesized estrogen as well a. Now a first line treatment for breast cancer b. Shown to improve disease-free survival after tamoxifen c. As effective as tamoxifen, but does not increase uterine cancer d. Side effects- hot flashes, joint pain, weakness, nausea, osteoporosis e. Contraindications- premenopausal, pregnant, breastfeeding, male
	Danazol	a 17 alpha-alkyl testosterone derivative acts as a pure anti-estrogen to suppress ovarian function - inhibits midcycle LH/FSH surge major use is for endometriosis - also used for fibrocystic breast disease; idiopathic thrombocytopenia purpura adverse effects; - weight gain; edema; decreased breast size; hot flashes; headache; muscle cramps; increased hair growth; acne; deeper voice
	Anti-progestins	Mifepristone (RU486) - competitive progesterone receptor antagonist - used to terminate pregnancy - higher doses also inhibit glucocorticoid receptor binding (treat Cushing’s disease)
	Mifepristone (RU486)	Anti-progestins - competitive progesterone receptor antagonist - used to terminate pregnancy - higher doses also inhibit glucocorticoid receptor binding (treat Cushing’s disease)
	treat Cushing’s disease	Anti-progestins --> Mifepristone (RU486) - competitive progesterone receptor antagonist - used to terminate pregnancy - higher doses also inhibit glucocorticoid receptor binding (treat Cushing’s disease)
	Uses for Androgens (e.g., Testosterone, Oxandrolone )	Androgen replacement therapy Testicular hypofunction Anabolic effects-increase in muscle mass Carcinoma of the breast Treatment of anemias - testosterone stimulates RBC production
	Androgen Side Effects	Virilization Salt and water retention --> HTN Raise LDL and lower HDL cholesterol -->Problem for CVD Gynecomastia (bitch tits) Hepatic dysfunction (with methyl, ethyl group on C-17) Dilatation of biliary ducts Cholestasis Obstructive jaundice Hepatic adenoma
	Antiandrogens	Steroid synthesis Inhibitors - Ketoconazole (antifungal) – inhibits adrenal and gonadal steroid synthesis but not ovarian aromatase. Conversion of Steroid Precursors to Androgens - Finasteride – steroid like inhibitor of conversion of testosterone to dihydrotestosterone (5α-reductase) - Treatment of benign prostate hypertrophy (prostate cells are dependent on androgen stimulation for growth). - Also used in hair loss treatments Receptor Inhibitors - Competitive antagonists compete with dihydrotestosterone and testosterone for binding to the cytoplasmic receptor - Flutamide – used to treat metastatic prostate cancer and benign prostatic hypertrophy - Spironolactone – competitive inhibitor of aldosterone, also competes with dihydrotestosterone for androgen receptors.
	Antiandrogens --> Steroid synthesis Inhibitors	Steroid synthesis Inhibitors - Ketoconazole (antifungal) – inhibits adrenal and gonadal steroid synthesis but not ovarian aromatase. Conversion of Steroid Precursors to Androgens - Finasteride – steroid like inhibitor of conversion of testosterone to dihydrotestosterone (5α-reductase) - Treatment of benign prostate hypertrophy (prostate cells are dependent on androgen stimulation for growth). - Also used in hair loss treatments Receptor Inhibitors - Competitive antagonists compete with dihydrotestosterone and testosterone for binding to the cytoplasmic receptor - Flutamide – used to treat metastatic prostate cancer and benign prostatic hypertrophy - Spironolactone – competitive inhibitor of aldosterone, also competes with dihydrotestosterone for androgen receptors.
	Antiandrogens --> Conversion of Steroid Precursors to Androgens	Steroid synthesis Inhibitors - Ketoconazole (antifungal) – inhibits adrenal and gonadal steroid synthesis but not ovarian aromatase. Conversion of Steroid Precursors to Androgens - Finasteride – steroid like inhibitor of conversion of testosterone to dihydrotestosterone (5α-reductase) - Treatment of benign prostate hypertrophy (prostate cells are dependent on androgen stimulation for growth). - Also used in hair loss treatments Receptor Inhibitors - Competitive antagonists compete with dihydrotestosterone and testosterone for binding to the cytoplasmic receptor - Flutamide – used to treat metastatic prostate cancer and benign prostatic hypertrophy - Spironolactone – competitive inhibitor of aldosterone, also competes with dihydrotestosterone for androgen receptors.
	Antiandrogens --> Receptor Inhibitors	Steroid synthesis Inhibitors - Ketoconazole (antifungal) – inhibits adrenal and gonadal steroid synthesis but not ovarian aromatase. Conversion of Steroid Precursors to Androgens - Finasteride – steroid like inhibitor of conversion of testosterone to dihydrotestosterone (5α-reductase) - Treatment of benign prostate hypertrophy (prostate cells are dependent on androgen stimulation for growth). - Also used in hair loss treatments Receptor Inhibitors - Competitive antagonists compete with dihydrotestosterone and testosterone for binding to the cytoplasmic receptor - Flutamide – used to treat metastatic prostate cancer and benign prostatic hypertrophy - Spironolactone – competitive inhibitor of aldosterone, also competes with dihydrotestosterone for androgen receptors.
	Ketoconazole	Steroid synthesis Inhibitors - Ketoconazole (antifungal) – inhibits adrenal and gonadal steroid synthesis but not ovarian aromatase. Conversion of Steroid Precursors to Androgens - Finasteride – steroid like inhibitor of conversion of testosterone to dihydrotestosterone (5α-reductase) - Treatment of benign prostate hypertrophy (prostate cells are dependent on androgen stimulation for growth). - Also used in hair loss treatments Receptor Inhibitors - Competitive antagonists compete with dihydrotestosterone and testosterone for binding to the cytoplasmic receptor - Flutamide – used to treat metastatic prostate cancer and benign prostatic hypertrophy - Spironolactone – competitive inhibitor of aldosterone, also competes with dihydrotestosterone for androgen receptors.
	Finasteride	Steroid synthesis Inhibitors - Ketoconazole (antifungal) – inhibits adrenal and gonadal steroid synthesis but not ovarian aromatase. Conversion of Steroid Precursors to Androgens - Finasteride – steroid like inhibitor of conversion of testosterone to dihydrotestosterone (5α-reductase) - Treatment of benign prostate hypertrophy (prostate cells are dependent on androgen stimulation for growth). - Also used in hair loss treatments Receptor Inhibitors - Competitive antagonists compete with dihydrotestosterone and testosterone for binding to the cytoplasmic receptor - Flutamide – used to treat metastatic prostate cancer and benign prostatic hypertrophy - Spironolactone – competitive inhibitor of aldosterone, also competes with dihydrotestosterone for androgen receptors.
	Flutamide	Steroid synthesis Inhibitors - Ketoconazole (antifungal) – inhibits adrenal and gonadal steroid synthesis but not ovarian aromatase. Conversion of Steroid Precursors to Androgens - Finasteride – steroid like inhibitor of conversion of testosterone to dihydrotestosterone (5α-reductase) - Treatment of benign prostate hypertrophy (prostate cells are dependent on androgen stimulation for growth). - Also used in hair loss treatments Receptor Inhibitors - Competitive antagonists compete with dihydrotestosterone and testosterone for binding to the cytoplasmic receptor - Flutamide – used to treat metastatic prostate cancer and benign prostatic hypertrophy - Spironolactone – competitive inhibitor of aldosterone, also competes with dihydrotestosterone for androgen receptors.
	Spironolactone	Steroid synthesis Inhibitors - Ketoconazole (antifungal) – inhibits adrenal and gonadal steroid synthesis but not ovarian aromatase. Conversion of Steroid Precursors to Androgens - Finasteride – steroid like inhibitor of conversion of testosterone to dihydrotestosterone (5α-reductase) - Treatment of benign prostate hypertrophy (prostate cells are dependent on androgen stimulation for growth). - Also used in hair loss treatments Receptor Inhibitors - Competitive antagonists compete with dihydrotestosterone and testosterone for binding to the cytoplasmic receptor - Flutamide – used to treat metastatic prostate cancer and benign prostatic hypertrophy - Spironolactone – competitive inhibitor of aldosterone, also competes with dihydrotestosterone for androgen receptors.
	Anti-Inflammatory Corticosteroids	PROTOTYPE DRUGS: Hydrocortisone/Cortisol Prednisolone Triamcinolone Dexamethasone
	Biological Effects of Cortisol	In the liver, cortisol has anabolic effects and stimulates RNA, enzyme synthesis, gluconeogenesis and glycogen deposition. With extrahepatic (muscle, adipose, bone, lymphoid) tissues, its effects are catabolic (breakdown of proteins and fats) and it inhibits uptake and metabolism of glucose (‘anti-insulin’ effect) in adipose tissue and skin.
	effects of cortisol in the ilver	In the liver, cortisol has anabolic effects and stimulates RNA, enzyme synthesis, gluconeogenesis and glycogen deposition. With extrahepatic (muscle, adipose, bone, lymphoid) tissues, its effects are catabolic (breakdown of proteins and fats) and it inhibits uptake and metabolism of glucose (‘anti-insulin’ effect) in adipose tissue and skin.
	effects of cortisol outside the liver	In the liver, cortisol has anabolic effects and stimulates RNA, enzyme synthesis, gluconeogenesis and glycogen deposition. With extrahepatic (muscle, adipose, bone, lymphoid) tissues, its effects are catabolic (breakdown of proteins and fats) and it inhibits uptake and metabolism of glucose (‘anti-insulin’ effect) in adipose tissue and skin.
	Hematologic effects of cortisol	Hematologic effects: - decreases lymphocytes, basophils, and eosinophils - increases neutrophils - decreases phagocytosis by white cells Mesenchymal system: - alters connective tissue response to injury. --> decrease collagen synthesis - Excess cortisol results in thinning of skin and capillary walls.
	effects of cortisol onMesenchymal system	Hematologic effects: - decreases lymphocytes, basophils, and eosinophils - increases neutrophils - decreases phagocytosis by white cells Mesenchymal system: - alters connective tissue response to injury. --> decrease collagen synthesis - Excess cortisol results in thinning of skin and capillary walls.
	Anti-inflammatory and Immunosuppressive Actions of cortisol	inhibits phospholipase A2 a rate-limiting enzyme in prostaglandin, leukotriene, and thromboxane synthesis. Inhibits the immune response . High cortisol concentrations lower the number of circulating T cells and inhibit their ability to migrate to the site of antigenic stimulation.
	cortisol & immune response	inhibits phospholipase A2 a rate-limiting enzyme in prostaglandin, leukotriene, and thromboxane synthesis. Inhibits the immune response . High cortisol concentrations lower the number of circulating T cells and inhibit their ability to migrate to the site of antigenic stimulation.
	Uses of Glucocorticoids in Dentistry	Against unwanted inflammatory or immune reactions - Oral ulcerations - Pulpal hypersensitivity - TMJ disorders (type of arthritis) - Postoperative complications - Allergic reactions
	Adverse Effects of Glucocorticoids	Failure of wounds to heal - Due to decrease in collagen synthesis Fluid retention - Due to high levels acting on the corticoid receptor Osteoporosis (shutdown of osteoblast and osteoclast) Thinning of skin and connective tissues - Due to decrease in collagen synthesis Neurologic - A lot of sleep-cycle is regulated by glucocorticoids, so administering these drugs will have an effect Increased infections - Due to decreased in WBC’s Hypertension - Due to fluid retention Glucose intolerance
	Thyroid drug list	triodothyronine (T3) levothyroxine sodium (L-T4) iodide propylthiouracil methimazole
	Thyroid Hormones Regulate	Growth and development Temperature and oxygen consumption Metabolism of carbohydrate, protein, and lipid Anterior pituitary thyrotropin secretion (TSH)
		1. Iodide is concentrated in follicular epithelial cells after entry via a sodium iodide symporter, before 2. oxidation by thyroid peroxidase (TPO) in the peroxisome to iodine. 3. At the plasma membrane adjacent to the follicular lumen, conversion of tyrosyl (Y) residues on the surface of thyroglobulin to either mono-iodotyrosine (MIT) or di-iodotyrosine (DIT) occurs. 4. Coupling of iodinated tyrosines to form either T4 (DIT+DIT) or T3 (MIT+DIT) then occurs. 5. Thyroglobulin is endocytosed and 6. hydrolyzed in lysosomes to release free T3 and free T4. 7. The thyroid hormones are transported to the plasma membrane and released into the bloodstream by mechanisms which are not yet clear. **TSH influences virtually every step in thyroid hormone synthesis and release through the cAMP/protein kinase A pathway.
	biosynthesis of thyroid hormones	1. Iodide is concentrated in follicular epithelial cells after entry via a sodium iodide symporter, before 2. oxidation by thyroid peroxidase (TPO) in the peroxisome to iodine. 3. At the plasma membrane adjacent to the follicular lumen, conversion of tyrosyl (Y) residues on the surface of thyroglobulin to either mono-iodotyrosine (MIT) or di-iodotyrosine (DIT) occurs. 4. Coupling of iodinated tyrosines to form either T4 (DIT+DIT) or T3 (MIT+DIT) then occurs. 5. Thyroglobulin is endocytosed and 6. hydrolyzed in lysosomes to release free T3 and free T4. 7. The thyroid hormones are transported to the plasma membrane and released into the bloodstream by mechanisms which are not yet clear. **TSH influences virtually every step in thyroid hormone synthesis and release through the cAMP/protein kinase A pathway.
	in the biosynthesis of thyroid hormones.... which drugs block the transport of iodide into the cell	1. Iodide is concentrated in follicular epithelial cells after entry via a sodium iodide symporter, before 2. oxidation by thyroid peroxidase (TPO) in the peroxisome to iodine. 3. At the plasma membrane adjacent to the follicular lumen, conversion of tyrosyl (Y) residues on the surface of thyroglobulin to either mono-iodotyrosine (MIT) or di-iodotyrosine (DIT) occurs. 4. Coupling of iodinated tyrosines to form either T4 (DIT+DIT) or T3 (MIT+DIT) then occurs. 5. Thyroglobulin is endocytosed and 6. hydrolyzed in lysosomes to release free T3 and free T4. 7. The thyroid hormones are transported to the plasma membrane and released into the bloodstream by mechanisms which are not yet clear. **TSH influences virtually every step in thyroid hormone synthesis and release through the cAMP/protein kinase A pathway.
	in the biosynthesis of thyroid hormones.... which drugs block the conversion of tyrosyl (Y) residues on the surface of thyroglobulin to either mono-iodotyrosine (MIT) or di-iodotyrosine (DIT)	1. Iodide is concentrated in follicular epithelial cells after entry via a sodium iodide symporter, before 2. oxidation by thyroid peroxidase (TPO) in the peroxisome to iodine. 3. At the plasma membrane adjacent to the follicular lumen, conversion of tyrosyl (Y) residues on the surface of thyroglobulin to either mono-iodotyrosine (MIT) or di-iodotyrosine (DIT) occurs. 4. Coupling of iodinated tyrosines to form either T4 (DIT+DIT) or T3 (MIT+DIT) then occurs. 5. Thyroglobulin is endocytosed and 6. hydrolyzed in lysosomes to release free T3 and free T4. 7. The thyroid hormones are transported to the plasma membrane and released into the bloodstream by mechanisms which are not yet clear. **TSH influences virtually every step in thyroid hormone synthesis and release through the cAMP/protein kinase A pathway.
	in the biosynthesis of thyroid hormones.... which drugs block the hydrolysis of thyroglobulin to produce T3 and T4	1. Iodide is concentrated in follicular epithelial cells after entry via a sodium iodide symporter, before 2. oxidation by thyroid peroxidase (TPO) in the peroxisome to iodine. 3. At the plasma membrane adjacent to the follicular lumen, conversion of tyrosyl (Y) residues on the surface of thyroglobulin to either mono-iodotyrosine (MIT) or di-iodotyrosine (DIT) occurs. 4. Coupling of iodinated tyrosines to form either T4 (DIT+DIT) or T3 (MIT+DIT) then occurs. 5. Thyroglobulin is endocytosed and 6. hydrolyzed in lysosomes to release free T3 and free T4. 7. The thyroid hormones are transported to the plasma membrane and released into the bloodstream by mechanisms which are not yet clear. **TSH influences virtually every step in thyroid hormone synthesis and release through the cAMP/protein kinase A pathway.
	in the biosynthesis of thyroid hormones.... which drugs block the transformation of T4 into T3 in the peripheral tissues	1. Iodide is concentrated in follicular epithelial cells after entry via a sodium iodide symporter, before 2. oxidation by thyroid peroxidase (TPO) in the peroxisome to iodine. 3. At the plasma membrane adjacent to the follicular lumen, conversion of tyrosyl (Y) residues on the surface of thyroglobulin to either mono-iodotyrosine (MIT) or di-iodotyrosine (DIT) occurs. 4. Coupling of iodinated tyrosines to form either T4 (DIT+DIT) or T3 (MIT+DIT) then occurs. 5. Thyroglobulin is endocytosed and 6. hydrolyzed in lysosomes to release free T3 and free T4. 7. The thyroid hormones are transported to the plasma membrane and released into the bloodstream by mechanisms which are not yet clear. **TSH influences virtually every step in thyroid hormone synthesis and release through the cAMP/protein kinase A pathway.
	Primary pathway for peripheral metabolism of thyroxine is ______	Primary pathway for peripheral metabolism of thyroxine is deiodination. Deiodination of T4 may occur by monodeiodination of the outer ring, producing 3,5,3’-T3, which is 3-4 times more potent than T4. Alternatively, deiodination may occur in the inner ring, producing 3,3’,5’-triiodothyronine (rT3) which is metabolically inactive. Drugs such as ipodate, B-blockers, and corticosteroids, and severe illness or starvation inhibit the 5’-deiodinase necessary for the conversion of T4 to T3, resulting in low T3 and high rT3 levels in the serum.
	most active form of thyroxine is .....	Primary pathway for peripheral metabolism of thyroxine is deiodination. Deiodination of T4 may occur by monodeiodination of the outer ring, producing 3,5,3’-T3, which is 3-4 times more potent than T4. Alternatively, deiodination may occur in the inner ring, producing 3,3’,5’-triiodothyronine (rT3) which is metabolically inactive. Drugs such as ipodate, B-blockers, and corticosteroids, and severe illness or starvation inhibit the 5’-deiodinase necessary for the conversion of T4 to T3, resulting in low T3 and high rT3 levels in the serum.
	thalamic-pituitary-thyroid axis	Hypothalamic cells secrete thyrotropin-releasing hormone (TRH). TRH is secreted into capillaries of the pituitary portal venous system, and in the pituitary gland, TRH stimulates the synthesis and release of thyroid-stimulating hormone (TSH). TSH in turn stimulates an adenylyl cyclase-mediated mechanism in the thyroid cell to increase the synthesis and release of T4 and T3. These thyroid hormones act in a negative feedback manner in the pituitary to block the action of TRH and in the hypothalamus to inhibit the synthesis and secretion of TRH. Other hormones or drugs may also affect the release of TRH or TSH. There are also TSH-independent mechanisms to regulate uptake of iodide and thyroid hormone synthesis. - They are related to level of iodine in the blood. - Large doses of iodine inhibit iodide organification.
	what do large doses of iodine in the blood do	Hypothalamic cells secrete thyrotropin-releasing hormone (TRH). TRH is secreted into capillaries of the pituitary portal venous system, and in the pituitary gland, TRH stimulates the synthesis and release of thyroid-stimulating hormone (TSH). TSH in turn stimulates an adenylyl cyclase-mediated mechanism in the thyroid cell to increase the synthesis and release of T4 and T3. These thyroid hormones act in a negative feedback manner in the pituitary to block the action of TRH and in the hypothalamus to inhibit the synthesis and secretion of TRH. Other hormones or drugs may also affect the release of TRH or TSH. There are also TSH-independent mechanisms to regulate uptake of iodide and thyroid hormone synthesis. - They are related to level of iodine in the blood. - Large doses of iodine inhibit iodide organification.
	what do hypothalamic cells secrete?	Hypothalamic cells secrete thyrotropin-releasing hormone (TRH). TRH is secreted into capillaries of the pituitary portal venous system, and in the pituitary gland, TRH stimulates the synthesis and release of thyroid-stimulating hormone (TSH). TSH in turn stimulates an adenylyl cyclase-mediated mechanism in the thyroid cell to increase the synthesis and release of T4 and T3. These thyroid hormones act in a negative feedback manner in the pituitary to block the action of TRH and in the hypothalamus to inhibit the synthesis and secretion of TRH. Other hormones or drugs may also affect the release of TRH or TSH. There are also TSH-independent mechanisms to regulate uptake of iodide and thyroid hormone synthesis. - They are related to level of iodine in the blood. - Large doses of iodine inhibit iodide organification.
	what does thyrotropin-releasing hormone (TRH) stimulate?	Hypothalamic cells secrete thyrotropin-releasing hormone (TRH). TRH is secreted into capillaries of the pituitary portal venous system, and in the pituitary gland, TRH stimulates the synthesis and release of thyroid-stimulating hormone (TSH). TSH in turn stimulates an adenylyl cyclase-mediated mechanism in the thyroid cell to increase the synthesis and release of T4 and T3. These thyroid hormones act in a negative feedback manner in the pituitary to block the action of TRH and in the hypothalamus to inhibit the synthesis and secretion of TRH. Other hormones or drugs may also affect the release of TRH or TSH. There are also TSH-independent mechanisms to regulate uptake of iodide and thyroid hormone synthesis. - They are related to level of iodine in the blood. - Large doses of iodine inhibit iodide organification.
	Hypothyroidism	May result from variety of congenital disorders (with or without goiters) or iodine deficiency Hashimoto’s thyroiditis-most common cause in U.S.A. (chronic autoimmune) Characterized by decreased BMR, CO, fatigue, myxedema, lethargy, cold dry skin, etc.
	most common hypothyroidism in US	May result from variety of congenital disorders (with or without goiters) or iodine deficiency Hashimoto’s thyroiditis-most common cause in U.S.A. (chronic autoimmune) Characterized by decreased BMR, CO, fatigue, myxedema, lethargy, cold dry skin, etc.
	Levothyroxine	Hypothyroidism - Levothyroxine sodium (T4)-drug of choice. - L-T4 is given once daily because of long half life (goal: keep TSH in normal range) Steady state is achieved at 6-8 weeks. - Toxicity is directly related to T4 levels (nervousness, heart palpitations and tachycardia, intolerance to heat, and weight loss).
	drug of choice for hypothyroidism	Hypothyroidism - Levothyroxine sodium (T4)-drug of choice. - L-T4 is given once daily because of long half life (goal: keep TSH in normal range) Steady state is achieved at 6-8 weeks. - Toxicity is directly related to T4 levels (nervousness, heart palpitations and tachycardia, intolerance to heat, and weight loss).
	why is Levothyroxine given once daily ?	Hypothyroidism - Levothyroxine sodium (T4)-drug of choice. - L-T4 is given once daily because of long half life (goal: keep TSH in normal range) Steady state is achieved at 6-8 weeks. - Toxicity is directly related to T4 levels (nervousness, heart palpitations and tachycardia, intolerance to heat, and weight loss).
	how long until steadystate using Levothyroxine occurs?	Hypothyroidism - Levothyroxine sodium (T4)-drug of choice. - L-T4 is given once daily because of long half life (goal: keep TSH in normal range) Steady state is achieved at 6-8 weeks. - Toxicity is directly related to T4 levels (nervousness, heart palpitations and tachycardia, intolerance to heat, and weight loss).
	Pharmacokinetics of Levothyroxine	Both T4 and T3 are absorbed after oral administration. T4 is converted to T3 by one of two distinct deiodinases, depending on tissue. T3 binds to nuclear receptor Hormones metabolized via P450 Thus, drug-drug interactions occur with phenytoin, rifampin, carbamazepine In liver, deaminated, decarboxylated, glucuronidated In periphery, deiodinated
	how are hypothyroidism drugs processed in the liver?	Hormones metabolized via P450 In liver, deaminated, decarboxylated, glucuronidated In periphery, deiodinated
	how are hypothyroidism drugs processed in the periphery?	Hormones metabolized via P450 In liver, deaminated, decarboxylated, glucuronidated In periphery, deiodinated
	normal plasma levels of T3	Normal plasma levels of T3 =0.1-0.15 ug/100 ml T4 = 5-12 ug/100 ml Free hormone is biologically active; metabolized faster T1/2 of T4 = 7 days T1/2 of T3 = 2 days (4 X more potent)
	T4 is present in much higher concentration than T3 normally.... why ?	much more T4 is bound to the thyroxin binding globulin in the plasma Also, note that because free horome (not bound to plasma protein) is the active form, T3 gets metabolized faster than T4
	normal plasma levels of T4	Normal plasma levels of T3 =0.1-0.15 ug/100 ml T4 = 5-12 ug/100 ml Free hormone is biologically active; metabolized faster T1/2 of T4 = 7 days T1/2 of T3 = 2 days (4 X more potent)
	Patient with Grave’s Disease	- Antibody is made against the TSH receptor on the thyroid - Constant stimulation of TSH effect in the thyroid as a result - Whole thyroid grows because it is making way too much thyroid hormone - Exopthalmia  as a result of this autoimmune antibody - Excessive thyroid hormone - Tremor in the hands - Rapid relaxation of reflexes - Moist skin - Tachycardia - GI problem; diarrhea, weight loss, increased bowel motility
	- Antibody is made against the TSH receptor on the thyroid - Constant stimulation of TSH effect in the thyroid as a result - Whole thyroid grows because it is making way too much thyroid hormone - Exopthalmia  as a result of this autoimmune antibody - Excessive thyroid hormone - Tremor in the hands - Rapid relaxation of reflexes - Moist skin - Tachycardia - GI problem; diarrhea, weight loss, increased bowel motility	Patient with Grave’s Disease
	Hyperthyroidism	Excessive amounts of thyroid hormones in the circulation are associated with Graves’ disease, toxic adenoma, goiter, and thyroiditis. 2. Goal of treatment is to reduce synthesis and/or release of hormone. 3. Accomplished by removing part or all of thyroid gland, or by blocking release of hormones from the follicle.
	Hyperthyroidism	Inhibition of thyroid hormone synthesis: -by inactivating the peroxidase enzyme -blocks oxidative steps and condensation (aka organification)
	Anti-thyroid Drugs	Thioamides are well absorbed via the GI tract; short T1/2s. PTU blocks deiodinase in peripheral tissues; methimazole does not Effects are slow in onset and thus drugs don’t work for thyroid storm.
	PTU vs. methimazole ... Anti-thyroid Drugs	Thioamides are well absorbed via the GI tract; short T1/2s. PTU blocks deiodinase in peripheral tissues; methimazole does not Effects are slow in onset and thus drugs don’t work for thyroid storm.
	Adverse effects of Anti-thyroid Drugs	agranulocytosis (reversible) rash (most common) edema
	Blockade of Hormone Release	Iodide is not useful for long-term therapy Adverse effects: metallic taste in mouth, rashes, sore mouth
	Calcium and Bone Metabolism --> drug list	Calcium Vitamin D Teriparatide (PTH1-34) Bisphosphonates-Alendronate Denosumab Estrogens Raloxifene Calcitonin
	Calcium Levels, Turnover and Function	Plasma [Ca] maintained within narrow limits, normal concentration ~10 mg/dl or 2.5 mM. Ionized calcium (free calcium), 1.16 mM, biologically available.
	normal plasma levels of calcium	Plasma [Ca] maintained within narrow limits, normal concentration ~10 mg/dl or 2.5 mM. Ionized calcium (free calcium), 1.16 mM, biologically available.
	Recommended Daily Intake of Calcium	Teenagers require 1,300 mg per day (very high amount) but they are at a phase where they are growing, so they must intake high concentrations of calcium Normal adults should take 1,000 mg per day peak bone mass is not achieved until age of 26 in men Recommended dose is even higher for postmenopausal women, older men, and pregnant/lactating women
	Vitamin D comes from where?	- Vitamin D comes from conversion of cholesterol via UV - Hydroxylation in the 25’ position in the liver - Hydroxylation in the 1’ position in the kidney - 1,25 dihydroxy is the most potent form of vitamin D --> primary site of action is intestine to stimulate calcium uptake --> however, note that high levels can also stimulate bone breakdown
	what is the most potent form of vitamin D	- Vitamin D comes from conversion of cholesterol via UV - Hydroxylation in the 25’ position in the liver - Hydroxylation in the 1’ position in the kidney - 1,25 dihydroxy is the most potent form of vitamin D --> primary site of action is intestine to stimulate calcium uptake --> however, note that high levels can also stimulate bone breakdown
	describe the hydroxylation of vitamin D	- Vitamin D comes from conversion of cholesterol via UV - Hydroxylation in the 25’ position in the liver - Hydroxylation in the 1’ position in the kidney - 1,25 dihydroxy is the most potent form of vitamin D --> primary site of action is intestine to stimulate calcium uptake --> however, note that high levels can also stimulate bone breakdown
	PTH response to drop in calcium level	PTH has two sites of action 1) Kidney - immediate effect on kidney to stimulate calcium reabsorption - Stimulate 25’ hydroxy vitamin D3 to get hydoxylated to become dihydroxy form 2_ Bone - causes bone breakdown  calcium released Calcitonin is made by L cells of the thyroid gland - they respond to increase in the calcium level in bloodstream - acts in opposition to PTH to inhibit bone breakdown
	PTH in the kidney	PTH has two sites of action 1) Kidney - immediate effect on kidney to stimulate calcium reabsorption - Stimulate 25’ hydroxy vitamin D3 to get hydoxylated to become dihydroxy form 2_ Bone - causes bone breakdown  calcium released Calcitonin is made by L cells of the thyroid gland - they respond to increase in the calcium level in bloodstream - acts in opposition to PTH to inhibit bone breakdown
	PTH in the bone	PTH has two sites of action 1) Kidney - immediate effect on kidney to stimulate calcium reabsorption - Stimulate 25’ hydroxy vitamin D3 to get hydoxylated to become dihydroxy form 2_ Bone - causes bone breakdown  calcium released Calcitonin is made by L cells of the thyroid gland - they respond to increase in the calcium level in bloodstream - acts in opposition to PTH to inhibit bone breakdown
	Calcitonin is made by ____________	PTH has two sites of action 1) Kidney - immediate effect on kidney to stimulate calcium reabsorption - Stimulate 25’ hydroxy vitamin D3 to get hydoxylated to become dihydroxy form 2_ Bone - causes bone breakdown  calcium released Calcitonin is made by L cells of the thyroid gland - they respond to increase in the calcium level in bloodstream - acts in opposition to PTH to inhibit bone breakdown
	Synthesis pathway of Vitamin D	Cholesterol --> 7-dehydrocholesterol --> with UV, ring opens --> pre-vitamin D3 --> vitamin D3 --> further modifications via serial hydroxylations Kidney has another set of hydroxylase that act on the 24’ position to make 24,25-dihydroxy vitamin D - this is the degradation pathway - not much biological activity - activated when excessive amount of 1,25 dihydroxy form is being made Vitamin D2 is the plant form of vitamin D
	Actions of 1,25(OH)2 vitamin D3	Biological effects and mechanism of action: Acts in the same way as steroid hormones, via nuclear receptor. Intestine: -- promotes active Ca uptake and transport across intestinal cells. I -- ncreases amount of Ca channels, high affinity Ca- binding proteins and Ca pumps. ****1,25(OH)2D3 also increases intestinal Pi (inorganic phosphate) absorption via increasing the amount of the Na/Pi co-transporter.
	Actions of 1,25(OH)2 vitamin D3 on intestines	Biological effects and mechanism of action: Acts in the same way as steroid hormones, via nuclear receptor. Intestine: -- promotes active Ca uptake and transport across intestinal cells. I -- ncreases amount of Ca channels, high affinity Ca- binding proteins and Ca pumps. ****1,25(OH)2D3 also increases intestinal Pi (inorganic phosphate) absorption via increasing the amount of the Na/Pi co-transporter.
	Actions of 1,25(OH)2 vitamin D3 on intestinal organic phosphate	Biological effects and mechanism of action: Acts in the same way as steroid hormones, via nuclear receptor. Intestine: -- promotes active Ca uptake and transport across intestinal cells. I -- ncreases amount of Ca channels, high affinity Ca- binding proteins and Ca pumps. ****1,25(OH)2D3 also increases intestinal Pi (inorganic phosphate) absorption via increasing the amount of the Na/Pi co-transporter.
	Serum 25-Hydroxyvitamin D [25(OH)D] Concentrations and Health
	<10-11 ng/mL of vitamin D	Associated with vitamin D deficiency, leading to rickets in infants and children and osteomalacia in adults
	<10-15 ng/mL vitamin D	Generally considered inadequate for bone and overall health in healthy individuals
	≥15 ng/mL vitamin D	Generally considered adequate for bone and overall health in healthy individuals
	>200 ng/mL vitamin D	Considered potentially toxic, leading to hypercalcemia and hyperphosphatemia, although human data are limited.
	Adequate Intakes (AIs) for Vitamin D
	Parathyroid Hormone	Synthesized by 4 parathyroid glands located behind 2 lobes of thyroid gland Upon secretion, it is very rapidly turned over 84AA long.. but all of the biological activity is maintained in the first ~33 AA Short half-life: ~15 minutes
	where is PTH synthesized?	Synthesized by 4 parathyroid glands located behind 2 lobes of thyroid gland Upon secretion, it is very rapidly turned over 84AA long.. but all of the biological activity is maintained in the first ~33 AA Short half-life: ~15 minutes
	Actions of 1,25(OH)2 vitamin D3 on bone	- Physiological role is to stimulate resorption when the calcium level is below normal - They do it via acting directly on the osteoblast or osteoblast precursors in the bone marrow - PTH --> RANKL --> RANK/RANKL interaction --> osteroclast action --> bone breakdown PTH itself does NOT directly act on the gut (the action is via 1,25 dihydroxy vitamin D3) Negative feedback mechanism - increased level of 1,25 (OH)2 Vitamin D --> PTH synthesis/secretion inhibited - increased level of calcium --> PTH synthesis/secretion inhibited
	Hyperparathyroidism	1° hyperparathyroidism - Usually PT adenoma. - Treatment is normally surgical removal 2° hyperparathyroidism - Increased PTH secretion due to a 1° defect such as vitamin D deficiency or chronic renal failure. - The 1° cause must be treated.
	cause of primary Hyperparathyroidism	1° hyperparathyroidism - Usually PT adenoma. - Treatment is normally surgical removal 2° hyperparathyroidism - Increased PTH secretion due to a 1° defect such as vitamin D deficiency or chronic renal failure. - The 1° cause must be treated.
	cause of secondary Hyperparathyroidism	1° hyperparathyroidism - Usually PT adenoma. - Treatment is normally surgical removal 2° hyperparathyroidism - Increased PTH secretion due to a 1° defect such as vitamin D deficiency or chronic renal failure. - The 1° cause must be treated.
	Hypoparathyroidism	Usually due to accidental surgical removal of PT gland during thyroid surgery. Can result in hypocalcemia with neuromuscular excitability. Treatment is with i.v. calcium gluconate and vitamin D
	treatment for hypothyroidism	Usually due to accidental surgical removal of PT gland during thyroid surgery. Can result in hypocalcemia with neuromuscular excitability. Treatment is with i.v. calcium gluconate and vitamin D
	Vitamin D Deficiency	Rickets – children Osteomalacia – adults
	Vitamin D Genetic abnormalities	Genetic abnormalities e.g. mutation of the Vit D. receptor
	Osteoporosis	**too much cortisol loss of bone mass Postmenopausally, due to loss of estrogen Can also occur in men due to hypogonadism, and can also occur in Cushing’s and hyperthyroidism.
	characteristic features of osteoporosis	curvature of the spine, Dowager’s hump, and out-pouching of the abdomen
	PTH as Single Therapy inPostmenopausal Osteoporosis	PTH used to treat post-menopausal osteoporosis PTH is a peptide hormone, so it must be used as a daily injection hPTH administration (just the first 34 AA portion; biologically active)  significant increase in BMD hPTH administration (full length PTH)  good result for spine, but not for femur
	what kind of hormone is PTH?	PTH used to treat post-menopausal osteoporosis PTH is a peptide hormone, so it must be used as a daily injection hPTH administration (just the first 34 AA portion; biologically active)  significant increase in BMD hPTH administration (full length PTH)  good result for spine, but not for femur
	treating osteoporosis	Bisphosphonate is another option for treating osteoporosis --> Alendronate- N (been used the most)
	Alendronate- N\	Bisphosphonate is another option for treating osteoporosis --> Alendronate- N (been used the most)
	Adverse effects of Bisphosphonates	GI disturbances Osteonecrosis of the jaw Possible unusual femoral fractures
	Denosumab	- Treats osteoporosis Humanized monoclonal antibody to RANK ligand Injected twice per year Inhibits osteoclast differentiation and activation May have the same adverse effects on ONJ and skeletal fractures **Advantage that it has is that it can be used via injection
	Paget’s disease	this is a defect of increased osteoclast activity with major changes in bone remodeling. Treated with calcitonin.
	how do you treat paget's disease?	this is a defect of increased osteoclast activity with major changes in bone remodeling. Treated with calcitonin.
	Mental Illness	- 20% of the population - diagnosable mental disorder in their lifetime The more common types include: - Anxiety - Eating Disorders Impulse control and addiction disorders - Personality disorders - Psychotic disorders – Schizophrenia and Mood disorders
	Being a neurotransmitter: What does it take?	•  Exists presynaptically •  Synthesis enzymes exist presynaptically •  Released in response to action potential •  Postsynaptic membrane has receptors •  Application at synapse produces response •  Blockade of release stops synaptic function
	The classical neurotransmitters	Amines - Monoamines --> catecholamines (dopamine, noradrenaline) --> indoleamines (serotonin, melatonin) - Quaternary Amines Amino Acids (glutamate, GABA) --> glutamate = excitatory --> GABA = inhibitory
	quaternary amines	Amines - Monoamines --> catecholamines (dopamine, noradrenaline) --> indoleamines (serotonin, melatonin) - Quaternary Amines Amino Acids (glutamate, GABA) --> glutamate = excitatory --> GABA = inhibitory
	monoamines	Amines - Monoamines --> catecholamines (dopamine, noradrenaline) --> indoleamines (serotonin, melatonin) - Quaternary Amines Amino Acids (glutamate, GABA) --> glutamate = excitatory --> GABA = inhibitory
	Catecholamine synthesis	Tyrosine in the brain is converted to L-dopa by tyrosine hydroxylase (follow chart above)
		Catecholamine synthesis - Tyrosine in the brain is converted to L-dopa by tyrosine hydroxylase (follow chart above)
	Mesocorticolimbic system	Mesocorticolimbic system is the most impt sys in schizophrenia Starts in the ventral tegmental area in the midbrain This pathway connects to the striatum, nucleus accumbens, basal ganglia, amygdala  emotions, cognitions, motivation
	dopamine	neurotransmitter that helps control the brain reward and pleasure centers. A chemical released by a nerve cell to send signals to other nerve cells.
	Schematic representation of the Dopamine receptors in the human brain	We have 5 dopamine receptors D1-5 which are widely distributed in the brain D1 –D5 found in the cerebral cortex and the limbic system D3 and D5 are found in hypothalamus (produces hormones which control temperature, release of other hormones) and substantia nigra In schizo, D1 and D2 are the main receptors involved – still controversial as dx of schizo occurs post mortem
	for dopamine... D1-D5 receptors are found where?	We have 5 dopamine receptors D1-5 which are widely distributed in the brain D1 –D5 found in the cerebral cortex and the limbic system D3 and D5 are found in hypothalamus (produces hormones which control temperature, release of other hormones) and substantia nigra In schizo, D1 and D2 are the main receptors involved – still controversial as dx of schizo occurs post mortem
	for dopamine... D3 & D5 receptors are found where?	We have 5 dopamine receptors D1-5 which are widely distributed in the brain D1 –D5 found in the cerebral cortex and the limbic system D3 and D5 are found in hypothalamus (produces hormones which control temperature, release of other hormones) and substantia nigra In schizo, D1 and D2 are the main receptors involved – still controversial as dx of schizo occurs post mortem
	for dopamine... D1 & D2 receptors are found where?	We have 5 dopamine receptors D1-5 which are widely distributed in the brain D1 –D5 found in the cerebral cortex and the limbic system D3 and D5 are found in hypothalamus (produces hormones which control temperature, release of other hormones) and substantia nigra In schizo, D1 and D2 are the main receptors involved – still controversial as dx of schizo occurs post mortem
	Schizophrenia	ETIOLOGY and PATHOGENESIS – unknown Affects about 1/100 people; begins after 20 years old •  Often triggered by stress and illness, but there is also a genetic predisposition
	The dopamine theory of schizophrenia	it is caused by HYPERACTIVITY of central dopamine pathways --> based primarily on indirect pharmacologic evidence (Simple and attractive mechanism – clearly we are far from understanding the disease)
	Schizophrenia Positive Symptoms	Beliefs that have no basis in reality (delusions) Hearing, seeing, feeling, smelling, or tasting things that have no basis in reality (hallucinations) disorganized speech & behaviors catatonic behaviors
	delusions	Beliefs that have no basis in reality (delusions) Hearing, seeing, feeling, smelling, or tasting things that have no basis in reality (hallucinations) disorganized speech & behaviors catatonic behaviors
	hallucinations	Beliefs that have no basis in reality (delusions) Hearing, seeing, feeling, smelling, or tasting things that have no basis in reality (hallucinations) disorganized speech & behaviors catatonic behaviors
	Schizophrenia Negative Symptoms	interpersonal withdrawal, •  loss of drive, and restricted range of emotions **There is a disagreement regarding whether these symptoms represent different disease states or variable presentations of the same illness
		- Pts who have Parkinsons: nigrostriatal is affected  tremors
	major therapeutic targets for antpsychotics
	nigrostriatal	related to motor side effects of antipsychotics
	tuberoinfundibular	mediate side effects such as galactorrhea
	chemoreceptor trigger zone	mediate antiemetic actions
	medullary-pericentricular	appetite
	what is upregulated in the brain of schizo patients?	dopamine - D1 and D2 is upregulated in the brain in schizo pts
	major psychiatric disorders --> affective disorders --> depression and mania	Expressed as dysregulations of MOOD Most people have had reactive, or secondary depression with feelings and sadness or grief associated with a personal loss. In normal circumstances, such reactions are related to SPECIFIC CAUSES, are not incapacitating, and are generally SHORT LIVED (1-2 weeks) In contrast, for the mentally ill patient depression is a SEVERE, DISABLING disorder characterized by reclusiveness and non-verbalization that may last for EXTENDED periods of time (2-5 weeks)
	manic disorders	Persons with mania exhibit a DISTINCT PERIOD of abnormallyelevated, expansive, or irritable mood, sometimes requiringhospitalizations
	Three or more of the following symptoms also suggest a manic episode:	• Inﬂated self-esteem • Decreased need for sleep • Talkativeness • Flight of ideas •Distractibility •Increased goal-direct activity •Excessive interest in pleasure
	bipolar disorder	Manic individuals may also have alternating periods of severe depression, in which case the disorder may be referred to as BIPOLAR(manic- depressive) illness. --> Most common in 25% women –
	Three forms of bipolar disorder have been distinguished	• Bipolar I - involves cycles of mania and depression • Bipolar II - involves cycles of hypomania and depression • Bipolar III - mania associated with the use of antidepressants
	Bipolar I	Three forms of bipolar disorder have been distinguished: • Bipolar I - involves cycles of mania and depression • Bipolar II - involves cycles of hypomania and depression • Bipolar III - mania associated with the use of antidepressants
	Bipolar II	Three forms of bipolar disorder have been distinguished: • Bipolar I - involves cycles of mania and depression • Bipolar II - involves cycles of hypomania and depression • Bipolar III - mania associated with the use of antidepressants
	Bipolar III	Three forms of bipolar disorder have been distinguished: • Bipolar I - involves cycles of mania and depression • Bipolar II - involves cycles of hypomania and depression • Bipolar III - mania associated with the use of antidepressants
	Bipolar Disorder	Shares some characteristics with unipolar depression, there are several important differences treatment It has a stronger genetic involvement; is thought to have somewhat brain morphological structures change Treatment = aimed at the MANIC PHASE ﬁrst, which is treated with lithium salts and anticonvulsants
	difference between bipolar and unipolar disorders	Shares some characteristics with unipolar depression, there are several important differences treatment It has a stronger genetic involvement; is thought to have somewhat brain morphological structures change Treatment = aimed at the MANIC PHASE ﬁrst, which is treated with lithium salts and anticonvulsants
	treatment for bipolar disorder is aimed at which phase	Shares some characteristics with unipolar depression, there are several important differences treatment It has a stronger genetic involvement; is thought to have somewhat brain morphological structures change Treatment = aimed at the MANIC PHASE ﬁrst, which is treated with lithium salts and anticonvulsants
	which is thought to have e stronger genetic involvement... bipolar o unipolar manic disorders?	Shares some characteristics with unipolar depression, there are several important differences treatment It has a stronger genetic involvement; is thought to have somewhat brain morphological structures change Treatment = aimed at the MANIC PHASE ﬁrst, which is treated with lithium salts and anticonvulsants
	A characteristic of many antipsychotic drugs is interference with _____	A characteristic of many antipsychotic drugs is interference with MULTIPLE NEUROTRANSMITTER systems • These drugs have a number of side effects that can be relate to these multiple receptor actions
	therapeutic effect of blocked histamine receptor	sedation, anxiolysis (inhibits anxiety), antiallergic effect
	adverse effect of blocked histamine receptor	CNS depression, hypotension, dry mouth weight gain
	therapeutic effect of blocked muscarinic receptor	reduction of extrapyrimidal side effects
	adverse effect of blocked muscarinic receptor	dry mouth, blurred vision, sinus tachycadia, constipation , urinary retention, memory dysfunction
	therapeutic effect of blocking alpha-1-adrenergic adenoreceptor	antidepressant effect?>
	adverse effect of blocking alpha-1-adrenergic adenoreceptor	memory dysfunction, postural (irthostatic) hypotension, reflex tachycardia, epinephrine reversal, dry mouth, weight gain
	therapeutic effect of blocking alpha-2-adrenergic adenoreceptor	blockade of presynaptic autoregulation, increasing CNS 5 HT & NE
	adverse effect of blocking alpha-2-adrenergic adenoreceptor	priapism ( a potentially painful medical condition in which the erect penis does not return to its flaccid state)
	therapeutic effect of blocking dopamine (D2) adenoreceptor	amelioration of the positive signs and symptoms of psychosis
	adverse effect of blocking dopamine (D2) adenoreceptor	extrapyramidal movement disorders, sexual dysfunction, dry mouth, weight gain
	therapeutic effect of blocking 5-HT (serotonin) uptake	reversal of depression
	advers effect of blocking 5-HT (serotonin) uptake	GI disturbance , sexual dysfunction, activating effects, dry mouth
	therapeutic effect of blocking NE uptake	reversal of depression
	adverse effect of blocking NE uptake	dry mouth, urinary retention, erectile dysfunction, CNS stimulation, tremor, poconvulsant
	therapeutic effect of blocking dopamine reuptake	antidepressant effect
	adverse effect of blocking dopamine reuptake	psychomotor activation, psychosis, pre-convulsant action, dependence
	What medications are used to treat schizophrenia	Antipsychotic medications are used to treat schizophreniaand schizophrenia-related disorders. Some of these medications have been available since the mid-1950's. They are also called conventional "typical" Antipsychotics or “old school medications” •  Chlorpromazine (Thorazine) •  Haloperidol (Haldol) •  Perphenazine (generic only) •  Fluphenazine (generic only)
	Clozapine (Clozaril)	second generation or "atypical" antipsychotics Clozapine might cause a serious problems, such as agranulocytosis, which is a loss of the white blood cellsthat help a person ﬁght infection
	what serious problems may clozapine cause?	second generation or "atypical" antipsychotics Clozapine might cause a serious problems, such as agranulocytosis, which is a loss of the white blood cellsthat help a person ﬁght infection
	Antipsychotic Mechanism of action	- Function of neurons is by NT which interact with certain receptors - When drugs block dopamine receptors in basal ganglia, symptoms of schizo are reduced - Lot of dopamine receptors in substantia nigra - Action can be pre-or post synaptically, depending on location of receptors - People who use amphetamines also get hallucinations and have same behaviours as they stimulate basal ganglia - Amphetamines were once used to block apetite/reduce weight
	antipsychotic drugs --> Pharmacologic Effects - Sedative actions	Phenothiazines and related antipsychotics produce sedation on initial administration tolerance develops in 1-4 weeks making the t progressively alert as treatment continues --> sedation is the most commonly reported side effect of clozapine
	what is the most commonly reported side effect of clozapine?	Phenothiazines and related antipsychotics produce sedation on initial administration tolerance develops in 1-4 weeks making the t progressively alert as treatment continues --> sedation is the most commonly reported side effect of clozapine
	extrapyramidal effects of antipsychotics	INCLUDE: acute dystonias, a Parkinson like syndrome,akathisia, and tardive dyskinesia The different types of phenothiazines produce varying degrees of extrapyramidal side effects; in descendingorder of most to least potent are the piperazines, aliphatics, and piperidines ANTIPARKINSON drugs may be used to antagonize certain antipsychotic-induced motor disturbances
	what drugs may be used to antagonize certain antipsychotic-induced motor disturbances	INCLUDE: acute dystonias, a Parkinson like syndrome,akathisia, and tardive dyskinesia The different types of phenothiazines produce varying degrees of extrapyramidal side effects; in descendingorder of most to least potent are the piperazines, aliphatics, and piperidines ANTIPARKINSON drugs may be used to antagonize certain antipsychotic-induced motor disturbances
	Interactions of Antipsychotic Drugs with Other Drugs
	Interactions of Antipsychotic Drugs with benzodiazepines
	Interactions of Antipsychotic Drugs with anticholinergics
	Interactions of Antipsychotic Drugs with antihistamines
	Interactions of Antipsychotic Drugs with epinephrine
	Phenothiazines	antipsychotic Phenothiazines - antiemetics, preoperative mds to relax and calm the patient antihistamines, and antiheleminitcs
	antipsychotics --> “old school medications”	Antipsychotics, such as: phenothiazines, thioxanthenes, and butyrophenones were for decades the drugs of choice in the treatment of schizophrenia Olazapine, quetiapine, and possibly low doses of risperidone are now the preferred agents and are of particular use in cases of schizophrenia refractory to older antipsychotics or when administration of other antipsychotics results in unacceptable adverse effects
	preferred agents in schizophrenia	Antipsychotics, such as: phenothiazines, thioxanthenes, and butyrophenones were for decades the drugs of choice in the treatment of schizophrenia Olazapine, quetiapine, and possibly low doses of risperidone are now the preferred agents and are of particular use in cases of schizophrenia refractory to older antipsychotics or when administration of other antipsychotics results in unacceptable adverse effects
	Persons who require treatment antipsychotics usually take these drugs for how long?	Persons who require treatment antipsychotics usually take these drugs for a LONG PERIOD OF TIME, if not for life
	Prolonged phenothiazine use may lead to what	reduction in leukocyte count infection frequent oral CANDIDIASIS
	Clozapine-induced HYPERSALIVATION	problematic for some clinical procedures
	antimanics	Manic disorder or bipolar disorder presents as a unique diagnostic condition A genetic component is suspect Elevated concentrations of Ca2+ have been observed in brain cells, platelets and lymphocytes. Brain mitochondrial function and intracellular pH are decreased ... choline/creatine-phosphocheatine reactions are higher than normal, and phosphocreatine and N-acetylaspartate concentrations are decreased in speciﬁc brain regions
	describe findings in a manic patient	Manic disorder or bipolar disorder presents as a unique diagnostic condition A genetic component is suspect Elevated concentrations of Ca2+ have been observed in brain cells, platelets and lymphocytes. Brain mitochondrial function and intracellular pH are decreased ... choline/creatine-phosphocheatine reactions are higher than normal, and phosphocreatine and N-acetylaspartate concentrations are decreased in speciﬁc brain regions
	and phosphocreatine and N-acetylaspartate concentrations are (decreased/increased) in speciﬁc brain regions for manic patients	Manic disorder or bipolar disorder presents as a unique diagnostic condition A genetic component is suspect Elevated concentrations of Ca2+ have been observed in brain cells, platelets and lymphocytes. Brain mitochondrial function and intracellular pH are decreased ... choline/creatine-phosphocheatine reactions are higher than normal, and phosphocreatine and N-acetylaspartate concentrations are decreased in speciﬁc brain regions
	Lithium salts	Lithium salts are important for treating mania, but Lithium alone may be inadequate treatment for half of the patients exhibiting bipolar disorders •  Antipsychotic drugs are used in 85% of patients during initiation of therapy •  The mechanism of action of Lithium is not established •  Clinically, Lithium alleviates the manifestations of mania over a course of 1 to 2 weeks ****Sleep and appetite disturbances abate and swings in mood are prevented
	antimantics - adverse effects	lithium salts - GI irritation, ﬁne hand tremor, muscular weakness, polyuria, thirst, sleepiness, and a sluggish feeling - are often associated with initial therapy and usually fade within 1 to 2 weeks The therapeutic window for Lithium is low, and plasma liters of Lithium must be carefully monitored to ensure therapeutic effectiveness and avoid toxicity
	how do antipsychotics affect dental treatment?	NSAIDs may decrease the renal excretion of Lithium and lead to toxic plasma concentrations after several days of combined therapy *** Lithium+ Pilocarpine = seizures
	Primary parkinsons disease	Primary: or idiopathic form - typical late onset disorder with motor signs and a poorly understood cause - may have a genetic contribution Secondary: preceded by cerebral infections (syphilis, influenza) , toxic chemicals ( carbon monoxide, manganese, pesticides, welding-related foams), cerebral hypoxia (vascular defects) traumatic brain injury, or antipsychotic drugs Parkinson’s Plus: - groups of maladies in which the signs and symptoms of a Parkinson’s disease contributes to a larger disorder
	Secondary Primary parkinsons disease	Primary: or idiopathic form - typical late onset disorder with motor signs and a poorly understood cause - may have a genetic contribution Secondary: preceded by cerebral infections (syphilis, influenza) , toxic chemicals ( carbon monoxide, manganese, pesticides, welding-related foams), cerebral hypoxia (vascular defects) traumatic brain injury, or antipsychotic drugs Parkinson’s Plus: - groups of maladies in which the signs and symptoms of a Parkinson’s disease contributes to a larger disorder
	Parkinson’s Plus	Primary: or idiopathic form - typical late onset disorder with motor signs and a poorly understood cause - may have a genetic contribution Secondary: preceded by cerebral infections (syphilis, influenza) , toxic chemicals ( carbon monoxide, manganese, pesticides, welding-related foams), cerebral hypoxia (vascular defects) traumatic brain injury, or antipsychotic drugs Parkinson’s Plus: - groups of maladies in which the signs and symptoms of a Parkinson’s disease contributes to a larger disorder
	what is the major location of dopamine system	Substantia nigra is the major location of dopamine system Info from the cortex goes to striatum and returns back to the cortex through the thalamus Striatum controls the substantia nigra which regulates posture and muscle tones
	what controls the substantia nigra which regulates posture and muscle tones	Substantia nigra is the major location of dopamine system Info from the cortex goes to striatum and returns back to the cortex through the thalamus Striatum controls the substantia nigra which regulates posture and muscle tones
	synthesis of dopamine	Dopamine is synthesized from tyrosine L- DOPA  carboxylated to dopamine which are stored in vesicles and released to synaptic cleft and will bind to D1-D5 receptors which activate 2nd messengers in cells Reuptake of DA by DA transporters into the cytosol, then oxidized by monoamine oxidase
	levodopa	precursor of dopamine.. that can cross the BBB and used to treat parkinsons efficacy tends to decrease as the disease progresses
	COMT inhibitor	A COMT inhibitor is a drug that inhibits the action of catechol-O-methyl transferase. This enzyme is involved in degrading neurotransmitters. COMT inhibitors are used in the treatment of Parkinson's disease. Pharmaceutical examples include entacapone
	limitations of levodopa	does NOT prevent the continuous degeneration of nerve cells in the substantia nigra... the treatment therefore being SYMPTOMATIC
	Free Radical hypothesis of parkinsons	Based on the concept that free radicals, generated from oxidative reactions, react with membrane lipids and cause lipid peroxidation, cell injury, and subsequent cell death Mitochondrial damage and inhibition of oxidative phosphorylation also occur as result of free radical attack  The brain is usually protected from damage caused by free radicals because it contains protective substances (e.g., glutathione, ascorbicacid, melatonin, vitamin E) and enzymes (e.g., glutathione peroxidase, superoxidase dismutase) that prevent their buildup • The SNc (Substantia nigra compacta) of parkinsonian patients has reduced concentrations of bothglutathione and glutathione peroxidase
	what does the substantia nigra of parksonian patients have decreased amounts of ?	The brain is usually protected from damage caused by free radicals because it contains protective substances (e.g., glutathione, ascorbicacid, melatonin, vitamin E) and enzymes (e.g., glutathione peroxidase, superoxidase dismutase) that prevent their buildup • The SNc (Substantia nigra compacta) of parkinsonian patients has reduced concentrations of bothglutathione and glutathione peroxidase
	what do glutathione and glutathione peroxidase do?	The brain is usually protected from damage caused by free radicals because it contains protective substances (e.g., glutathione, ascorbicacid, melatonin, vitamin E) and enzymes (e.g., glutathione peroxidase, superoxidase dismutase) that prevent their buildup • The SNc (Substantia nigra compacta) of parkinsonian patients has reduced concentrations of bothglutathione and glutathione peroxidase
	Before the discovery of levodopa, the standard drugs for the treatment of Parkinson s disease were _____	Before the discovery of levodopa, the standard drugs for the treatmentof Parkinson s disease were antimuscarinic agents Antimuscarinic agents may be effective because they restore the dopaminergic/cholinergic balance that is upset when the dopaminergic nigrostriatal pathway degenerates • The classic dopaminergic/cholinergic imbalance concept of Parkinson s disease explains a variety of clinical and pharmacologic responses, but clinical parkinsonism is more complicated than an imbalance between of two neurotransmitters
	what would antimuscarinic drugs do for parkinsons disease patients?	Before the discovery of levodopa, the standard drugs for the treatmentof Parkinson s disease were antimuscarinic agents Antimuscarinic agents may be effective because they restore the dopaminergic/cholinergic balance that is upset when the dopaminergic nigrostriatal pathway degenerates • The classic dopaminergic/cholinergic imbalance concept of Parkinson s disease explains a variety of clinical and pharmacologic responses, but clinical parkinsonism is more complicated than an imbalance between of two neurotransmitters
	which dopamine receptors are most important for antiparkinson effectiveness?	Dopamine D2, D3, and D4receptors are thought to be more important than D1 and D2 receptors for antiparkinson effectiveness, but stimulation of both groups of receptors appears to be involved in the therapeutic of levodopa
	cardinal symptoms of Parkinson s disease	tremor, rigidity, bradykinesia, and postural instability do not respond uniformly to the antiparkinson drugs raises the possibility that these symptoms may be associated with other receptor, including muscarinic (M1 and M2) and nicotinic receptors, which may provide different functions in the basal ganglia
	Drugs affecting dopaminergic transmission (parkinsons)	The drug reserpine was known to reduce catecholamines and produce characteristic PD like effects (extrapyramidal signs) •  Levodopa (the precursor of dopamine) was shown to reverse reserpine-induced bradykinesia, and a link between dopamine and extrapyramidal motor function was established Precursor of the endogenous catecholamines, including dopamine and norepinephrine
	reserpine	The drug reserpine was known to reduce catecholamines and produce characteristic PD like effects (extrapyramidal signs) •  Levodopa (the precursor of dopamine) was shown to reverse reserpine-induced bradykinesia, and a link between dopamine and extrapyramidal motor function was established Precursor of the endogenous catecholamines, including dopamine and norepinephrine
	Drugs affecting dopaminergic transmission	major metabolic fate --> decarboxylation to dopamine by aromatic L-amino acid decarboxylase, commonly referred to as dopa decarboxylase the central and peripheral nervous system actions of levodopa are thought to result from its conversion to dopamine
	what symptoms of parkinsons improve with levodopa	All clinical manifestations of parkinsonism respond in some degree to levodopa therapy • Tremor is less responsive to levodopa than is rigidity or bradykinesia, but abnormalities of posture, equilibrium and locomotion all improve with treatment Whereas levodopa initially improves the mental status of the parkinsonian patient, a progressive dementia may still occur
	parkinson behavioralbehaviors vs symptoms related to levodopa	levodopa-induced behavioral changes are dose dependent and subside with dose reduction... but parkinsonian symptoms then worsen a typical antipsychotic like clozapine may be preferred for treating levodopa induced psychosis bc they are effective and have a reduced potential for extrapyramidal side effects
	Drug interactions of concern with COMT inhibitors include:	• Drug interactions of concern with COMT inhibitors include: catecholamines (epinephrine), drugs that interfere with biliary excretion (including ampicillin and erythromycin), drugs with sedative actions (anxiolytics, sedative antihistamines, barbiturates, opioid agonists, antipsychotics and many tricyclic antidepressants), and nonselective MAO inhibitors
	direct dopamine receptor agonists offer several advantages over levodopa:	These drugs offer several advantages over levodopa: 1)  Do not require metabolic conversion to an active compound 2)  Do not require the presence of nigrostriatal neurons of nerve impulses for their activity 3) Have longer duration of action thanlevodopa with fewer on-off changes 4)  Are more selective than levodopa on specific sub-populationsof dopamine receptors 5)  Are less likely to generate damaging free radicals
	Bromocriptine	Bromocriptine – the oldest and best studied of this group of drugs - Potent D2 receptor agonist and weak D1antagonist -can be useful in patients who are unresponsive to levodopa-carbidopa Pergolide - D1, D2, and D3 receptor agonist - prolonged action -may decrease levodopa-induced dyskinesias and increase “on” time after the patient begins on-off fluctuations Lisuride - more potent than bromocriptine - primarily a D2 agonist, but it is a 5-HT receptor agonist as well - Not available in the US
	Pergolide	Bromocriptine – the oldest and best studied of this group of drugs - Potent D2 receptor agonist and weak D1antagonist -can be useful in patients who are unresponsive to levodopa-carbidopa Pergolide - D1, D2, and D3 receptor agonist - prolonged action -may decrease levodopa-induced dyskinesias and increase “on” time after the patient begins on-off fluctuations Lisuride - more potent than bromocriptine - primarily a D2 agonist, but it is a 5-HT receptor agonist as well - Not available in the US
	Lisuride	Bromocriptine – the oldest and best studied of this group of drugs - Potent D2 receptor agonist and weak D1antagonist -can be useful in patients who are unresponsive to levodopa-carbidopa Pergolide - D1, D2, and D3 receptor agonist - prolonged action -may decrease levodopa-induced dyskinesias and increase “on” time after the patient begins on-off fluctuations Lisuride - more potent than bromocriptine - primarily a D2 agonist, but it is a 5-HT receptor agonist as well - Not available in the US
	Clonazepam + parkinsons	Clonazepam which is a benzodiazepine have been used in the treatment of parkinsonian tremor Clonazepam may be effective in treating some aspects of Parkinson s disease, presumably because of its GABAergicactivity
	what is the most effective antiparkinson treatment available to date	Combination of levodopa and carbidopa is the most effective antiparkinson treatment available to date However, because of the serious side effects associated with levedopa therapy and its limited period of effectiveness, other drugs and drug combinations are commonly used •  There is still a strong interest in drugs that may provide a neuroprotective effect and reduce progression of the disease
	Hypertension	Persistently elevated arterial blood pressure (BP) - Systolic BP ≥ 140 mmHg - Diastolic BP ≥ 90 mmHg 1/3 Americans - Morbidity and mortality linear with increasing BP Long term consequences - Coronary artery disease - Stroke - Renal failure - Heart failure
	systolic increases by 20, your risk for cardiovascular events ___	doubles
	Blood Pressure	Pressure exerted by circulating blood against artery walls during cardiac cycle Systolic blood pressure (SBP) - Cardiac contraction Diastolic blood pressure (DBP) - Cardiac filling Mean arterial pressure - Average pressure through cardiac cycle of contraction - 1/3 (SBP) + 2/3 (DBP)
	Mean arterial pressure	- Average pressure through cardiac cycle of contraction - 1/3 (SBP) + 2/3 (DBP)
	BP =	BP = Cardiac output (CO) x total peripheral resistance (TPR)
	Hypertension Classification
	Hypertensive crises at what BP	Hypertensive crises at BP > 180/120 mmHg - Urgency - Emergency – target organ damage
	Types of Hypertension	Essential or Primary – 90% of cases - Unknown etiology Secondary -Chronic kidney disease -Obstructive sleep apnea -Pheochromocytoma -Thyroid disease -Medications --Corticosteroids --Non-steroidal anti-inflammatory drugs (NSAIDs) --Antidepressants --Decongestants
	Humoral mechanisms of hypertension
	Neuronal regulation of hypertension
	Peripheral autoregulatory & vascular endothelial of hpyertension
	Electrolytes during hypertension
	Renin-angiotensin-aldosterone system (RAAS)
	what stimulates renin release	release of renin is modulated by several factors: intrarenal factors (e.g., renal perfusion pressure, catecholamines, angiotensin II) and extrarenal factors (e.g., sodium, chloride, and potassium). Juxtaglomerular cells function as a baroreceptor-sensing device. Decreased renal artery pressure and kidney blood flow is sensed by these cells and stimulates secretion of renin. The juxtaglomerular apparatus also includes a group of specialized distal tubule cells referred to collectively as the macula densa. A decrease in sodium and chloride delivered to the distal tubule stimulates renin release. Catecholamines increase renin release probably by directly stimulating sympathetic nerves on the afferent arterioles that in turn activate the juxtaglomerular cells.
	Long term control of RAAS	Liver secretes angiotensinogen in blood. Kidneys release Renin that converts Angiotensinogen --> Angiotensin I. Then ACE converts Angiotensin I --> angiotensin II Angiotensin II: increases BP 1) Potent vasoconstrictor 2) Affects baroreceptors on sympathetic vessels 3) Stimulates Adrenal Cortex --> Aldosterone --> Na, Water retention Some people have higher/lower levels of renin therefore pharmacotherapeutic agents may not work for everyone
	ACE in the lungs does what	Liver secretes angiotensinogen in blood. Kidneys release Renin that converts Angiotensinogen --> Angiotensin I. Then ACE converts Angiotensin I --> angiotensin II Angiotensin II: increases BP 1) Potent vasoconstrictor 2) Affects baroreceptors on sympathetic vessels 3) Stimulates Adrenal Cortex --> Aldosterone --> Na, Water retention Some people have higher/lower levels of renin therefore pharmacotherapeutic agents may not work for everyone
	what secretes angiotensinogen	Liver secretes angiotensinogen in blood. Kidneys release Renin that converts Angiotensinogen --> Angiotensin I. Then ACE converts Angiotensin I --> angiotensin II Angiotensin II: increases BP 1) Potent vasoconstrictor 2) Affects baroreceptors on sympathetic vessels 3) Stimulates Adrenal Cortex --> Aldosterone --> Na, Water retention Some people have higher/lower levels of renin therefore pharmacotherapeutic agents may not work for everyone
	what releases renin	Liver secretes angiotensinogen in blood. Kidneys release Renin that converts Angiotensinogen --> Angiotensin I. Then ACE converts Angiotensin I --> angiotensin II Angiotensin II: increases BP 1) Potent vasoconstrictor 2) Affects baroreceptors on sympathetic vessels 3) Stimulates Adrenal Cortex --> Aldosterone --> Na, Water retention Some people have higher/lower levels of renin therefore pharmacotherapeutic agents may not work for everyone
	what converts angiotensinogen into angiotensin 1 ?	Liver secretes angiotensinogen in blood. Kidneys release Renin that converts Angiotensinogen --> Angiotensin I. Then ACE converts Angiotensin I --> angiotensin II Angiotensin II: increases BP 1) Potent vasoconstrictor 2) Affects baroreceptors on sympathetic vessels 3) Stimulates Adrenal Cortex --> Aldosterone --> Na, Water retention Some people have higher/lower levels of renin therefore pharmacotherapeutic agents may not work for everyone
	Pathogenesis of HTN
	Pathogenesis of HTN --> increased cardiac output
	Pathogenesis of HTN --> increasd total peripheral resistance
	Four subtypes of diuretics	Thiazide – hydrochlorothiazide and chlorthalidone Loop – furosemide, bumetanide, torsemide Potassium-sparing – amiloride, triamterene Aldosterone antagonists – spironolactone, eplernone Mechanism of action Diuresis ==> decreased plasma & stroke volume & ==> decreased CO, increased TPR Chronic therapy leads to reequlibration of plasma and extracellular fluid but more pronounced decreased TPR - vasodilation
	mechanism of action for diuresis	Thiazide – hydrochlorothiazide and chlorthalidone Loop – furosemide, bumetanide, torsemide Potassium-sparing – amiloride, triamterene Aldosterone antagonists – spironolactone, eplernone Mechanism of action Diuresis ==> decreased plasma & stroke volume & ==> decreased CO, increased TPR Chronic therapy leads to reequlibration of plasma and extracellular fluid but more pronounced decreased TPR - vasodilation
	Diuretics	Generally well tolerated Side effects of thiazide diuretics -Inacrease glucose levels -Erectile dysfunction -Orthostatic hypotension, especially in women -Electrolyte imbalances – hypokalemia, hypomagnesemia, hyponatremia Thiazide-type initial drug of therapy for most - Least expensive
	side effects of thiazide diuretics	Angiotensin-Converting Enzyme Inhibitors (ACE-I)
	Inhibiton of ACE	Inhibiton of ACE --> no Angiotensin II (lower BP)
	ACE-Inhibitors	Mechanism of action - Inhibit angiotensin converting enzyme --> Decrease angiotensin II in blood vessels and kidney - Increase bradykinin by blocking degradation by ACE (inhibit ACE) - Vasodilation (due to increase in bradykinin) - Decrease total peripheral resistance Side effects - Hyperkalemia - Cough – most common - Angioedema – life threatening
	side effects of ACE inhibitors	Mechanism of action - Inhibit angiotensin converting enzyme --> Decrease angiotensin II in blood vessels and kidney - Increase bradykinin by blocking degradation by ACE (inhibit ACE) - Vasodilation (due to increase in bradykinin) - Decrease total peripheral resistance Side effects - Hyperkalemia - Cough – most common - Angioedema – life threatening
	mechanism of action for ACE inhibitors	Mechanism of action - Inhibit angiotensin converting enzyme --> Decrease angiotensin II in blood vessels and kidney - Increase bradykinin by blocking degradation by ACE (inhibit ACE) - Vasodilation (due to increase in bradykinin) - Decrease total peripheral resistance Side effects - Hyperkalemia - Cough – most common - Angioedema – life threatening
	most common side effect of ACE inhibitors	Mechanism of action - Inhibit angiotensin converting enzyme --> Decrease angiotensin II in blood vessels and kidney - Increase bradykinin by blocking degradation by ACE (inhibit ACE) - Vasodilation (due to increase in bradykinin) - Decrease total peripheral resistance Side effects - Hyperkalemia - Cough – most common - Angioedema – life threatening
	Anything that ends in ‘pril’ is	Anything that ends in ‘pril’ is an ace inhibitor. ACE inhibitors decrease morbidity and mortality in congestive heart failure, MI, coronary artery disease, diabetes, chronic kidney disease. Not so much for any other class of drug (ie diuretics).
	Angiotensin II Receptor Blockers (ARBS)	Black angiotensin II at the receptor. Advantages: Not affecting the degradation of bradykinin (no cough), and no angioedema as well. ARB- have same compelling indications as the ACE-I but more mortality assoc in ARB vs ACE-I
	advantages of using ARB over ACE inhibitor	Advantages: Not affecting the degradation of bradykinin (no cough), and no angioedema as well. ARB- have same compelling indications as the ACE-I but more mortality assoc in ARB vs ACE-I
	disadvantages of using ARB over ACE inhibitor	Advantages: Not affecting the degradation of bradykinin (no cough), and no angioedema as well. ARB- have same compelling indications as the ACE-I but more mortality assoc in ARB vs ACE-I
	ARBs	Mechanism of action -Block angiotensin II type 1 receptor -Decrease angiotensin II in blood vessels and kidney -Decrease: vasoconstriction, aldosterone release, sympathethic activation, antidiuretic hormone release Side effects -Hyperkalemia -Angioedema, less common ARBS --> “-sartan”
	mechanism of action of ARBs	Mechanism of action -Block angiotensin II type 1 receptor -Decrease angiotensin II in blood vessels and kidney -Decrease: vasoconstriction, aldosterone release, sympathethic activation, antidiuretic hormone release Side effects -Hyperkalemia -Angioedema, less common
	Side Effects of ARBs	Mechanism of action -Block angiotensin II type 1 receptor -Decrease angiotensin II in blood vessels and kidney -Decrease: vasoconstriction, aldosterone release, sympathethic activation, antidiuretic hormone release Side effects -Hyperkalemia -Angioedema, less common
	any ARB ends with	ARBS --> “-sartan”
	-"sartan"	ARBS --> “-sartan”
	β Receptors	β1 receptors -Heart, kidney -Stimulation increases heart rate, contractility, renin release β2 receptors -Lungs, liver, pancreas, arteriolar smooth muscle -Stimulation causes vasodilation and bronchodilation -Insulin secretion and glycogenolysis * Want to block B1, and do not want to antagonize B2 receptors. -Some agents that are not cardioselective can have other downstream effects due to B2-R -Ideal to agonize B2-R (vasodilation)
	β1 receptors	β1 receptors -Heart, kidney -Stimulation increases heart rate, contractility, renin release β2 receptors -Lungs, liver, pancreas, arteriolar smooth muscle -Stimulation causes vasodilation and bronchodilation -Insulin secretion and glycogenolysis
	β2 receptors	β1 receptors -Heart, kidney -Stimulation increases heart rate, contractility, renin release β2 receptors -Lungs, liver, pancreas, arteriolar smooth muscle -Stimulation causes vasodilation and bronchodilation -Insulin secretion and glycogenolysis
	β Blockers	Only to be used for hypertension if compelling indication Mechanism of action -Negative chronotropic and inotropic effects -Decreased cardiac output -Inhibit release of renin from juxtaglomerular cells Pharmacodynamic properties -Cardioselectivity -Intrinsic sympathomimetic activity -Membrane-stabilizing effects BB: “-olol”
	which HTN drug inhibits release of renin	β Blockers Only to be used for hypertension if compelling indication Mechanism of action -Negative chronotropic and inotropic effects -Decreased cardiac output -Inhibit release of renin from juxtaglomerular cells Pharmacodynamic properties -Cardioselectivity -Intrinsic sympathomimetic activity -Membrane-stabilizing effects
	side effects of β Blockers	Side effects -Tolerance -Nausea/vomiting -Confusion -Dizziness -Fatigue -Depression -Bronchospasms in asthmatics Abrupt withdrawal in CHD may increase ischemia
	-"olol"	beta blocker
	Calcium Channel Blockers (CCB)	Two subtypes -Dihydropyridine -Non-dihydropyridine Compelling indications -Only in addition to or instead of other first line agents Mechanism of action -Block high-voltage L-type calcium channels -Coronary and peripheral vasodilation Side effects -Dizziness, flushing, headache, peripheral edema, gingival hyperplasia
	mechanism of action of Calcium Channel Blockers (CCB)	Two subtypes -Dihydropyridine -Non-dihydropyridine Compelling indications -Only in addition to or instead of other first line agents Mechanism of action -Block high-voltage L-type calcium channels -Coronary and peripheral vasodilation Side effects -Dizziness, flushing, headache, peripheral edema, gingival hyperplasia
	side effects of Calcium Channel Blockers (CCB)	Two subtypes -Dihydropyridine -Non-dihydropyridine Compelling indications -Only in addition to or instead of other first line agents Mechanism of action -Block high-voltage L-type calcium channels -Coronary and peripheral vasodilation Side effects -Dizziness, flushing, headache, peripheral edema, gingival hyperplasia
	Dihydropyridine CCB	Dihydropyridine CCB -Amlodipine, Nifedipine XL, Felodipine, Isradipine -Effective for isolated systolic hypertension in elderly patients -Potent peripheral vasodilator resulting in reflex tachycardia Non-dihydropyridine CCB -Diltiazem and Verapamil -Decrease heart rate and slow atrioventricular nodal conduction -Effective for treating supraventricular tachyarrhythmia -Negative inotropic and chronotropic effects
	Non-dihydropyridine CCB	Dihydropyridine CCB -Amlodipine, Nifedipine XL, Felodipine, Isradipine -Effective for isolated systolic hypertension in elderly patients -Potent peripheral vasodilator resulting in reflex tachycardia Non-dihydropyridine CCB -Diltiazem and Verapamil -Decrease heart rate and slow atrioventricular nodal conduction -Effective for treating supraventricular tachyarrhythmia -Negative inotropic and chronotropic effects
	- dipine	Calcium Channel Blockers
	Treatment Algorithms for HTN	Compelling indication -Agent as recommended by JNC-7 No compelling indication -Stage 1: <160/100mmHg --> Monotherapy --- Thiazide-diuretic for most --- Consider ACE inhibitor, ARB, Beta blocker, Calcium channel blocker, or combination -Stage 2: ≥ 160/100mmgHg --> 2 drug combination for most ---Thiazide-diuretic with ACE inhibitor, ARB, Beta blocker, or CCB
	compelling indications for HTN meds
	HTN α1 blockers	Prazosin, terazosin, doxazosin Inhibit cathecholamines in peripheral vasculature - Vasodilation Benefit in BPH - Bc Inhibit α1 receptors of prostate ‘First dose phenomenon’ - Dizziness, syncope, orthostatic hypotension
	HTN Central α2 agonists	Clonidine- resistant HTN Methyldopa- pregnancy Stimulate α2 receptors in brain - ↓ sympathetic tone Increase heart vagal tone - Decrease HR, CO, TPR Abrupt cessation may lead to rebound HTN
	Direct arterial vasodilator for HTN	Vasodilation -Hydralazine -Minoxidil Compensatory baroreceptor response -Increase in heart rate -Best used with β-blocker Tachyphylaxis
	Direct renin inhibitor	Aliskiren - Inhibits RAAS at point of activation - Not much long-term CV event reduction data
	Aliskiren	Direct renin inhibitor Aliskiren - Inhibits RAAS at point of activation - Not much long-term CV event reduction data
	-Hydralazine -Minoxidil	Direct arterial vasodilator for HTN Vasodilation -Hydralazine -Minoxidil Compensatory baroreceptor response -Increase in heart rate -Best used with β-blocker Tachyphylaxis
	Hypertension Urgency	> 180/120 mmHg Control blood pressure within several hours to days -Reduce target organ damage Adjust maintenance therapy or add new therapy Oral short acting agents followed by observation -Labetalol -Captopril -Clonidine Follow up MD visit in several days
	Hypertension Emergency	Hypertensive crisis (>180/120 mmHg) with evidence of target organ damage -Admission to ICU -Continuous BP management Parenteral agents for management preferred -Nicardipine -Esmolol -Enaliprilat Decrease MAP by no more than 25% -Within minutes to hours
	Drug Interactions w/ HTN Meds	Hydrocortisone as anti-inflammatory - Hypokalemia slow in onset and termination with diuretics Sedative-hypnotics and opioid analgesics - Syncope and orthostatic hypotension Antianxiety agent or other drugs that depress CNS - Smaller doses in patients taking methyldopa or clonidine
	Normal insulin function	When Glucose lvls increase Act on beta cells of pancreas Insulin is released Insulin acts on every cell of body except RBCs -Anabolic effect at the liver --> Glucose packaging -Catabolic everywhere else --> Glucose mobilization
	Insulin acts on every cell of body except ____	When Glucose lvls increase Act on beta cells of pancreas Insulin is released Insulin acts on every cell of body except RBCs -Anabolic effect at the liver --> Glucose packaging -Catabolic everywhere else --> Glucose mobilization
	Types of Diabetes	Type I aka juvenile diabetes -5-10% -Early onset -Autoimmune -Absolute requirement for insulin (can’t make any) -Defect is in insulin production Type II -90-95% -Incidence is increasing -Usually older ppl, but now kids are getting it -Defect is in insulin secretion/action -Lifestyle/genetic disease
	Type I Diabetes	Type I aka juvenile diabetes -5-10% -Early onset -Autoimmune -Absolute requirement for insulin (can’t make any) -Defect is in insulin production Type II -90-95% -Incidence is increasing -Usually older ppl, but now kids are getting it -Defect is in insulin secretion/action -Lifestyle/genetic disease
	Type II Diabetes	Type I aka juvenile diabetes -5-10% -Early onset -Autoimmune -Absolute requirement for insulin (can’t make any) -Defect is in insulin production Type II -90-95% -Incidence is increasing -Usually older ppl, but now kids are getting it -Defect is in insulin secretion/action -Lifestyle/genetic disease
	Insulin Resistance: The Path to Type II Diabetes	Start w/ Too much food - then too much insulin - Then resistance to insulin effects build up - Less glucose use at tissues and glucose packaging at liver = more glucose circulating = Positive fdbk Resistance gets worse Eventually pancreas runs out of insulin (and insulin dips)
	Type I vs Type II Diabetes
	which type of diabetes has LOW -ABSENT insulin levels	Type I
	which type of diabetes has islet antibodies	Type I
	Goal of Therapy for Diabetes	Maintain blood glucose concentrations as close to normal as possible: Fasting: 90-120 mg/dl (5-6.7 mM) 2-hr postprandial: <150 mg/dl (8.4 mM)
	Chronic Complications of Diabetes
	Description of endogenous insulin	Insulin (51-aa polypeptide) made in islet beta cells in pancreas from preproinsulin. Half-life = 5-6 min. Peptide complexed with zinc as hexamers Regulated by blood glucose and other hormones and autonomic mediators.
	Most Patients with Type 2 DM will Need Insulin Eventually	Steady decline up to 6 years following diagnosis of B cell function. If 50% of normal B cell function at diagnosis, no function by year 14
	Insulin Products	Purified Animal Insulins (porcine, bovine) purified by gel filtration, single peak purity, few contaminants, not used now in the U.S. - Recombinant human insulins (Humulin) Extremely low-risk of insulin antibodies - “Designer Insulins” – biochemical modifications of human insulins altering their absorption profile, duration of action
	Hazards of Insulin Use	-Hypoglycaemia -Weight gain- anabolic hormone -Lipohypertrophy- injection to same site -Insulin edema -Transient deterioration in retinopathy -Insulin neuritis – actively regenerating neuron, uncommon -Postural hypotension -Immunologic toxic effects from development of antibodies
	Sick day rules	never stop insulin monitor more frequently maintain your hydration check for ketones know when & how to call for help
	Oral Antihyperglycemic Agents:Mechanisms of Action
	Metformin	1st line drug nowadays Multiple effects Liver Inhibit gluconeogenesis and glycogenolysis (~insulin) Downregulates glucose absorption/uptake
	A-glucosidase inhibitors	block breakdown of starches (in the gut) (tf less absorption)
	Thiazolidinediones	promote insulin action at muscle/fat
	Considerations in Pharmacologic Treatment of Type 2 Diabetes	-Efficacy (HbA1c lowering capacity) -Mechanisms of action of drugs -Impact on weight gain -Complications/tolerability -Frequency of hypoglycemia -Compliance/complexity of regimen -Cost
	Regulation of Insulin Secretion from the Pancreas	Sulfonylureas -Old drugs -Promote insulin secretion from beta cells -Block atp dep K+ channels -Only works if the pt has enough insulin inside cells made Effective -->lowers blood glucose ~3 mmM, lowers HBa1c by ~2% -Cheap -Causes weight gain via too much glucose absorption at tissues (related to hypoglycemia) -No effect on plasma lipids or Blood pressure
	The Key Elements in Insulin Secretion	The Key Elements in Insulin Secretion • Glucose transport 2 (GLUT2) • Glucokinase (GK) • Mitochondria • ATP-sensitive K+channels (K+ATP-channels) • Voltage-dependent Ca2+-channels (VDCC) • Exocytosis
	Sulfonylureas Insulin Secretagogues	***Sulfonylureas increase endogenous insulin secretion by blocking ATP-dependent K+ channel in ß cells Efficacy - Decrease fasting plasma glucose 3.3-3.9 mmol/L -Reduce HbA1C by 1.0-2.0% Other Effects - Hypoglycemia - Weight gain - No specific effect on plasma lipids or blood pressure - Generally the least expensive class of medication Medications in this Class: - First generation : chlorpropamide , tolazamide, acetohexamide , tolbutamide - Second generation : glyburide , glimepiride , glipizide
	How do Sulfonylureas increase endogenous insulin secretion	***Sulfonylureas increase endogenous insulin secretion by blocking ATP-dependent K+ channel in ß cells Efficacy - Decrease fasting plasma glucose 3.3-3.9 mmol/L -Reduce HbA1C by 1.0-2.0% Other Effects - Hypoglycemia - Weight gain - No specific effect on plasma lipids or blood pressure - Generally the least expensive class of medication Medications in this Class: - First generation : chlorpropamide , tolazamide, acetohexamide , tolbutamide - Second generation : glyburide , glimepiride , glipizide
	Sulfonylureas	-Oral administration and bind to plasma proteins -Actions can be enhanced by alcohol ~50% of new onset Type II diabetic can reach appropriate glycemic control First Generation: less potent but some longer half life -Acetohexamide rapidly metabolized but active metabolite 4-7 hrs -Chlorpropamide (24-48 hours) -Tolazamide (4-7 hrs) -Tolbutamide (4-7 hrs) 2nd Generation: 100x more potent but shorter half life (2-10 hrs) -Glyburide (glibenclamide) (may cause hypoglycemia) -Glimeporide -Glipizide
	First Generation Sulfonylureas	-Oral administration and bind to plasma proteins -Actions can be enhanced by alcohol ~50% of new onset Type II diabetic can reach appropriate glycemic control First Generation: less potent but some longer half life -Acetohexamide rapidly metabolized but active metabolite 4-7 hrs -Chlorpropamide (24-48 hours) -Tolazamide (4-7 hrs) -Tolbutamide (4-7 hrs) 2nd Generation: 100x more potent but shorter half life (2-10 hrs) -Glyburide (glibenclamide) (may cause hypoglycemia) -Glimeporide -Glipizide
	2nd Generation Sulfonylureas	-Oral administration and bind to plasma proteins -Actions can be enhanced by alcohol ~50% of new onset Type II diabetic can reach appropriate glycemic control First Generation: less potent but some longer half life -Acetohexamide rapidly metabolized but active metabolite 4-7 hrs -Chlorpropamide (24-48 hours) -Tolazamide (4-7 hrs) -Tolbutamide (4-7 hrs) 2nd Generation: 100x more potent but shorter half life (2-10 hrs) -Glyburide (glibenclamide) (may cause hypoglycemia) -Glimeporide -Glipizide
	Meglitinides	2nd drug class Also stimulate release of insulin Unrelated chemically to sulfonyls, but work in the same way ****Blocks atp dep K+ channels

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