Pharmacology Notes UNIT 1: Fundamental Principles of Pharmacology (Chapter 1 & 2) Pharmacology- is the study of how chemical agents effect biological systems. Chemical name- this is the name of drug based on the chemical formula, all drugs are chemicals. When first discovered they are often named this. Generic name- this is a nonproprietary, usually easier to communicate name. Brand name (trade name)- this is the name given to drugs that are marketed by pharmaceutical companies. Prototype- this is a representative of a large group of drugs that act similar. Drug examples: Generic- Acetaminophen Trade/ Brand- Tylenol Prototype- Analgesic Prescription Drugs require a written or phone order to an individual who is licensed to dispense prescription medications. Non-prescription drugs are referred to as over the counter OTC, they do not require a written order. Drugs that have the potential for abuse are called controlled substances and they are divided into 5 groups. SCHEDULE I II III IV V FDA Pregnancy Categories DEFINITION Drugs with high abuse potential only used in research Drugs with high abuse potential and some acceptable medical use in humans Drugs with moderate abuse potential and acceptable medical use in humans Drugs with low abuse potential and acceptable medical use in humans. Drugs with limited abuse potential and acceptable medical use in humans EXAMPLE Heroin Morphine Anabolic steroids Benzodiazepines Narcotic drugs in small, limited quantities Pregnancy Categories A B C D X XR Description Drugs studies in pregnant women have not yet demonstrated risk to the fetus Drug studies have not been performed in pregnant women; animal studies have n ot demonstrated fetal risk Drug studies have not been performed in pregnant women or animals, or animal studies have revealed some teratogenic potential but the risk to the fetus is unknown. Drug studies have revealed adverse risk to the fetus. The benefit-to-risk ration of the drug must be established before use during pregnancy, Drug studies have revealed teratogenic effects in women and/or animals. Fetal risk clearly outweighs benefit. Drug is contraindicated in pregnancy. Drug has not been rated by the FDA Teratogenic Effect on Drugs Androgens (male hormones) Carbamazepine Diethylstilbestrol Estrogen (female hormones) Lithium Phenytoin Retinoic Acid Thalidomide Warfarin Masculinization of female fetus Craniofacial and fingernail deformities Vaginal tumors and genital malformations in offspring Feminization of male fetus Cardiac defects Craniofacial and limb deformities, growth retardation Craniofacial, cardiac and CNS defects Phocomelia (limb deformities) Facial, cartilage, and CNS defects Pharmacodynamics- the study of the action of drugs on living tissue Pharmcokinetics- study of the processes of drug absorption, distribution, metabolism, and excretion Pharmacotherapeutics- study of the use of drugs in trating disease Pharmacy- science of preparing and dispensing medicines Posology- study of the amount of drug that is required to produce therapeutic effects Toxicology- study of harmful effects of drugs on living tissue Efficacy- is defined as the maximum effect a drug can produce, regardless of the dose. Potency- is determined by both the affinity of the drug for the receptor as well as the number of receptors available for binding. Tachyphylaxis- is when there is decreased drug response after repeated doses. Desensitization- is the receptors decreased ability to respond after a single or multiple doses. Inactivation- is a complete turning off of the receptor. Refractory state- of a receptor is when it cannot respond for a period of time. Down regulation- of a receptor causes the receptor to be removed after repeated exposure to a drug. Pharmcokinetics Absorption: Drug absorption may occur by a number of mechanisms and is defined as the movement of a drug from the site of administration into the rest of the body. - Enteral (oral) - Parenteral (subQ, IM, IV, intrathercal) - mucous membrane - Transdermal A number of local, regional, and systemic factors can affect absorption such as: - Lipid solubility Ionization Route of admin Bloodflow GI motility Distribution: Drug distribution is the process by which absorbed drugs are distributed to the tissues and is influenced by the volume of distribution (Vd), protein binding, drugs affinity to the tissue, and blood flow. Influencing factors: - Protein binding Blood flow Body fat content Blood brain barrier Placental barrier Metabolism: Metabolism is the process in which the body creates inactive metabolites that are readily excreted by the body. This can happen in multiple organs, but the liver is the main site of biotransformation due to the variety of enzymes found here. Influencing factors: - Drug Microsomal Metabolizing System (DMMS) - Cytochrome P450 First pass effect Individual variables Excretion: Excretion or elimination is primarily through the kidneys, and to a lesser extend through the bile, feces, lungs, saliva, sweat and breast milk. The pH of urine can effect drug secretion. Recall that urine can range from a pH of 4-8. Acidic urine promotes the excretion of weak base drugs, and vice versa. When kidney disease is present, drug excretion is slowed or stopped. Renal function tests include creatinine clearance and BUN. Excretion routes: - Renal GI Respiratory Other (breast milk, skin) Bioavailability: Bioavailability, the dose that reaches the systemic circulation which can be affected by the route of administration, chemical form of the drug, and a number of patient specific factors. Variables to bioavailability include: - Weight Age Sex Underlying diseases Genetic variation Patient compliance Side Effects - physiological effects - NOT related to the desired drug effect. - However sometimes a drug can be used due to the side effects. - For example: Using Benadryl or Diphenhydramine to cause sedation. - Side effects usually occur due to a lack of specificity. These may also be referred to as on-target effects. Adverse Reactions - more severe than side effects. - They are unintended, BUT always undesirable effects, even at normal doses. - Examples of adverse effects include anaphylaxis or heart failure. These may be referred to as off-target effects. - Pharmacology intersects with toxicology when the physiological response to a drug results in an adverse effect. - Toxic effects or toxicity occurs when the drug levels exceed the therapeutic range - How does drug toxicity occur? - Overdoses, drug-drug or drug-herb interactions Side effects are expected and usually NOT life threatening, where as adverse reactions are unpredictable and can often me life threatening. Therapeutic dosing- seeks to maintain a peak plasma (serum) concentration below the toxic level, and trough level above the minimally effective dose, thus the sweet spot. Loading dose- is aimed at achieving the therapeutic doe quickly and thus is usually a larger dose. Maintenance dose- is used when steady state drug concentrations have already been met and only drug that has been metabolized needs to be replaced. This is dependent then on clearance of the drug. Clearance- is defined as the rate of elimination from the body relative to the plasma concentration of the drug. The formula for clearance is: Clearance = metabolism + excretion [drug] in plasma Polypharmacy- is the simultaneous use of multiple drugs. This becomes an issue with competing mechanisms of action various side effects. As we talk about specific drugs, we will discuss interactions in the units to come. UNIT 2: Pharmacology of the Autonomic Nervous System (Chapter 5-7,8,9) Adrenergic- Drugs that activate the sympathetic system via activation or inhibition of alpha and beta receptors Sympathomimetic- Drugs that mimic or act like norepinephrine or epinephrine Adrenergic Agonists Spinal Cord (CNS) eyes- dilate pupil, increase intraoccular pressure lung- dilate bronchioles heart- increased heart rate blood vessels- constricts, increases BP gastrointestinal- relax (reduces gastric secretions and motility) bladder- relax (decreases urination) uterus- relax (decreases contractions) liver- glucose release, increased blood glucose Mixed Agonist Mixed, non selective adrenergic agonist: Epinephrine Emergency use Increases HR, blood pressure, promotes vasoconstriction Alpha 1 Agonist Phenylephrine (Neo-synephrine) Action Alpha 1 agonist Uses Nasal congestion-local Maintain/Elevate blood pressure during anesthesia Eye drops to cause dilation Alpha 2 Agonist Clonidine, Methyldopa Action Alpha 2 agonist Uses Hypertension Can be used during pregnancy to treat hypertension Beta 2 Agonist Albuterol (Proventil) Action Selective β2 agonist Uses Bronchospasm Asthma Bronchitis COPD Epinephrine Classification- nonselective (mixed) agonist Mechanism of action Activates the SNS Alpha1: Increases BP (Vasoconstriction) Beta 1: Increased HR Beta 2: Promotes bronchodilation Method to Remembering Beta 1 and Beta 2 Beta 1 – 1 heart so it affects the heart Beta 2 – 2 lungs so it affects the lungs Indications o o o o Anaphylaxis Asthma & bronchospasm Hypotension/shock Cardiac arrest Side Effects - Anxiety - Tremors - Sweating - GI disturbances - Headache - Insomnia - Dizziness - Agitation Adverse Reactions Contraindications - Severe headache No absolute contraindications - Urinary retention - Hypertension - Shortness of breath - BPH - Hyperglycemia - Diabetes mellitus - Palpitations - Tachycardia - Hypertension - Necrosis if out of vein - Anxiety Therapeutic Consideration MAOI’s Tricyclic antidepressants Beta blockers Digoxin Lab – increases blood sugar Alpha receptor effects predominate at high doses Extravasation When the IV is not properly placed inside the vessel this can cause the leakage of the drug. Because epinephrine/norpeinephrine is a potent vasoconstrictor and vesicant, this leakage has the potential to result in rapid tissue necrosis. Albuterol Classification Beta 2 agonist Mechanism of Action Selective to beta 2 adrenergic receptors relaxes smooth muscle which promotes bronchodilation Indications Asthma COPD Side Effects Tremors Nervousness Restlessness Insomnia GI upset Sweating Adverse Reactions Hypertension Tachycardia Palpitations Hyperglycemia Contraindications - Allergy Caution - Cardiac problems - Hypertension - Hyperthyroidism - Diabetes - Renal dysfunction Therapeutic Considerations o o o o Other drugs that increase the blood pressure and heart rate Antagonist effect with other drugs that lower the blood pressure and heart rate Lab – may increase glucose level This drug is a ‘rescue drug’ for acute asthma attacks: almost immediate bronchodilation after inhalation (4-6 hours duration of action) Phenylephrine Classification Vasopressors Mechanism of Action Alpha 1 agonist with minimal to no beta-adrenergic activity Normal blood vessel=> adrenergic=> narrowing of blood vessel Indications Hypotension related to shock and anesthesia (IV) Nasal congestion (intranasal) Mydriasis (ophthalmic drops) Conjunctivitis Side Effects - Blurred vision - Insomnia - Tremors - The most common side effect of decongestant use is irritation of the nasal sinuses or eyes due to excessive dryness caused by the vasoconstrictive decrease in blood flow. Adverse Reactions - Excessive vasoconstriction with parenteral administration - Hypertensive crisis - Hemorrhage (usually cerebral) - Cardiac arrhythmias Contraindications - Hypersensitivity Therapeutic Considerations Extreme caution during IV infusion must be observed with hypertensive or cardiac patients, with blood pressure recording at frequent intervals. Clonidine Classification antihypertensives Mechanism of Action Alpha-2 effect, negative feedback effect to decrease release of NE Indication Hypertensive urgency (limited situations) ADHD Tourette syndrome Symptoms control in opioid withdrawal Side Effects - Dry mouth - Constipation - Drowsiness Adverse Reactions Contraindications Risk of orthostatic - Anticoagulant hypotension and adverse CNS therapy effects in geriatric patients - Bleeding problems Therapeutic Consideration If clonidine is abruptly discontinued, a withdrawal reaction may occur, with patients experiencing rebound sympathetic activity and hypertensive crisis. Methyldopa Classification antihypertensives Mechanism of Action Stimulates Alpha 2-adrenergic receptors in the CNS, which results in decreased sympathetic outflow inhibiting cardio-acceleration and vasoconstriction centers. Indications Hypertension in pregnancy Side Effects - Nausea - Vomiting - Diarrhea - Nasal congestion - Bradycardia Adverse Reactions - Direct Coombs hemolysis - Drug-induced lupus - Hyperprolactinemia - Drug fever - Liver dysfunction Contraindications - Active liver disease - Hypersensitivity Therapeutic Considerations Drowsiness and/or sedation occurs with initial treatment, but usually disappear as treatment continues. Adrenergic Antagonists Adrenergic Antagonists are sympatholytic drugs that block or inhibit activation of the sympathetic nervous system. Prazosin *** All drugs in this class end in ‘sin’, such as prazosin. These drugs work mainly on the vessels and urinary bladder. *** Classification Alpha 1 Mechanism of Action Vasodilation, leading to decreased blood pressure Relaxation of smooth muscles in bladder and prostate Indications Uses include: Raynaud's disease Essential hypertension Benign prostatic hypertrophy Pheochromocytoma Side Effects - Miosis - Nasal congestion - Increased GI activity - Reflex tachycardia Adverse Reactions Hypotension due to excessive vasodilation Contraindications Use Cautiously in: Renal insufficiency (↑ sensitivity to effects; dose ↓ may be required) Therapeutic Consideration After taking the first dose be careful with changing position suddenly, the vasodilation causes orthostatic hypotension, client can become dizzy and lightheaded went hey stand up. Alternatively, they can take medication at night. Initially, when starting medications, headaches are common, but usually subside. Metoprolol Drugs in this class end in ‘olol’. These drugs work on the heart, vessels, and kidneys. Beta 1 receptors are primarily located in the heart and thus have major effects there, but also located in smaller numbers in the kidney and vasculature. Classification Beta 1 Mechanism of Action Blocking beta adrenergic receptor sites Decreasing movement of epinephrine Suppressing the renin-angiotensin-aldosterone system Beta Blocker responses Reduces cardiac contractility, heart rate Decreases pulse Decreased heart rate Decreased force of contraction Decreased velocity of the cardiac conduction system Indications Uses of Beta Blockers Angina Pectoris Hypertension Cardiac dysrhythmias Myocardial infarction Heart failure Side Effects - Hypotension - Fatigue - Headache - GI disturbances Adverse Reactions - Bradycardia - Congestive heart failure - Cardiac arrest - Bronchoconstriction Contraindications - Hyperthyroidism - Pregnancy - Diabetes mellitus - Cardiac dysrhythmias - Hypertension Therapeutic Considerations o o Patients with diabetes may experience hypoglycemia. Caution for hypertension in pregnancy (treated with methyldopa). Cholinergic Agonists Classifications Nicotinic Agonist: succinylcholine (in skeletal muscle relaxants), varenicline Muscarinic Agonist: bethanechol Acetylcholinesterase inhibitors: neostigmine Cholinergic: Drug that activates the parasympathetic nervous system Parasympathomimetic: Drug that mimics the actions of the parasympathetic nervous system Acetylcholine: Neurotransmitter responsible for parasympathetic activity Mechanism of Action Stimulates the parasympathetic nervous system Mimics the neurotransmitter acetylcholine Muscarinic receptors: Affect smooth muscles, slow heart rate Nicotinic receptors: Affect skeletal muscles Indications Indications for Cholinergics will vary based on the pathology. Myasthenia Gravis Goal is to increase Acetylcholine activity in the neuromuscular junction to strengthen muscle tone. Learning and memory Goal is to increase Acetylcholine in the synapse. Stimulating urination Drugs like bethanechol chloride are used to treat urinary retention. Side Effects - Blurred vision - Hypotension - Bradycardia - Diarrhea - Urinary frequency - Increased secretions - Bronchoconstriction Adverse Reactions - Cardiac dysrhythmia - Reflex tachycardia Contraindications - Bradycardia, hypotension - COPD, asthma - Peptic ulcer - Parkinson’s disease Therapeutic Consideration Other drugs that lower the heart rate/blood pressure Atropine Neostigmine Classification Acetylcholinesterase inhibitors Mechanism of Action increases the amount of acetylcholine for use in the nerves acetylcholine helps nerves transfer signals throughout the brain assisting in memory and cognition The enzyme acetylcholinesterase degrades acetylcholine, by blocking this enzyme acetylcholine is allowed to build up and can increase acetylcholine transmission. Indications Indications for acetylcholinesterase inhibitor neostigmine Myasthenia Gravis Glaucoma Urinary or GI motility agent Side Effects - GI distress including anorexia that leads to weight loss and dehydration - Dizziness, headache, depression, confusion, dry mouth - Peripheral edema Adverse Reactions - Bradycardia - Orthostatic hypotension - Myocardial infarction, heart failure - Hepatoxicity Therapeutic Consideration NSAIDS – increase GI upset Other drugs that cause bradycardia and hypotension Bethanechol Classification Muscarinic agonist Contraindications - Liver/renal disease - Hypotension - Bradycardia Mechanism of Action Activates muscarinic receptors Indications increase bladder tone increase urine output Side Effects - Headache - Malaise - Lacrimation - Miosis discomfort - Diarrhea - Nausea - Salivation - Vomiting - Flushing - Sweating - Hypothermia Adverse Reactions - Bronchospasm. - Heart block - Syncope/cardiac arrest - Bradycardia - Hypotension Contraindications - Hypersensitivity - Mechanical obstruction of the GI or GU tract Therapeutic Consideration o o o o Drugs that antagonize cholinergic effects Additive cholinergic effects with cholinesterase inhibitors Use with ganglionic blocking agents may result in severe hypotension Do not use with depolarizing neuromuscular blocking agents Succinylcholine Classification Nicotinic agonist Mechanism of Action Prevents neuromuscular transmission by blocking the effect of acetylcholine at the myoneural junction. Indications Neuromuscular blocker used during surgical procedures to produce skeletal paralysis after induction of anesthesia and provision of opioid analgesics. Side Effects Adverse Reactions Contraindications muscle - Hyperkalemia - Respiratory collapse - - Hypersensitivity History of anaphylaxis with other neuromuscular blockers, Chronic renal disease Burn patients Patients with crush injuries and rhabdomyolysis Therapeutic Considerations o o Should be avoided in traumatic injuries and burn due to high probability of acute hyperkalemia Do not use in chronic renal disease and those who have had previous anaphylactic reactions to neuromuscular blockers Varenicline Classification Partial agonist at the nicotinic receptor Mechanism of Action Partial agonist at the nicotinic receptor. It works by blocking the effects of nicotine on the brain Indications Smoking cessation Side Effects - Nausea - Insomnia - Headaches Adverse Reactions - Abnormal vivid dreams - Aggressive mood changes Contraindications - Severe psychiatric symptoms, including suicidal ideation, as there are reports of such adverse outcomes with varenicline Therapeutic Consideration o Patients taking varenicline should have closer therapeutic supervision to monitor for behavioral symptoms. o Varenicline excretion is via the renal route, and thus it is crucial to monitor renal function. Cholinergic Antagonists Classification Nicotinic Antagonist: tubocurarine Muscarinic Antagonist: atropine, scopolamine *** These are drug classes that block parasympathetic activity*** Cholinergic antagonists are also known as anti-cholinergics, or blockers because they do exactly the opposite of cholinergic agonists. of acetylcholine, but each anti-cholinergic affects a different area cholinergic T They Inhibit the action of the body. Characteristics of Anticholinergic Drugs Anticholinergic-drugs that block the parasympethic response, often act as a sympathetic medication. Characteristics of Parasympatholytic Drugs Another way to say this is by using the term parasympatholytic. These are drugs that block or inactivate the parasympathetic response, often act like a sympathetic medication. Atropine Classification Muscarinic Antagonist Mechanism of Action Inhibits acetylcholine by occupying receptors Increases heart rate by blocking vagal nerve stimulation Indications decreases salivation and respiratory and GI secretions before surgery increases heart rate when bradycardic dilates pupils for eye exam prevention of motion sickness, nausea and vomiting *** Anticholinergics are also an antidote for overdose of cholinergic drugs that cause muscle paralysis and respiratory depression. *** Side Effects Adverse Reactions Contraindications - Dry mouth and skin Inability to sweat Flushing, blurred vision Constipation Urinary retention - Dysrhythmias Palpitations - Possible intestinal obstruction Glaucoma GI disorders that slow the GI tract Tachycardia Benign Prostatic Hypertrophy Myasthenia Gravis Therapeutic Consideration Can increase anticholinergic effects with antihistamines and antidepressants. Scopolamine Classification Muscarinic Antagonist Mechanism of Action Muscarinic antagonist Indications prevention of motion sickness Scopolamine and atropine have similar effects on the peripheral nervous system. However, scopolamine has greater effects on the central nervous system (CNS) than atropine due to its ability to cross the blood–brain barrier. Side Effects - Dry mouth and skin - Inability to sweat - Flushing, blurred vision - Constipation - Urinary retention Therapeutic Considerations available in patch form Curare (Tubocurarine) Adverse Reactions - Dysrhythmias - Palpitations Contraindications - Glaucoma - GI disorders that slow the GI tract - Tachycardia - Benign Prostatic Hypertrophy - Myasthenia Gravis Classification Nicotinic Antagonist Mechanism of Action Tubocurarine is a non-depolarizing agent meaning the complete blockage of nicotinic acetylcholine receptors by inhibiting sodium. Indications Muscle relaxant often used during surgery in an anesthetic cocktaail. Side Effects - Dry mouth, constipation - Ice chips, increase fiber, etc. - Dry skin, heat stroke Be careful if patient is active - Mydriasis, Blurred vision, photophobia, photosensitivity, - Palpitations, urinary retention, tachycardia - Confusion, agitation in elderly - Drowsiness, heat stroke Adverse Reactions - Sudden drop in blood pressure CI anyone with renal dysfunction Contraindications - Severe allergic reaction to an NMBA or anaphylaxis Therapeutic Consideration Tubocurarine has greater potential to release massive amounts of histamine compared to other non-depolarizing agents. UNIT 3: Pharmacology of Pain Control (Chapters 10, 15,18-20) Pathways and Mediators of Pain control Pain is a complex biological response that we try to manage with various medications we will discuss later. Nociceptive Pain Pathway Nociception is the detection of pain through a receptor called a nociceptor. This pain signal that is derived from the injured area must travel to the brain via afferent or sensory neurons through depolarization or action potentials. Recall that depolarization requires the ion sodium, this will be critical when we talk about mechanisms of action for the the way to the CNS (brain) local anesthetics. The signal is propagated all where it is processed. Nerve conduction Stimuli sent to CNS via afferent, sensory neurons During depolarization of impulse conduction, this requires Na+ Propagation of signal continues to CNS Nerve Fiber Characteristics The neurons or nerve fibers that transmit pain signals can be classified by diameter and amount of myelination. Understanding this for a nerve fiber helps us estimate if and how to what degree they will be sensitive to anesthetics Diameter/ Myelination - A largest, usually heavily myelinated, FASTEST, lease sensitive to anesthetics - B intermediate diameter, light myelination - C smallest, no myelination SLOWEST, most sensitive to anesthetics The sensory nerves (C fibers) are the first fibers to become blocked by local anesthetics because these fibers are relatively small in diameter and unprotected by myelin sheaths (unmyelinated). In contrast, the motor nerves that supply skeletal muscle (A fibers) are the last fibers to be inhibited because motor nerves are large fibers with thick myelin coverings. Stages of Anesthesia Stage I: Analgesia - Less pain perception, but still conscious (used for outpatient procedures) Responses - Euphoria, giddiness, loss of pain, loss of consciousness Stage II: Excitement Responses - Increased sympathetic tone, elevated blood pressure and heart rate, hyper-reaction to stimulation Stage III: Surgical Anesthesia Responses - Sleep, normal blood pressure, and respiration Dilated pupils, loss of corneal reflex Skeletal muscle relaxation Stage IV: Medullary Suppression Responses - Paralysis of the diaphragm hypotension Respiratory paralysis leads to circulatory collapse and death Types of pain Acute vs Chronic Intermittent vs Prolonged Neuropathic Pain Referred Pain Short or Long term Variable or constant Caused by damage to nerves Pain caused in body coming from a different location Local Anesthetics Types General Depresses the CNS Alleviates pain Causes a loss of consciousness Local Pain relief in limited area Routes - Inhalation IV Topical Local Spinal Lidocaine Classification Amide local anesthetic Mechanism of Action Inhibits transport of sodium ions across neurol membranes Indications - Dental procedures Suturing skin lacerations Short-term (minor) surgery at a localized area - Blocking nerve impulses (nerve block) below the insertion of a spinal anesthetic Diagnostic procedures such as lumbar puncture and thoracentesis Regional blocks Side Effects - Loss of sensation in affected area Adverse Reactions - The symptoms of cortical stimulation are nervousness, excitation, tremors, and convulsions. Contraindications - During pregnancy, hepatic blood is increased, and plasma protein binding is decreased, making the amide local anesthetics more available for metabolism and excretion. Therapeutic Consideration Monitor cardiovascular and respiratory vital signs Procaine Classification Local ester anesthetic Mechanism of Action inhibits sodium influx through voltage gated sodium channels. Indications dental anesthetics Side Effects - Dizziness or drowsiness - Anxiety or restlessness - Nausea or vomiting Adverse Reactions - An allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives Contraindications Hypersensitivity reaction Therapeutic Consideration Procaine has also been shown to bind or antagonize nicotinic acetylcholine receptors and the serotonin receptors ion channel complex. General Anesthetics Midazolam Classification Intravenous general anesthetic; benzodiazepine Mechanism of Action binds with GABA receptor (inhibitory chloride ion channel) and decreases neuronal membrane excitability Indications Pre-operative sedation and induction Conscious sedation (monitored anesthesia care) for brief diagnostic endoscopic procedures or Along with neuromuscular blockers for sedation and amnesia during intubation Side Effects - Adverse Reactions Postoperative nausea and vomiting (PONV) - Respiratory depression Cardiac depression Contraindications - - Patients with COPD, due to the risk for respiratory depression Pregnancy (FDA Pregnancy Category D) Therapeutic Considerations - Monitoring vital signs frequently pre- and post-operatively should be the standard of care. Metabolism of midazolam is inhibited by grapefruit juice and alcohol. Midazolam has a specific receptor antagonist, flumazenil, used as an antidote or reversal agent in case of overdose. It does not produce analgesia, so another anesthetic may be added. Its anticonvulsant/seizure suppressant activity is an advantage during surgery. Vecuronium Classification Nondepolarizing neuromuscular blocker Mechanism of Action Binds to nicotinic-muscle (Nm) receptors at the neuromuscular junction, preventing acetylcholine binding. This produces paralysis by inhibiting depolarization or nerve transmission. Indications Skeletal muscle relaxation of abdominal or intrathoracic muscles for procedures surgical Facilitation of airway management (intubation/mechanical ventilation) Side Effects Adverse Reactions - Paralysis of respiratory muscles Contraindications - Hypersensitivity - Neuromuscular dysfunction (myasthenia gravis, spinal cord lesions) Therapeutic Consideration Monitoring vital signs frequently pre- and post-operatively should be the standard of care. Extreme caution is needed for patients with neuromuscular dysfunction (myasthenia gravis, spinal cord lesions). The specific antidote or reversal agent in case of vecuronium overdose is anticholinesterase drug neostigmine. the CNS depressant drugs and alcohol are to be avoided. Propofol Classification Intravenous general anesthetic Mechanism of Action NMDA (N-methyl D- aspartate) glutamate receptor antagonist: blocks influx into neuronal cell membranes and prevents depolarization/excitation cation Indications Preferred anesthetic for induction, maintenance and conscious sedation (monitored anesthesia care) during diagnostic and surgical procedures Side Effects - Pain on injection (due to emulsifiers in injection) Adverse Reactions - Respiratory depression - Apnea - Cardiac depression - Hypotension Contraindications - Hypersensitivity - Lipid metabolism disorders and hyperlipidemia (due to emulsifiers in injection) Therapeutic Consideration Monitoring vital signs frequently pre- and post-operatively should be the standard of care. Propofol has a narrow therapeutic index. It is the only anesthetic that is antiemetic. Pain on injection can be avoided by using lidocaine. Provides an uncomplicated post-operative recovery due to preventing nausea/vomiting, no adipose tissue accumulation, no potentiation of neuromuscular blockers Special consideration for strict aseptic handling technique (due to emulsifiers in injection) Ketamine Classification Intravenous general anesthetic Mechanism of Action NMDA glutamate receptor antagonists Indications Induction and maintenance for monitored anesthesia care during diagnostic and surgical procedures (analgesia and sedation) Side Effects - Postoperative nausea and vomiting (PONV) - Salivation - Vivid dreams and hallucinations - Out-of-body experiences and increased auditory sensitivity Therapeutic Consideration Adverse Reactions Contraindications - Hypersensitivity - Hypertension - Increased intracranial pressure - Monitoring vital signs frequently pre- and post-operatively should be the standard of care. Anesthetic of choice for patients with asthma or bronchospasm due to bronchodilation and preventing respiratory depression. Activation of sympathetic nervous system explains many drug effects. It is a dissociative anesthetic - a form of general anesthesia in which patients do not appear to be unconscious. Post-operative delirium can be treated with benzodiazepines. Unlike other general anesthetic, ketamine increases skeletal muscle tone. Nitrous Oxide Classification Inhalation anesthetic Mechanism of Action NMDA antagonist Indications Dental anesthesic Side Effects - Dizziness or drowsiness - Anxiety or restlessness - Nausea or vomiting Adverse Reactions - An allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives - Chest pain or slow or irregular heartbeats - Trembling, shaking, or seizures (convulsions) Contraindications Hypersensitivity reaction Therapeutic Consideration Fastest onset, colorless, odorless gas Opiates and Non-opioid Analgesics Classification Non-opioid analgesics Analgesics (pain relievers) and antipyretics (fever reducers) ex: acetaminophen Opiates Morphine Classification Opioid agonist Prototype: Morphine Other opioids to consider: Fentanyl Hydrocodone Mechanism of Action Opioids receptors modulate synaptic transmission- close presynaptic Ca channels, inhibiting release of ACh, norepinephrine, 5-HT, glutamate.. 2+ Indications Pain associated with procedures Trauma Cancer Visceral pain Decrease cough reflex (antitussive) Decrease GI motility in diarrhea Side Effects - Nausea Vomiting - Pruritus - Addiction - Constipation - Miosis Adverse Reactions - Respiratory depression - Hypotension - Bradycardia - Contraindications - Hypersensitivity - CNS or respiratory depression - Status asthmaticus - Increased ICP Therapeutic Considerations There is a risk of tolerance and physical dependence for morphine, fentanyl, and hydrocodone. Non-Opioid Analgesic Acetaminophen Classification non-opioid analgesic and antipyretic agent Mechanism of Action inhibits the cyclooxygenase (COX) pathways lacks peripheral antiinflammatory properties reduces the production of prostaglandins in the brain allowing the brain to tolerate a greater amount of pain before the patient feels it fever is reduced by sending signals to the brain's heat control center, it to lower the body's temperature telling Indications used to treat pain and fever prescribed as a single agent for mild to moderate pain and in combination with an opioid analgesic for severe pain Side Effects - Skin rash Adverse Reactions - Decreased levels of sodium and calcium - Hyperammonemia - Hyperchloremia - Hyperuricemia - Increased serum glucose - Increased liver enzymes - Nephrotoxicity (elevations in BUN, creatinine) - Hematological: anemia, leukopenia, neutropenia, pancytopenia - Metabolic and electrolyte Contraindications - Hypersensitivity to acetaminophen - Severe hepatic impairment, or severe active hepatic disease Therapeutic Consideration Healthy liver => diseased liver Non-steroidal Anti-inflammatory Drugs (NSAIDs) Ibuprofen Classification NSAIDs Mechanism of Action Exact mechanism of action unknown; thought to work by inhibiting action of enzyme cyclooxygenase (COX) responsible for prostaglandin synthesis. Produces pain relief by inhibiting both COX1 and COX 2 - therefore, it is a nonselective COX inhibitor. COX-1 is inhibited more potently than COX-2, causing stomach irritation. COX-2 is the enzyme that causes pain and inflammation COX-1 is the enzyme that helps to maintain the stomach lining Indications mild to moderate pain inflammation fever Dysmenorrhea Side Effects - Nausea - GI distress Adverse Reactions - Ulceration - GI bleeding - Kidney failure - Liver failure Contraindications - Drug hypersensitivity/allergy - Pregnancy Therapeutic Consideration Potential risk for severe stomach bleeding in patients: that are elderly, consuming alcohol while using NSAIDs, taking blood thinners, steroids, or other NSAIDs. NSAIDs may be taken with meals or milk to minimize GI side effects. NSAIDs should not be used during pregnancy. Celecoxib Classification NSAIDs Mechanism of Action Celecoxib selectively inhibits action of only COX-2, inhibiting prostaglandin synthesis and producing pain relief (analgesia) and reducing inflammation. Indications - Osteoarthritis Rheumatoid arthritis, and other musculoskeletal disorders Mild to moderate pain Fever reduction Celecoxib is preferred over ibuprofen for long-term use. Selectively inhibits COX-2 having less potential for GI adverse reactions. Used for : Osteoarthritis Rheumatoid arthritis, and other musculoskeletal disorders Mild to moderate pain Fever reduction Celecoxib is preferred over ibuprofen for long-term use. Side Effects - COX-2 inhibitors (Celecoxib) still have a risk for GI upset and GI bleeding, but not as great as COX-1 inhibitors. - GI distress - Dizziness Adverse Reactions - Cardiovascular risk, including the increased risk of heart attacks and strokes Contraindications - Coronary artery disease - Hypersensitivity - Like all NSAIDs, celecoxib should not be taken after 29 weeks of pregnancy. Therapeutic Consideration Monitor a patient’s blood pressure, renal and liver function, and monitor for signs and symptoms of GI bleeding Cannabinoid Dronabinol Classification Cannabinoid agonist Mechanism of Action Coronary artery disease Hypersensitivity Like all NSAIDs, celecoxib should not be taken after 29 weeks of pregnancy. Indications - Nausea/vomiting induced by cancer chemotherapy Stimulate appetite and prevention of weight loss in AIDS patients only Side Effects - Drowsiness - Dizziness - Appetite stimulant Adverse Reactions - Overactivation of sympathetic nervous system - Mood changes (euphoria, confusion, depression) - Withdrawal syndrome (irritability, insomnia, restlessness) Contraindications - Hypertension - Mania - Schizophrenia - Pregnancy Therapeutic Consideration - Caution with simultaneous use of herbal products, opioids, sleeping pills. Dronabinol is a Schedule C-III drug with a high abuse potential. - Use with caution in elderly patients as mood changes (euphoria, confusion, depression, dizziness) can develop. Reversal Agents/ Antidotes Buprenorphine Naloxone N-acetylcysteine Flumazenil Opioid addiction treatment; partial agonist/antagonist Opiate overdose Acetaminophen overdose Benzodiazepine overdose UNIT 4: Pharmacology of the Central Nervous System (Chapters 11-14, 16-17) Parts of the Brain CNS: Brain + Spinal cord receive ==== process==== TO SENSORY INFORMATION respond==== Parts of the CNS Cerebrum Controls: somatosensory, motor, language, cognitive thought, memory, emotions, hearing, vision Grey matter: Basal ganglia- helps coordinate and regulate the muscular act Limbic System Located laterally to the thalamus underneath the cerebral cortex and abbove brainstem Assist cognition process: spatial memory, learning, motivation, emotional processing, social processing. Diencephalon Located superior to the brainstem Four major portions: epithalamus, subthalamus, hypothalamus, and thalamus Reticular Formation the In the anterior portion of the brainstem Functions: Movement coordination, autonomic regulation of blood pressure, rate, respiratory rate, postural reflexes, neuro-vegetative wakefulness, sleep. heart reflexes, taste, Cerebellum Located behind the pons of the brainstem Responsible for coordination voluntary movements, Brainstem Connects the cerebrum of the brain to the spinal cord and the cerebellum Three parts: midbrain - Between the pons and the diencephalon - contain dopaminergic neurons and serotonergic neurons - involved in pain suppression Pons - Connect the medulla oblongata inferiorly and to the superiorly midbrain - produce and spread norepinephrine - relate to coordinate movement and modulate breathing medulla oblongata - connect the pons to the spinal cord - motor neurons cross to the contralateral side of the body - it carries the CV- respiratory regulation system, descending motor tracts, ascending sensory tracts, and 9,10,11 &12 Mental Health Disorders Classifications Disruptive mood dysregulation disorder Major depressive disorder Persistent depressive disorder (dysthymia) Premenstrual dysphoric disorder Depressive disorder due to another medical condition origin of CN Features Sadness Emptiness Irritable mood Treatments Sedatives- Sedatives are a type of medication that slows down your brain activity and an agent that exerts a soothing or tranquilizing effect. Hypnotics- Hypnotics are drugs that are used to help people fall asleep. GABA Neurotransmitter Gamma-aminobutyric acid (GABA) acts as the principal inhibitory neurotransmitter in the central nervous system (CNS). GABA usually causes hyperpolarization of the postsynaptic neuron to generate an inhibitory postsynaptic potential. GABA Receptors GABA-A receptors - involves two alpha-1 subunits, two beta-2 subunits, and one gamma-2 subunit all situated in a ring around a selective pore. Sedative- Hypnotic Drugs Sedative-hypnotic drugs are chemical substances used to reduce anxiety and induce calm (sedative effect) or to induce sleep (hypnotic effect). GABA Potentiators Diazepam Classification Benzodiazepine Mechanism of Action - - Benzodiazepines are a class of drugs that act upon benzodiazepine receptors (BZ-R) in the central nervous system (CNS). The extracellular portions of the alpha and gamma subunit proteins of the GABA receptor form a binding site for benzodiazepines and increase the frequency of chloride ion channel opening. When the channel is open, it functions to reduce neuronal excitability by increasing the influx of chloride ions (Cl-) and inhibiting nerve transmission. Indications - Anxiety Sedation - Seizures *** Drug of choice for status epilepticus (administered IV)*** Side Effects - Drowsiness - Lethargy - Lack of coordination Adverse Reactions - Respiratory depression - Ataxia - Fall risk - Confusion - Slurred speech - Paradoxical excitement - Agranulocytosis Contraindications - Hypersensitivity - Pregnancy (FDA Pregnancy Category D) Therapeutic Consideration Flumazenil is a benzodiazepine receptor antagonist. Flumazenil injection is indicated for a complete or partial reversal of the sedative effects of benzodiazepines in conscious sedation and general anesthesia in the adult and pediatric populations. Avoid combining with other CNS depressants including alcohol. Used as an adjunct therapy to mitigate withdrawal symptoms associated with alcohol detoxification. Never suddenly discontinue benzodiazepine therapy as this may precipitate seizures. Phenobarbital Classification Barbiturates Mechanism of Action Phenobarbital is a long-acting barbiturate that enhances GABA receptors. This increases the influx of chloride ions and membranes. results in hyperpolarization of nerve Indications Seizures Anxiety Side Effects - Drowsiness - Dry mouth - Lethargy Adverse Reactions Cardiovascular and CNS depression Contraindications - Acute intermittent porphyria - Lack of coordination Mental confusion and memory difficulties in older patients - Pregnancy (FDA Pregnancy Category D) Therapeutic Consideration Enzyme induction results in faster metabolism of the barbiturate, and drug tolerance There is no antidote for barbiturate overdose. Used as a component of balanced anesthesia for induction. Prolonged use can lead to tolerance and physical dependence. Never suddenly discontinue barbiturate therapy as this may precipitate seizures. Serotonin Modulators Fluozetine Classification Selective Serotonin Reuptake Inhibitor (SSRI) Mechanism of Aciton Fluoxetine very selectively blocks serotonin (5-HT) reuptake back into the serotonergic nerve endings. This increases serotonin concentration in the synapse and results in increased stimulation of serotonin receptors. Indications Major depression OCD: Obsessive Compulsive Disorder GAD: Generalized Anxiety Disorder Side Effects - Gastrointestinal disorders - Nausea - Diarrhea - Dry mouth - Sexual dysfunction - Headache - Insomnia - Tremors Therapeutic Consideration Adverse Reactions - Serotonin syndrome (confusion, fever, tremor agitation, restlessness, seizures) Contraindications - Hypersensitivity - Use of monoamine oxidase inhibitors (MAOI) - Use with caution in those with a history of seizures. It normally takes 4–8 weeks for antidepressants to show appreciable effect. There is a warning for suicidal ideations in those treated with fluoxetine, especially in the 18 to 24 year age range. Fluoxetine should never be abruptly stopped as this will lead to discontinuation syndrome (dizziness, nausea, anxiety, insomnia). Duloxetine Classification Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) Mechanism of Action Duloxetine is a serotonin and norepinephrine reuptake inhibitor (SNRI) Indications Major depression Side Effects - Headache - Drowsiness and fatigue - Weight loss Adverse Reactions - Serotonin syndrome (confusion, fever, tremor agitation, restlessness, seizures) - Increased norepinephrine levels (hypertension, increased heart rate and CNS activation) Contraindications Uncontrolled acute-angle glaucoma, or hypersensitivity Therapeutic Consideration Sudden discontinuation will lead to discontinuation syndrome (dizziness, nausea, anxiety, insomnia). Both fluoxetine and duloxetine can cause discontinuation syndrome which include the following signs and symptoms seizures, somnolence, syncope, tachycardia, diarrhea, and vomiting. Signs and symptoms of overdose include serotonin syndrome, seizures, coma, somnolence, syncope, tachycardia, autonomic instability, diarrhea, and vomiting. Sumatriptan Classification Serotonin Agonist (antimigraine) Mechanism of Action - Sumatriptan works on the serotonin (or 5-HT) receptors located on blood vessels in your brain. This causes them to narrow and helps take away the headache and eases other symptoms such as feeling or being sick and sensitivity to light and sound. Indications Acute migraine Cluster headache attack Side Effects - Nausea - Vomiting Adverse Reactions - High BP - Serotonin Syndrome Contraindications - Hypersensitivity Therapeutic Consideration The drug is an effective and well-tolerated treatment for a migraine when given intravenously, subcutaneously, or orally. However, when prescribing sumatriptan the nurse must be fully aware of its CNS adverse effects. Ondansetron Classification Serotonin Antagonist Mechanism of Action Centrally, Ondansetron acts on 5 HT3 serotonin receptors in the brain stem, and peripherally on 5 HT3 serotonin receptors that can be found at the vagus nerve (parasympathetic) terminals. Indications Controls nausea and vomiting after aurgery and in patients receiving Side Effects - Headache - Constipation Adverse Reactions - Delayed ventricular relaxation chemotherapy Contraindications - Hypersensitivity Therapeutic Consideration Dopamine Modulators ECG monitoring along with potassium and magnesium monitoring in the elderly or other at-risk groups Preferred choice for severe nausea and vomiting Levodopa Classification dopamine precursor carbidopa: inhibitor of DOPA decarboxylase Mechanism of Action - Levodopa is a precursor that is converted to dopamine in the CNS and periphery. Carbidopa increases the bioavailability of dopamine in the CNS. It is administered together with carbidopa, to inhibit enzyme DOPA decarboxylase. Carbidopa inhibits DOPA decarboxylase to prevent premature formation of dopamine before reaching the brain. Indications Parkinson’s Disease Side Effects - Nausea - Somnolence - On-off phenomenon Adverse Reactions - Orthostatic hypotension - Fainting - Movement disorders Contraindications - MAO-A inhibitors used in treating mental depression also should not be taken with levodopa. Therapeutic Consideration - Patents should take medication on time to prevent on-off phenomenon. Ropinirole Classification Dopamine Agonists Mechanism of Action Dopamine receptor agonists Indications Parkinson’s Disease Side Effects - Nausea and vomiting - Abdominal pain - Somnolence - Dizziness Adverse Reactions - Orthostatic hypotension - Hallucinations - Liver toxicity Contraindications - Persons who misuse alcohol - Patients with liver failure Therapeutic Consideration - - Patients and caregivers should receive education about the medication, its use, side effects, signs of toxicity, and compliance. Assess Blood Pressure periodically during therapy, Assess patient for signs and symptoms of psychotic-like behavior. Risk of symptoms increases with age. Bupropion Classification Antidepressant Mechanism of Action Decreases neuronal reuptake of dopamine in the CNS, and neuronal of serotonin and norepinephrine uptake Indications Bipolar disorder Smoking cessation Obesity Side Effects - Dry mouth - Insomnia - Nausea - Tremor - Agitation - Anorexia - Insomnia Therapeutic Consideration Adverse Reactions - Seizures - Hypertension - Suicidal thoughts and psychotic behavior Contraindications - Seizure disorder - Use of MAOI's Assess mental status and mood changes in all patients, especially during months of therapy and during dose changes. Risk may be increased adolescents, and young adults (≤24 yrs). Haloperidol Classification typical antipsychotic Mechanism of Action blocks dopamine D2 receptor initial in children, Indications Used in the treatment of schizophrenia Side Effects - Produce the highest incidence of extra pyramidal symptoms (EPS) - Tardive dyskinesia - NMS - Movement disturbances Therapeutic Consideration Adverse Reactions Dysrhythmias - Cardiac monitoring should be in place until the ECG becomes normal. Contraindications - Dementia - Hypersensitivity - Parkinson's disease Blood levels should be monitored at 12-hour or 24-hour intervals, or after the last dose of haloperidol use in a patient. Watch for signs and symptoms of toxicities. The clinician should consider gastric lavage or induction of emesis as soon as possible. Olanzapine Classification atypical antipsychotic Mechanism of Action blocks dopamine D2 receptors Indications schizophrenia if the patient is over the age of 13 bipolar disorder including mixed or manic episodes Side Effects - Weight gain - Reduced insulin sensitivity Therapeutic Consideration Adverse Reactions - Akathisia - Extrapyramidal symptoms - Tardive dyskinesia - Neuroleptic malignant syndrome Contraindications - Elderly patients with dementia who present with symptoms of psychosis should not be prescribed olanzapine. - Hypersensitivity - Caution in patients with diabetes mellitus BLACK BOX WARNING ***There is a black box warning for olanzapine regarding dementia-related psychosis. *** Miscellaneous Mental Health Medications Phenelzine Classification Non-selective monoamine oxidase A and B inhibitor (MAOI) Mechanism of Action MAOI: phenelzine irreversibly blocks serotonin norepinephrine and being broken down dopamine from Indications Treatment for resistant depression, panic disorder, mood disorders and disorders Side Effects - Drowsiness or dizziness Adverse Reactions - Adverse effects on the GABA and melatonin receptors and can potentiate insomnia. social anxiety Contraindications - Tramadol because seizures may be potentiated. - Also, phenelzine may not be combined with sympathomimetic drugs (e.g., amphetamines, cocaine, methylphenidate) because it can cause a hypertensive crisis with a headache, intracranial bleeding, and even the potential of death occurring. - Contraindicated with other antidepressants due to risk of serotonin syndrome - usually need a two week wash out period before switching medications to or from an MAOI. Treatment Consideration Hypertensive crisis could occur when this drug is taken with tyraminefoods such as cheese and wine containing Amitriptyline classification Tricyclic antidepressants mechanism of action Blocks the reuptake of both serotonin and norepinephrine neurotransmitters indications Depression Note that SSRI’s and SNRI’s are preferred over TCA’s because of their toxicity Side Effects - Weight gain, gastrointestinal symptoms like constipation, xerostomia, dizziness, headache, and somnolence. Adverse Reactions - Orthostatic hypotension, dizziness, and sedation. It can also cause heart rate variability, arrhythmias. more limited Contraindications Amitriptyline should not be used if there is a history of QTc prolongation, arrhythmias, recent myocardial infarction, or heart failure. Use caution in patients with angleclosure glaucoma, urinary retention, seizures. Do not use with MAOI and also within 14 days use of MAOIs. Therapeutic Consideration Do not use with any medications that can also cause QTa prolongation increased risk Lithium Classification Mood stabilizer Mechanism of Action due to Lithium appears to reduce the hyperactivity and the excitement and also better organization of thought patterns. allows Lithium is an element similar in chemical properties to sodium. The body utilizes lithium as if it were sodium. Indications Bipolar affective disorder. It is used in combination with antidepressants control mania Side Effects Adverse Reactions - Thirst and frequency of - Heart and kidney urination are common damage - Polyuria and polydipsia - Nausea - Tremors - Vomiting - Diarrhea - Thyroid gland disturbances Therapeutic Consideration to Contraindications - Breastfeeding is not advisable - Existing thyroid condition - Renal impairment - Pregnancy Explain to patients that the therapeutic effects of lithium may require 1 or weeks of treatment 2 Methylphenidate Classification psychomotor stimulants Mechanism of Action Directly stimulates norepinephrine and dopamine receptors, they stimulate the release of norepinephrine and dopamine from the nerve endings, and they inhibit the reuptake of these neurotransmitters back nerve endings. into the Indications Narcolepsy and ADHD Side Effects - Decreased appetite - Weight loss Adverse Reactions - High abuse potential - Toxic doses may produce severe agitation and a paranoid type of psychosis Contraindications - Hyperthyroidis - Manic behavior - Suicidal thoughts and psychosis - Risk of cardiovascular events Therapeutic Consideration The same kind or category as amphetamines. Disulfiram Classification Disulfiram Indications Alcohol use disorder Mechanism of Action Inhibits the enzyme aldehyde dehydrogenase (ALDH) which converts to acetate, the 2nd step in ethanol breakdown. Side Effects - Diaphoresis - Palpitations - Facial flushing - Nausea - Vertigo - Hypotension - Tachycardia Adverse Reactions - Hepatitis - Hepatoxicity - Psychosis - Seizures - Peripheral neuropathy - Optic neuritis acetaldehyde Contraindications - Coronary artery disease - Heart failure Cases of heart failure and death have occurred in patients with severed myocardial disease shortly after the initiation of disulfiram. Therapeutic Consideration Close monitoring of adverse events is necessary, in particular, patients polysubstance abuse. with UNIT 5: Pharmacology of the Cardiovascular System- Part 1 (Chapter 21-23, 27) Cardiac Anatomy & Physiology Cardiac muscle (or myocardium) makes up the thick middle layer of the heart. Highly coordinated contractions of cardiac muscle pump blood into the vessels of the circulatory system. Cardiac muscle cells Rapid, involuntary contraction and relaxation of the cardiac muscle cells are vital for pumping blood throughout the cardiovascular system. A cardiac muscle cell activates from the release of calcium from the sarcoplasmic reticulum (SR). Cardiac Conducting system Cardiac Electrophysiology Cardiac Disorders CAD: Coronary Artery Disease one or both coronary arteries can no longer deliver sufficient amounts of blood and to the heart muscle. oxygen CHF: Congestive Heart Failure When the right side fails, fluid accumulates in the abdominal organs (ascites) and lower extremities. When the left side of the heart fails, fluid accumulates in the lungs (pulmonary edema) and interferes with gas exchange, resulting in shortness of breath. MI: Myocardial Infarction (Heart Attack) A myocardial infarction or MI occurs when an area of heart muscle is deprived of blood flow. The area deprived of blood dies unless immediate treatment is administered to restore blood flow. Blockage of blood flow is caused by the formation of a blood clot in one of the coronary arteries. The clot usually forms in a vessel where there are atherosclerotic plaques. Angina Pectoris Angina pectoris (AP) is a clinical syndrome that is characterized by episodes of intense pressure in the chest caused by inadequate blood flow to meet the oxygen heart muscle. pain or demand of the The cause of AP is usually atherosclerosis of the coronary arteries, which results in narrowing of the arteries. Physiology of Blood Clotting Blood Clotting Prevents the further loss of blood, oxygen and nutrients from a wounded area Heart, Lungs, Brain Susseptable to damage or loss or reduction of blood flow Aggregation Platelets stick to each other Adhesion Platelets stick to the vessel walls Stages of Healing Stage 1- initiation (thromboplastin is produced) Stage 2- propagation (thromboplastin converts to pro-thrombin to thrombin) Stage 3- fibrin formation (thrombin converts to fibrinogen to fibrin): activations of clotting factors Antiplatelet Agents Aspirin Classification NSAID Mechanism of Action Irreversibly inhibiting the cyclooxygenase enzyme (COX) activity in the prostaglandin synthesis pathway (PGH2Thromboxane A2 works by inducing platelet aggregation and vasoconstriction). Indications Used therapeutically to prevent myocardial infarction. Side Effects Adverse Reactions - Gastric Ulcer Contraindications Children and teenagers should never be given - - Potential for hemorrhage (choose opioids) Reye’s Syndrome salicylates for chicken pox or flu symptoms before a doctor is consulted because of the possibility for Reye’s syndrome to occur. Therapeutic Consideration Toxic doses of salicylates depress the medullary respiratory centers so that individuals cannot remove carbon dioxide (CO2) rapidly, leading to respiratory acidosis. Tinnitus- toxicity Clopidogrel Classification inhibit platelet aggregation Irreversible inhibitor of the platelet adenosine diphosphate (ADP) receptor. Indication Reduce myocardial infarction Reduce stroke and death Patients who are sensitive to gastrointestinal bleeding induced by aspirin Side Effects - Headache - Vomiting - Rash - Diarrhea - Dizzines Adverse Reactions Thrombocytopenia - a reduction in platelets that does not allow the patient to clot. Internal bleeding occurs. Contraindications Poor metabolizers of clopidogrel: These patients may be at increased risk of cardiovascular events due to inadequate drug effect if the patient is taking a proton pump inhibitor. Therapeutic Consideration patient must undergo routine blood and platelet counts. Anticoagulants Enoxaparin Classification Therapeutic: anticoagulants Pharmacologic: antithrombotic, low molecular weight heparins Mechanism of Action It binds to and potentiates antithrombin, to form a complex that irreversibly inactivates factor Xa. i Factor X (Stuart–Prower factor) is a vitamin K-dependent clotting factor. Indication Prevention and treatment of thrombotic events such as deep vein thrombosis and pulmonary embolism (PE), prevent excess coagulation during procedures such as cardiac surgery, and safe during pregnancy. Side Effects Adverse Reactions - Rash - Bleeding - Constipation - Thrombocytopenia - Nausea - Vomiting - Dizziness Therapeutic Consideration (DVT) Contraindications Known hypersensitivity to enoxaparin (urticaria, anaphylactic reactions) or any heparin products, GI bleed, CVA. It has an immediate onset of action when given in the intravenous form. Enoxaparin has less activity against factor IIa (thrombin) compared to unfractionated heparin. Enoxaparin has an advantage over heparin because of its bioavailability. Ninety percent of the drug is available when given in the subcutaneous form. Heparin Classification Therapeutic: anticoagulants Pharmacologic: antithrombotics Mechanism of Action Inhibitory (inactivation effect) effect of antithrombin on factor Xa and thrombin Indication Prevention and treatment of thrombotic events such as deep vein thrombosis (DVT) and pulmonary embolism (PE) as well as atrial fibrillation (AF), prevent excess coagulation during procedures such as cardiac surgery. Side Effects - - Fever Hypersensitivity reactions Adverse Reactions - Bleeding & thrombocytopenia (30% of patients who receive heparin) - Drug-induced hepatitis Contraindications - Thrombocytopenia - Uncontrollable bleed Therapeutic Considerations Protamine is recommended for reversal of heparin’s anticoagulant effect Warfarin Classification Anticoagulant (enteral) Mechanism of Action Competitively inhibits the vitamin K epoxide reductase complex 1, which is an essential enzyme for activating the vitamin K available in the body. Indications Treat and prevent blood clots. Prophylaxis and treatment venous thrombosis and arising pulmonary embolisms. Reduction in the risk of death, recurrent myocardial infarction. Side Effects Easy bleeding or bruising Adverse Reactions - Intracranial hemorrhage - Gastrointestinal (GI) bleed - Hematemesis - Intraocular bleeding - Hemarthrosis Contraindications - Hypersensitivity - Hemorrhagic tendencies Therapeutic Considerations Elderly patients are at an increased risk of bleeding complications secondary to falls, concomitant drug interactions, cognitive status, and living situation. Novel Oral Anticoagulants Apixaban Classification NOAC Mechanism of Action Direct factor Xa inhibitor, blocking the propagation phase of the coagulation cascade Indication Side Effects Non-valvular atrial fibrillation to reduce the risk of stroke and blood clots. Deep venous thrombosis (DVT) and pulmonary embolism (PE). Adverse Reactions Contraindications - Gingival bleeding Nausea - Hematuria Hypermenorrhea Active pathological bleeding and severe hypersensitivity reaction Therapeutic Consideration The antidote for the reversal of factor Xa inhibitors is called Andexanet alfa. The inhibitor binds to the drug rather than to natural Xa itself. Rivaroxaban Classification NOAC Mechanism of Action Competitively inhibits Factor Xa. Inhibits both free and clot-bound Factor Xa, as well as prothrombinase activity, thereby prolonging clotting times. Indication For patients undergoing elective orthopedic surgery like knee and hip replacement surgery postoperative thromboprophylaxis of DVT. Used for stroke prevention in people with cardiac arrhythmia. For patients undergoing hip replacement surgery. Used in the prevention of postoperative thromboprophylaxis and deep venous thrombosis. Side Effects Adverse Reactions Hemorrhage, including intracranial, GI, retinal, epidural hematoma, adrenal bleeding. Contraindications - Active pathological bleeding and severe hypersensitivity reaction - Hepatic impairment Therapeutic Consideration US boxed warning includes: Increased risk of thrombotic events can occur with premature cessation of rivaroxaban so, when discontinuing the drug, the addition of alternative anticoagulant therapy should merit consideration Thrombolytic Agents Alteplase Classification Thrombolytic (tPA: tissue plasminogen activator) Mechanism of Action tissue plasminogen activator Indications acute ischemic stroke, pulmonary embolism, acute myocardial infarction, and occluded catheters. Side Effects - fever Adverse Reactions - Bleeding - Angioedema - Anaphylaxis Contraindications - Internal bleeding Therapeutic Consideration Alteplase may be used in conjunction with heparin and aspirin for the treatment of myocardial infarction. Antidysrhythmic Procainamide Classification Antidysrhythmic Class 1- sodium channel blocker Mechanism of Action Blocks the influx of Na+ ions. Slows or blocks conduction Decrease slope of phase 0 depolarization Indications Supraventricular arrhythmias Atrial flutter and fibrillation Ventricular arrhythmias Outpatient treatment of ventricular arrhythmias Side Effects - Nausea - Diarrhea - Anorexia - Skin rash Adverse Reactions - Hypotension - Bradycardia - Atrioventricular block - Ventricular tachycardia - Reversible SLE like syndrome Contraindications - Electrolyte imbalances Therapeutic Consideration Monitoring QRS duration via cardiac monitoring Atenolol Classification Antidysrhythmic Class II Beta 1 adrenergic antagonist Mechanism of Action Selective Beta 1 Antagonist Indications Hypertension Angina pectoris Cardiac arrhythmias (tachycardia) Supraventricular Prevent Myocardial Infarction CHF Side Effects - Nausea - Diarrhea - Bronchospasm Adverse Reactions - Bradycardia - Hypotension - Heart failure - Cardiac arrest Contraindications - Bradycardia - Heart Failure - Asthma Therapeutic Consideration Tachycardia Increased lipolysis Increased myocardial contractility Increased release of renin Amiodarone Classification Antidysrhythmic Class III Potassium channel blockers Mechanism of Action Blocks potassium channels and interferes with the efflux of potassium ions (K +) during repolarization Prolongation of ventricular repolarization (Phases 1-3) Prolongation of QT interval Indications Supraventricular and ventricular arrythmias Side Effects - Dizziness - Tremors - Ataxia Adverse Reactions - Bracycardia - Heart block - Heart failure - Pulmonary fibrosis - Torsades de Pointes - Blue-gray skin discoloration Contraindications Pregnancy Breast feeding Therapeutic Consideration In addition to blocking potassium channels, amiodarone blocks sodium (Class 1) and calcium (Class 4) channels. It also has blocking actions on both beta- (Class 2) and alpha-adrenergic receptors. Verapamil Classification Antidysrhythmic Class IV Calcium channel blockers Mechanism of Action Decrease SA node activity, resulting in a slight decrease in heart rate Indications Supraventricular tachycardias Side Effects - Headache - Dizziness - GI disturbances (constipation) Therapeutic Consideration Adverse Reactions - Hypotension - Cardiac depression - Heart failure If used together with beta blockers it can lead to a hear block Antidysrhythmic Part II Digoxin Classification Class V digitalis cardiac glycosides (narrow therapeutic window) Mechanism of Action Increases the force of myocardial contractions (positive inotropic effect) Contraindications Existing SA and AV node disturbances or with heart failure Increases the concentration of calcium ions inside cardiac muscle cells Stimulates the vagus nerve Indications Heart failure Atrial fibrillation Side Effects - Nausea - Vomiting - Headache - Visual disturbances - Rashes Adverse Reactions Contraindications - Cardiac arrhythmias Hypokalemia - Extra heart beats - Premature ventricular contractions - Ventricular tachycardia - Ventricular fibrillation - Cardiac arrest Therapeutic Consideration Before administering glycosides, a patient’s pulse should be taken to ensure that the heart rate is between 60 and 100 beats per minute. Digitalization Patient should receive adequate amounts of potassium in their diets. Dopamine Classification Non-selective adrenergic agonist Mechanism of Action Normal artery => vasoconstriction artery Indications unstable bradycardia circulatory shock Side Effects - Mimics epinephrine Adverse Reactions - Orthostatic hypotension Contraindications Additive effect when combined with sympathomimetic drugs Therapeutic Consideration Low doses: vasodilation and increased renal blood flow Moderate doses: stimulates beta-1 (contraction and CO) Higher doses: Alpha effect (vasoconstriction) Antidote Digoxin Immune Fab Classification Antidote Mechanism of Action DIF binds to digoxin molecules and reduces free digoxin levels. The reduction results in an equilibrium shift away from receptor binding and thereby decreases cardiotoxic effects. Indications For use in treating cardiac glycoside (digoxin) toxicity Therapeutic considerations They are extremely useful in reversing severe intoxication with most glycosides UNIT 6: Pharmacology of the Cardiovascular System- Part 2 (Chapter 24-26,29) Variables Contributing to Cardiovascular Function Lipids 5 Main Classes of Lipoproteins Chylomicrons Very-low-density lipoprotein (VLDL) Intermediate-density lipoprotein (IDL) Low-density lipoprotein (LDL) High-density lipoprotein (HDL) HDL & LDL HDL (good cholesterol) function: help keep arteries clear and free of plaques LDL (bad cholesterol) function: form plaques in arteries causing them to harder and narrow. All calories which are not used immediately are converted into triglycerides and are stored in fat cells (adipose tissue). Triglycerides provide one’s body with energy. Determinants of Blood Pressure - Cardiac output, stroke volume and peripheral resistance. The cardiac output is the amount of blood pumped per minute by the heart. Cardiac Output (CO) = Heart Rate (HR) X Stroke Volume (SV) The blood volume can vary based on body size, ideal body weight, body composition (lean body mass vs. fat), basal metabolic rate, and nutrition, among others. Peripheral resistance (PR) is the resistance or friction that the arteries and arterioles have against the flow of blood. Three factors determine this force: the length of the blood vessels in the body, the diameter of the vessels, and the viscosity of the blood within them. Renin Angiotensin Aldosterone System (RAAS) Renin is produced by the kidneys. The contribution of the renin-angiotensin-aldosterone system is to increase blood pressure. It elevates the blood volume by causing vasoconstriction, and sodium and water retention. Types of Angina Angina pectoris (AP) is a clinical syndrome that is characterized by episodes of intense pain or pressure in the chest caused by inadequate blood flow to meet the oxygen demand of the heart muscle. The etiology of chest pain caused by cardiac ischemia is largely accepted to be due to atherosclerosis of coronary arteries and coronary vasospasm. Angina is chest pain, and other possible areas of radiating pain include the neck, jaw, upper abdomen, shoulders, and arms. Exertional angina: caused by exercise, overexertion or stress Variant or Prinzmetal angina: caused by vasospasm of coronary arteries Unstable angina: occurs when coronary arteries are almost completely blocked Renal System Sodium ions are extremely important because they are the principal cations (positively charged ions) in the extracellular fluid, and their large extracellular concentration creates an osmotic gradient that attracts water molecules. Thus, the renal mechanism for water conservation (balance) is directly dependent upon the tubular reabsorption of sodium ions. Lipid Lowering Agents Atorvastatin classification statin Mechanism of Action HMG-CoA reductase inhibitors lowers LDL and triglycerides Indications High cholesterol (hypercholesterolemia) and prevention of coronary disease Side Effects - Rash - Pruritis - Gastrointestinal symptoms Adverse Reactions - Chest pain - Peripheral edema - Rhabdomyolysis - Hyperglycemia Therapeutic Consideration Patients with impaired renal function may be at increased risk of developing rhabdomyolysis Ezetimibe Classification Contraindications - Hypersensitivity - Liver disease - Pregnancy (may cause fetal harm) lipid lowering agent Mechanism of Action Acts selectively on the surface of the small intestine to block the absorption of cholesterol Decreases VLDL and circulating LDL cholesterol Indications high cholesterol (hypercholesterolemia) Side Effects - Rash - Fatigue Adverse Reactions - Cholecystitis - Cholelithiasis - Increases liver enzymes Contraindications - Hypersensitivity - Liver disease Therapeutic Consideration Well-tolerated by most patients, while minimal joint and muscle pain may occur. Can be combined with other hypolipidemic drugs, for example HMG-CoA Inhibitors. Gemfibrozil Classification lipid lowering agent (fibrates) Mechanism of Action inhibits peripheral triglyceride lipolysis increases HDL cholesterol Indications high cholesterol (hypercholesterolemia) Side Effects Gastrointestinal symptoms Adverse Reactions - Vertigo - Alopecia - Atrial fibrillation Contraindications - Hypersensitivity - Liver disease Therapeutic Consideration Gemfibrozil may increase cholesterol excretion into the bile, leading to gallstone formation Niacin Classification lipid lowering agent Mechanism of Action decreases lipoprotein and triglyceride synthesis Indications hyperlipidemia Side Effects - Dizziness - Flushing with generalized pruritus and burning sensation Therapeutic Consideration Adverse Reactions Hepatotoxic Contraindications - Hypersensitivity Causes peripheral vasodilation in large doses. Flushing can be mitigated by taking aspirin. Vascular Tone and Volume Regulators Part I Furosemide Classification Loop diuretics (volume regulators) Mechanism of Action Inhibits the reabsorption of sodium and chloride from the loop of Henle and renal tubule. Increases renal excretion of water, sodium, chloride, magnesium, potassium, and calcium. distal Indications Congestive heart failure Hypertension Edema Renal disease Side Effects - Electrolyte depletion (imbalance): hypocalcemia, hypochloremia, hypokalemia, hypomagnesemia, hyponatremia, hypovolemia Adverse Reactions - Dehydration - Hyperglycemia - Hearing loss and Tinnitus - Metabolic alkalosis Contraindications - Hypersensitivity - Severe Liver Disease - Anuria - Hypotension - Bradycardia - Hearing loss - Orthostatic hypotension - Increased cholesterol and glycemic levels Therapeutic Consideration In cases of severe renal impairment, furosemide increases ototoxicity Special cautionary boxed warning for profound diuresis and electrolyte imbalance. Hydrochlorothiazide Classification Thiazide diuretic (volume regulators) Mechanism of Action Increases excretion of sodium and water by inhibiting sodium reabsorption in distal tubule. Promotes excretion of chloride, potassium, hydrogen, magnesium, phosphate, calcium and bicarbonate. the Indications congestive heart failure hypertension edema renal disease Side Effects - Electrolyte depletion (imbalance): hypocalcemia, hypochloremia, hypokalemia, hypomagnesemia, hyponatremia, hypovolemia - Orthostatic hypotension - Photosensitivity Therapeutic Consideration Adverse Reactions - Dehydration - Gout - Hyperglycemia - Hepatitis - Pancreatitis Contraindications - Hypersensitivity - Uncontrolled diabetes - Hepatic diseases Diuretic drug of choice for first-line treatment of hypertension . Not effective in patients with severe renal impairment due to low creatinine clearance. Monitor hyponatremia in elderly patients. Spironolactone Classification Potassium- sparing diuretic (volume regulators) Mechanism of Action Causes loss of sodium bicarbonate and calcium while saving potassium and hydrogen ions by antagonizing aldosterone. Indications Hyperaldosteronism Management of edema associated with HF, cirrhosis and nephrotic syndrome Can be used as an adjunct to other diuretics to prevent hypokalemia Side Effects Adverse Reactions - Dizziness - Metabolic acidosis - Hyperkalemia, - Arrhythmias hyponatremia, - Breast tenderness hyperchloremic and gynecomastia metabolic acidosis (males) - Erectile dysfunction - Hormonal imbalance Therapeutic Considerations Contraindications - Hyperkalemia - Hypersensitivity - Renal insufficiency - Addison's disease Off-label use for acne and hirsutism (females), hormonal therapy for transgender females (male to female transition) due to testosterone lowering effect Acetazolamide Classification diuretics (volume regulator) Mechanism of Action Inhibition of renal carbonic anhydrase, resulting in self-limiting urinary excretion of sodium, potassium, bicarbonate, and water. Indications Management of acute altitude sickness Edema due to HF Glaucoma Side Effects - Depression, weakness, drowsiness - Gastrointestinal issues Adverse Reactions - Aplastic anemia - Dizziness - Depression Contraindications - Hypersensitivity - Hepatic impairment - Transient nearsightedness - Hyperglycemia - Hyperchloremic, hypokalemia, metallic taste, nausea, vomiting, melena Therapeutic Consideration - Glucose dysregulation - Avoid during first trimester of pregnancy. Use Cautiously in: Chronic respiratory disease Electrolyte abnormalities Gout; Renal disease Vascular Tone and Volume Regulators Part II Antihypertensives Classification Hydralazine (vasodilator) Mechanism of Action Relaxes the arteriolar smooth muscle BUT NOT venous smooth muscle Indications Moderate to severe hypertension (with a diuretic) Side Effects - Headache - Nausea - Flushing - Hypotension - Dizziness Adverse Reactions - Angina and palpitations - Drug-induced lupus erythematosus (DILE), and glomerulonephritis are associated with the use of hydralazine Contraindications - Hypersensitivity. - Caution with Cardiovascular disease and renal impairment. - Lupus Therapeutic Consideration Losartan Hydralazine undergoes polymorphic acetylation. Those that are slow acetylators require lower doses of the drug. Reflex tachycardia is a concern when given intravenously to patients that already have elevated heart rate. MAO inhibitors may exaggerate hypotension Increases risk of low blood pressure with the use of antihypertensives, nitrates and alcohol. Classification Angiotensin II receptor antagonist/ blocker, remove antihypertensive Mechanism of Action Blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II at various receptor sites, including vascular smooth muscle and the adrenal glands. Indications Management of hypertension Treatment of diabetic nephropathy in patients with type 2 diabetes Prevention of stroke in patients with hypertension and left ventricular hypertrophy Side Effects - Dizziness, weakness - Chest pain, edema - Hypotension - Hypoglycemia, weight gain Adverse Reactions - Chest pain - Impaired renal function - Hypoglycemia - Hyperkalemia - Edema - Angioedema - Fever Contraindications - Hypersensitivity - Can cause injury or death of fetus –if pregnancy occurs, Lactation: Discontinue drug or use formula. - Hepatic impairment (lower initial doses recommended) Therapeutic Consideration Excessive hypotension may occur with concurrent use of diuretics. Risk of hyperkalemia with concurrent use of potassium potassium-sparing diuretics. It may not be effective in African American populations when used to reduce the risk for stroke. Lisinopril Classification Angiotensin converting enzyme (ACE) inhibitor Mechanism of Action Angiotensin-converting enzyme inhibitor and prevents the conversion of angiotensin I to angiotensin II, which is a potent vasoconstrictor. Indications Management of hypertension Management of heart failure Side Effects - Dry cough - Hypotension - Dizziness Adverse Reactions - Hyperkalemia - Angioedema - Renal insufficiency Contraindications - Hypersensitivity - History of angioedema with previous use of ACE inhibitors - US BOX WARNING: Can cause injury or death of fetus Therapeutic Consideration ACE inhibitor-induced cough is a dry, nonproductive, hacking cough. It usually begins in the first few months of treatment and resolves within 1 to 4 weeks after discontinuation of the medication. Nitroglycerin Classification Vasodilator Mechanism of Action Vasodilate by increase of nitrus oxide (NO) in vascular smooth muscle. Dilates veins to a greater degree than arteries . * Decrease preload Indications General vasodilation of systemic veins and arteries Acute Angina (sublingual) Prevention (daily capsules, ointment) Emergency medication for hypertensive crisis (IV) Presentations 1. Sublingual tablet & capsules 2. Sublingual spray 3. Nitroglycerin ointment 4. Transdermal nitroglycerine 5. IV in emergencies Side Effects Adverse Reactions - Headache - Fainting - Cutaneous flushing - Reflex tachycardia - Dizziness - Hypotension - Weakness Therapeutic Consideration Contraindications - Hypersensitivity - PDE-5 inhibitor use (ED) Important for patients to carry the prescribed medication at all times. Nitroglycerin is volatile, and tablets lose potency if exposed to air or light. Patients should be instructed to sit down before taking their emergency sublingual tablet for an angina attack to reduce the risk of fainting/falling. Nitroglycerin is contraindicated with Sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) that are used in the treatment of erectile dysfunction. UNIT 7: Pharmacology of the Endocrine System (Chapters 35-40) Variables Contributing to Endocrine Function Regulation of Hormone Secretion Positive Feedback In positive feedback, the end product stimulates more production of the end product. Negative Feedback Negative feedback is the mechanism that regulates most hormones that control the endocrine system. Posterior Pituitary Hormones: Antidiuretic Hormone (ADH, Oxytocin 2 hormones produced by the hypothalamus and stored in the posterior lobe is: 1. Antidiuretic hormone (ADH) 2. Oxytocin (OXT) ADH; Vasopressin Release stimulated Osmoreceptors in the hypothalamus when the body is low on water Decrease in blood volume and pressure - Kidney Decrease water loss from the kidney Triggers vasoconstriction to increase blood pressure Regulation: negative feedback Diabetes insipidus Large loss of body water: polyuria Primary target Effect ADH Deficiency Oxytocin Release stimulated Neurons in the hypothalamus Targets Uterus, mammary glands Effects Stimulates contraction of uterine muscles during labor and delivery Stimulates contraction of cells surrounding milk secretory cells in mammary glands Relationship bonding Regulation: positive feedback Endocrine Function Thyroid hormones: T3, T4 Hypothalamic � Anterior Pituitary � Thyroid(HPT)Axis Pancreatic Hormones: Insulin, Glucagon Insulin - Insulin is an anabolic hormone. It is produced by beta cells of the pancreatic islet to lower blood glucose levels. Stimulate glucose uptake by many cells that have insulin receptors. Inhibit glycogenolysis. Increase protein synthesis and fat storage. Glucagon is a catabolic hormone. It is produced by alpha cells of the pancreatic islets to raise blood glucose levels. Stimulate glycogenolysis in the liver an muscles to glucose and release into the bllod stream during fasting states(such as at night). Mobilize energy reserve and increase fat breakdown. Glucagon - Glucagon is a catabolic hormone. It is produced by alpha cells of the pancreatic islets to raise blood glucose levels. Stimulate glycogenolysis in the liver an muscles to glucose and release into the bllod stream during fasting states(such as at night). Mobilize energy reserve and increase fat breakdown. Blood Glucose Monitoring Assess response to insulin as indicated by blood glucose levels: Hyperglycemia/hypoglycemia Confirm/adjust antidiabetic drug dose needed for glycemic control Glucose meters Test daily glucose fluctuations blood glucose levels several times a day and adjust (meal planning, exercise) lifestyle 70 - 110 mg/dL: healthy fasting blood glucose level 111 to 125 mg/dl: impaired glucose tolerance (insulin resistance) Greater than 126 mg/dl: indicative of diabetes Blood sugar levels are affected by illness, stress and exercise Glycated Hemoglobin (HbA1c) Evaluates glucose levels over time (3 months) and elevated HbA1c levels (>6.4%) are indicative of the risk for diabetic complications like retinopathy, nephropathy, neuropathy, cardiovascular disease and stroke. Diabetes mellitus is a pathophysiology of faulty glucose metabolism causing buildup of glucose in the blood and urine. Female Sex hormones: Estrogen, Progesterone FSH Targets: Follicular cells of ovaries Effects: Follicle development Secretion of estrogens (and inhibin): o Female secondary sex characteristics and behaviors Secretion of inhibin LH Targets: Corpus luteum of ovaries Effects: Control of Ovulation Secretion of progesterone: o Prepares uterus for implantation of embryo o Prepares mammary glands for secretory functions Estrogen Deficiency Estradiol is the most abundant and most active, exerts a negative and a positive feedback effect on FSH and LH. In children: Hypogonadism and primary ovarian failure. Replacement therapy is required to complete puberty and permit adequate bone growth. In adults Removal of ovaries (surgical-induced menopause; premature menopause) and menopause. Hormone Replacement Therapy (HRT) is indicated for the management of vasomotor symptoms of menopause. Estrogen decline also leads to reduction in bone mass or osteoporosis. Male Sex Hormone FSH Targets: nurse cells of testes Effects: o o Sperm maturation Secretion of inhibin LH Targets: interstitial cells of testes Effects: - Secretion of tesosterone: o Protein synthesis in skeletal muscles o Male secondary sex characteristics and behaviors Erectile Dysfuntion ” Impotence” may be used to describe varied problems that interfere with sexual intercourse and reproduction, often associated in men with erectile dysfunction (ED). ED can be a total inability to achieve erection, an inconsistent ability to do so, or a tendency to sustain only brief erections. Process: To establish and maintain an erection, blood flow increases through the erectile tissue in the penis. During sexual arousal, nitric oxide (NO), an endogenous vasodilator, is released in the erectile tissue of the penis. NO stimulates production of cyclic guanosine monophosphate (cGMP) which results in arterial smooth muscle relaxation and thus, vasodilation - blood flows into erectile tissue and the penis inflates (erection). Eventually, phosphodiesterase (PDE-5) degrades cGMP. Degenerative Bone Disease: Osteoporosis Bone remodeling consists of two phases: Bone resorption Bone deposition Two critical cells which balance the plasma calcium concentration through bone remodeling are: Osteoclasts Osteoblasts Role of Estrogens in Osteoporosis Estrogen inhibits PTH: post-menopause, negative feedback mechanism to control PTH secretion is lost – with age, bone deposition decreases while bone resorption increases, causing osteoporosis. Estrogens When combined with calcium, it stimulates bone mineralization Increases bone mineral density Estrogen inhibits PTH; thus, after menopause, the negative feedback mechanism to control PTH secretion is lost. As one ages, the amount of time spent in bone deposition decreases and bone resorption increases, causing osteoporosis. Pituituary Hormones Desmopressin Classification Antidiuretic hormone (ADH)/ Vasopressin analogue Mechanism of Action Mimics normal ADH secretion and regulates renal reabsorption of sodium and This reduces water loss in the urine. water. Indications - diabetes insipidus - nocturnal enuresis Side Effects - Nausea - GI cramping Adverse Reactions - Cutaneous vasoconstriction (pallor) - Increased blood pressure Contraindications Therapeutic Consideration Caution must be observed with individuals who have coronary artery disease (increase in blood pressure with high doses). Oxytocin Classification Oxytocin analogue Mechanism of Action Stimulates contraction of uterine muscles during labor and delivery Indications Medical induction of labor Side Effects - Nausea Adverse Reactions - Vomiting - Diarrhea - Bronchoconstriction - Hemorrhage Contraindications Patients with asthma - Uterine tetany/rupture Fetal distress Therapeutic Consideration Oxytocin IV infusion is adjusted to allow birth to follow the normal sequence Thyroid Hormones Levothyroxine Classification Thyroid hormone (thyroxine/T4) replacement Mechanism of Action increases metabolic rate Increases oxygen consumption Promotes glycogenesis and body growth Utilizes and mobilizes stored glycogen Stimulates protein synthesis Indications Hypothyroidism, goitere, cretinism, myxedema Side Effects - Nervousness - Sweating - Diarrhea - Metabolic stimulation resulting in weight loss Adverse Reactions - Hyperthyroidism - Increased blood pressure and heart rate (palpitations, tachycardia, hypertension) - Fever Contraindications - Hyperthyroidism - Cardiovascular conditions (hypertension, myocardial infarction, congestive heart failure) - Adrenal insufficiency - Treatment of weight loss in obesity Therapeutic Consideration Individualized therapy starts with the smallest effective dose (may be incrementally raised). Hormone replacement is a lifelong treatment. Morning daily dosing is recommended on an empty stomach. Recommended 30 minutes before eating or taking other medications. It is an FDA Pregnancy Category A drug. Levothyroxine increases sympathetic tone, explaining its side and adverse effects, so extreme caution should be exercised in patients with cardiovascular and renal disease. Blood glucose levels increase, so patients with diabetes may need an increased dose of insulin or oral hypoglycemic drugs. Long-term therapy may cause osteoporosis in postmenopausal women. Do not use for weight loss in obesity. Propylthiouracil Classification Thyroid hormone synthesis inhibitor Mechanism of action Inhibits incorporation of iodide into tyrosine, NO effect on hormone release Indications hyperthyroidism grave’s disease thyrotoxic crisis Side Effects - Nausea - Drowsiness - Weight gain Adverse Reactions - Bradycardia - Agranulocytosis (evidenced by fever) - Myalgia - Liver toxicity Contraindications - Pregnancy - Nursing mothers Therapeutic Consideration Antithyroid drugs should never be used during pregnancy and nursing to neonatal goiter and cretinism, and infant hypothyroidism. prevent Medications for Pancreas/ Glucose Homeostasis Types of Insulin -It is categorized based on the duration of action Establishing a dosing schedule for insulins -mimic insulin secretion over 24 hours in a normal, healthy nondiabetic person. Rapid-acting insulin Produce single peak in blood glucose, time to coincide with meals, usually administered 15 to 30 minutes before meals. Insulin lispro, insulin aspart, insulin gulisine Long-acting insulins Deliver consistent insulin concentration over 24 hours, produce ‘peakless’ blood glucose levels after a single subcutaneous injection; once-daily dosing. Insulin detemir, insulin glargine *** Insulin preparations have similar metabolic effects – vary in onset and duration of action.*** Changes in Insulin Requirements Colds, fevers, surgery, and stress all increase glucose levels, which increases insulin dose Heavy exercise can lower insulin dose Drugs can affect glucose levels, requiring changes to the insulin dose Allergic reactions may necessitate change to another species of insulin. Drugs that DECREASE the insulin requirement (potnetiate insulin) Drugs Alcohol, ACE inhibitors, adrenergic neuronal blockers, anabolic steroids, oral anticoagulants Beta-blockers, propranolol, chloroquine, clofibrate Lithium carbonate, MAO inhibitors, metoprolol, salicylates, pentamidine, pyridoxine (vitamin B₆), tetracyclines Response These drugs decrease blood glucose concentrations by: o Interfering with glucose metabolism o Inhibiting the sympathetic nervous system Parenteral Insulin Administration o Insulin is usually administered subcutaneously in the arm, thigh, or abdomen o Injection sites should be rotated to prevent lipodystrophy at the site of injection Hypoglycemia Short-term hypoglycemia Small snack high in glucose along with protein will supply an adequate amount of glucose in the short-term to correct hypoglycemia, followed by close monitoring. Severe hypoglycemia Severe hypoglycemia (diabetic coma) requires glucagon treatment intravenously for a rapid rise in blood glucose that lasts about 1 hour. Emergency Regular insulin is the only insulin administered IV in case of an emergency. Insulin replacement Classification Insulin hormone replacement Mechanism of Action Mimics endogenous insulin and stimulates glucose uptake by many cells that have insulin receptors Indications Parenteral administration Type 1 diabetes mellitus Type 2 diabetes mellitus Gestational diabetes mellitus Severe ketoacidosis Diabetic coma Side Effects - Blurred vision Adverse Reactions Contraindications - Allergic reaction (itching, urticarial swelling, or anaphylaxis) - Hypoglycemia (Hunger, Headache, Fatigue, Anxiety/Nervousness/Confusion, Paresthesia) Therapeutic Consideration Changes in insulin requirements Colds, fevers, surgery, and stress all increase glucose levels, which increases insulin dose Heavy exercise can lower insulin dose Drugs can affect glucose levels, requiring changes to the insulin dose Allergic reactions may necessitate change to another species of insulin. Parenteral insulin administration Insulin is usually administered subcutaneously in the arm, thigh, or abdomen Injection sites should be rotated to prevent lipodystrophy at the site of injection Hypoglycemia Small snack high in glucose along with protein will supply an adequate amount of glucose in the short-term to correct hypoglycemia, followed by close monitoring. Severe hypoglycemia (diabetic coma) requires glucagon treatment intravenously for a rapid rise in blood glucose that lasts about 1 hour. Regular insulin is the only insulin administered IV in case of an emergency. Metformin Classification Biguanide Mechanism of Action Indications Decreases blood glucose levels after meals (postprandial) by decreasing liver glucose production and intestinal glucose absorption Inhibits gluconeogenesis and glycogenolysis Enhances glucose use by other tissues in the body Oral antidiabetic drug Management of type 2 diabetes mellitus Side Effects - GI disturbances - Flatulence, Nausea - Weight loss Therapeutic Consideration Adverse Reactions - Diarrhea - Vomiting - Lactic acidosis (rare) Contraindications Alcohol Regulation of blood glucose levels demands patient compliance not only with antidiabetic medication, but also diet adjustment and exercise. Alcohol should be avoided as it potentiates the action of metformin on lactic acid metabolism. Rosiglitazone Classification Insulin sensitizer; thiazolidinediones (TZDs) Mechanism of Action Enhance peripheral cell response to insulin. Allow glucose to be used more efficiently. Decrease insulin resistance and increase insulin sensitivity of fat, skeletal muscle, and liver cells. Oral antidiabetic drug Management of type 2 diabetes mellitus Indications Side Effects - Headache Adverse Reactions - Fluid retention - Weight gain - Fatigue - Diarrhea Therapeutic Consideration Regulation of blood glucose levels demands patient compliance not only with antidiabetic medication, but also diet adjustment and exercise. Glyburide Classification Sulfonylurea; secretagogue Mechanism of Action Contraindications - Myocardial infarction - Congestive heart failure - Enter beta cells and cause the release of insulin (no insulin-like activity, so should not be used in type 1 diabetes). Indications Oral antidiabetic drug Management of type 2 diabetes mellitus Side Effects - GI irritation - Nausea - Headache Adverse Reactions - Hypoglycemia - Diarrhea - Fatigue - Dizziness Contraindications - Hypersensitivity - Liver and renal disease - Peptic ulcers - Ketosis Therapeutic Consideration Regulation of blood glucose levels demands patient compliance not only with antidiabetic medication, but also diet adjustment and exercise. Glucagon Classification Hormone Mechanism of Action - Mimics endogenous glucagon action of hepatic glycogenolysis, producing a rapid rise in blood glucose, lasting approximately an hour - Emergency acute management of severe hypoglycemia (IV) Indication Contraindications - Contraindication for glucagon includes hypersensitivity. Therapeutic Consideration Patient and family/caregiver should be advised about signs and symptoms of hypoglycemia. Counteracts insulin action or oral hypoglycemic agents. Intravenous dextrose can be given when hypoglycemia symptoms are controlled. Medications for Reproduction & Bone Homeostasis Part 1 Estrogen- Progesterone Contraception Classification Estrogen/Progesterone Hormone derivative Mechanism of Action - Maintain high blood levels of estrogen/progesterone, which inhibit release of FSH and LH - Prevent pregnancy; oral contraceptives Indications Side Effects - Nausea - Headache - Weight gain - Irritability - Breast tenderness Adverse Reactions - Vomiting - Dizziness - Depression - Fluid retention Contraindications - Pregnancy - Cardiovascular disease - Thromboembolic vascular disorders - Liver disease - Undiagnosed breast lumps - Unexplained vaginal bleeding Therapeutic Consideration Severity of side effects can be ameliorated by reducing the dose or changing to another product A variety of formulations and administration routes are available for hormonal delivery for contraception. Breakthrough bleeding or amenorrhea usually resolves to a consistent menstrual pattern within 3 months of continuing treatment. Oral contraceptives should be taken at the same time every day. Alternate forms of birth control should be utilized if antibiotics are being taken. Hormonal Replacement Therapy (HRT) Classification Estrogen hormone replacement (or estrogen with progestin) Mechanism of Action - Mimics and restores estrogen action and progesterone levels, provides adequate negative feedback to hypothalamus. - Symptoms of menopause such as hot flashes, sleep disturbances, vaginal dryness Indications Side Effects - Nausea - Headache - Breast tenderness Adverse Reactions - Vomiting - Fluid retention - Long-term effects Cardiovascular effects Contraindications - (thromboembolism, stroke) Breast and endometrial cancer Therapeutic Consideration - HRT is not an indefinite therapy. The lowest effective dose is to be taken for the shortest time. Regular general medical and breast examinations and mammograms are recommended. Mifepristone Classification Progesterone receptor antagonists Mechanism of Action - Mifepristone inhibits progesterone action by competitive blockade of endometrial progesterone receptors. This results in decay of the modified endometrium and detachment of the blastocyst, followed by decline of human chorionic gonadotropin (hCG) and progesterone levels. Indications - Abortifacient: Induction of abortion early in pregnancy (through day 70 of pregnancy) Side Effects - Nausea Adverse Reactions - Vomiting - Diarrhea - Excessive vaginal bleeding Contraindications - Patients with asthma - Pregnancy Terbutaline Classification Selective beta 2 adrenergic agonist Mechanism of action - Stimulation of uterine beta-2 receptors relaxes uterine smooth muscle and inhibits uterine contractions Indications Side Effects Arrest premature labor Adverse Reactions Contraindications - Nausea Headache Tremor - Increased blood glucose and fatty acids Fetal tachycardia Increased maternal blood pressure Risk of maternal morbidity in some cases Therapeutic Consideration Terbutaline should not be used beyond 48-72 hours due to potential of serious heart problems and death. Dose-related adverse effects of terbutaline will abate on discontinuation of the drug. Medications for Reproduction & Bone Homeostasis Part II Testosterone Replacement Classification testosterone hormone replacement Mechanism of Action Mimics testosterone action Indications testosterone deficiency due to pituitary disorders or testicular failure Side Effects - Nausea Adverse Reactions - Oligospermia - Gynecomastia - Jaundice - Diarrhea - Hirsutism in females Therapeutic Consideration Sildenafil Androgenic steroids are Schedule CIII drugs. For women and children, accidental exposure must be prevented to androgen products through touching medication application site or unwashed clothing with residual drug. Women and children should not touch these products to prevent masculinization/virilization. Contraindications Classification Phosphodiesterase type 5 (PDES) inhibitor Mechanism of Action Selective blockade of PDE-5 in the penis allows accumulation of cGMP to maintain a full erection Indications Erectile dysfunction Side Effects - Headache - Flushing - Upset stomach - Nasal congestion Adverse Reactions - Diarrhea - Rash - Priapism Contraindications - Nitrates - Antihypertensive medications Therapeutic Consideration Synergistic and severe hypotension will occur with nitrates and blood pressurelowering medications, leading to life-threatening cardiovascular conditions and myocardial infarction. Medications for Bone Disorders Bisphosphonates (Alendronate) Classification Bisphosphonate Mechanism of Action Protects by binding to mineral surface (calcium) of bone, keeping calcium in the and inhibiting bone resorption. matrix Indications Drug of choice for osteoporosis management Side Effects - Flatulence - Headache - Dry mouth Adverse Reactions - Gastritis - Esophageal ulcers - GI bleeding - Fractures of the vertebrae or femur when taking alendronate for over 5 years Contraindications - Hypersensitivity - Patients with hypocalcemia - Severe renal disease Therapeutic Consideration Milk, orange juice and fortified water can alter alendronate absorption. Alendronate irritates the lining of the esophagus, so patients must remain upright for 30 minutes after taking bisphosphonates. UNIT 8: Pharmacology of the Respiratory and GI systems (Chapter 31 & 32) Recognize Variables Contributing to Respiratory and GI Function Respiratory Function Bronchodilation The trachea and bronchi are composed of smooth muscle and cartilage for structural support, but there is no cartilage in the smaller airways such as the bronchioles and alveolar ducts. Only smooth muscle is present in the bronchioles and alveolar ducts. Thus, their diameter is determined by smooth muscle tone. Bronchiolar smooth muscle tone is regulated by both the sympathetic (bronchodilation) and parasympathetic (bronchoconstriction) branches of the autonomic nervous system. Bronchodilation is the relaxation of beta-2-mediated bronchiolar smooth muscle. Respiratory Diseases Asthma - Any pathophysiology that interferes with respiratory gas exchange results in serious alterations of O2 and CO2 concentrations in the blood. For the most common respiratory diseases, asthma and COPD, drug treatment consists of bronchodilators, anti-inflammatory and antiallergic agents. Chronic Obstructive Pulmonary (COPD) - Chronic bronchitis and emphysema are collectively referred to as chronic obstructive pulmonary disease (COPD). The primary caused of these conditions in COPD is tobacco smoking and chronic exposure to other environmental pollutants. Pro-Inflammatory Chemical Mediators Cyclooxygenase and Prostaglandins: Physiologic Effects - Most symptoms and complications of asthma and COPD are due to chemical mediators of inflammation. Chemical mediators like histamine, prostaglandins and leukotrienes (LT) are formed and released from injured tissue, mast cells and leukocytes during inflammatory reactions in the respiratory tract. Prostaglandins and leukotrienes are different chemical mediators both derived from arachidonic acid. Prostaglandins - The enzymes, cyclooxygenase-1 and -2, convert arachidonic acid into several different prostaglandins. Leukotrienes - The enzyme, lipoxygenase, converts arachidonic acid into leukotrienes. Histamine Receptors Histamine interacts with membrane receptors in certain tissues. There are four types of receptors associated with histamine: H1-, H2-, H3-, and H4-receptors. Physiologic/ allergic effects Anti-Inflammatory Steroids Corticosteroids: Physiologic Effects - Corticosteroids are released from the adrenal cortex. They are derivatives of the steroid hormone cortisol. An anti-inflammatory action of steroids is to inhibit arachidonic acid activation, thereby decreasing the formation of prostaglandins and leukotrienes. Corticosteroids also have several anti-inflammatory actions, by inhibiting: o inflammatory cell activity o release of inflammatory mediators from mast cells o production of allergic antibodies o Edema Drug Management for Asthma and COPD Bronchodilator Mechanism of Action Sympathomimetics: stimulate beta-2 adrenergic receptors Anticholinergics: inhibit cholinergic (muscarinic) receptors Methylxanthines such as theophylline Rescue Drugs - Bronchodilators that have a rapid onset of action, bronchodilating effects begin almost immediately after inhalation, providing immediate relief of bronchoconstriction. Nonselective beta-adrenergic drugs and selective beta-2 adrenergic drugs also inhibit the release of mast cell mediators. Reliever Drugs - Bronchodilators that are not considered “rescue drugs” because the onset of action usually requires 10 to 20 minutes, main effect is to relieve bronchoconstriction, particularly in asthma. Long-acting selective beta-2 provide a duration of action of approximately 12 hours, and are recommended to be administered in combination with an anti-inflammatory corticosteroid. Controller Drugs - Anti-inflammatory steroids and other drugs with anti-inflammatory actions that reduce and control the inflammatory response. Control of inflammation helps to enhance the effectiveness of bronchodilator drug (dosages can be reduced, thereby decreasing incidence/severity of adverse effects. Gastrointestinal Function Gastric Secretion Bowel Function Defecation is stimulated or inhibited by the autonomic nervous system. Stimulation of parasympathetic (cholinergic) nerves to the intestines increases peristalsis. Stimulation of the sympathetic (adrenergic) nerves decreases intestinal motility. Dietary fiber increases bulk and fluid content of feces, and decreases transit time through the colon, thus increasing frequency of defecation. Longer transit times will result in greater water reabsorption from feces, causing constipation. Drastic alteration of peristalsis (intestinal motility) will impair normal bowel function in diarrhea or constipation. Gastrointestinal Disorders Peptic Ulcers Gastrointestinal Esophageal Reflux Disease (GERD) GERD is a chronic disease characterized by the symptom of heartburn after meals, that worsens when lying down. In severe GERD, signs of chronic blood loss may be present, along with ulcers, inflammation and strictures, and fibrous tissue bands from chronic esophageal injury. Diarrhea/ Constipation Asthma and COPD Drugs Zafirlukast Classification Leukotriene receptor antagonists Mechanism of Action - Indications Blocks the leukotriene receptor and inhibits leukotriene actions as a chemical mediator of asthma, such as bronchoconstriction, mucus production, edema and inflammation Long term control and prevention of chronic asthma Side Effects - Headache - Gastrointestinal issues Adverse Reactions - Diarrhea - Hepatotoxicity (increased liver enzymes, fever, dark urine, jaundice) - Neuropsychiatric effects (agitation, depression, suicidal ideation) - Churg-Strauss syndrome (vasculitis) Contraindications - Liver impairment - Lactation Therapeutic Consideration - Available for inhalation and oral administration. Generally well-tolerated, but liver function and signs of liver toxicity should be explained, monitored and reported. Behavioral changes should be monitored. This drug does not have an immediate onset of action, so is not indicated for acute asthma attacks. Pregnancy Category B Prednisone Classification Corticosteroid (prednisone) Mechanism of Action Suppresses inflammatory response affects carbohydrate, protein, and fat metabolism affects muscle and blood cell activities Side Effects (Usually from high dose or prolonged use) - GI upset - Fluid and sodium retention - Edema - Weight gain - Appetite changes - Abnormal fat deposits in the face and trunk (Moon face) Adverse Reactions - Lab changes - Hypokalemia - Hyperglycemia - Hypernatremia - Hypertension - Immune function suppression (longterm use) Contraindications Caution with: - Diabetes mellitus - Hypertension - Renal disease Therapeutic Consideration - Available for inhalation and oral administration for acute asthma attacks Fluticasone Classification Corticosteroid Mechanism of Action Inhibits inflammatory response in the respiratory airways by inhibiting formation of prostaglandins and leukotrienes Indications Prophylactic or maintenance treatment of asthma (mild/persistent symptoms), in combination with bronchodilator (moderate symptoms) Side Effects - Headache - Dizziness Adverse Reactions - Cushing's syndrome - Churg-Strauss syndrome (vasculitis) Contraindications - Hypersensitivity Therapeutic Consideration Available for inhalation and oral administration. This drug does not have an immediate onset of action, so is not indicated for status asthmaticus (acute asthma attacks). Caution in: Active untreated infections, diabetes, glaucoma/cataracts, underlying immunosuppression (disease or concurrent therapy), systemic corticosteroid therapy. Pregnancy Category C Fluticasone/ Salmeterol Classification Corticosteroid/ long-acting selective beta-2-agonist (combination) Mechanism of Action Fluticasone inhibits respiratory airway inflammation by inhibiting formation of prostaglandins and leukotrienes. Salmeterol is a long-acting (12 hours) selective beta-2 agonist bronchodilator and reliever drug (10-20 minutes for onset of action). Bronchodilation by beta adrenergic agonists occurs by increasing adenylyl cyclase and cAMP levels. Indications Extended duration of action for chronic control and treatment of asthma (moderate symptoms), COPD Side Effects Generally, well tolerated Adverse Reactions Systemic effects due to oral administration: - Nervousness - Skeletal muscle tremors - Increased heart rate Contraindications - Hypersensitivity Therapeutic Considerations Available for inhalation. This drug does not have an immediate onset of action, so is not indicated for status asthmaticus (acute asthma attacks). FDA ‘black box’ warning to avoid high doses of long-acting beta drugs due to increased risk of mortality (reasons unknown). Ipratropium Classification Muscarinic cholinergic antagonist Mechanism of Action Atropine derivative that blocks actions of acetylcholine at muscarinic receptors, producing bronchodilation and reducing volume of respiratory secretions (reliever drug) thus Indications Chronic control and treatment of asthma First-line COPD drug for chronic bronchitis Side Effects Excessive drying of mouth and upper respiratory passages Adverse Reactions - Vomiting - Diarrhea - Bronchoconstriction Contraindications - Hypersensitivity Therapeutic Consideration Available for inhalation. Avoid use during acute bronchospasm (slow onset of action). Caution in: bladder obstruction, urinary retention, prostatic hyperplasia, glaucoma. Theophylline Classification Methylxanthine Mechanism of Action Inhibits phosphodiesterase (PDE), which slows cAMP inactivation, cAMP produces bronchodilation and inhibits release of mediators from mast cells. Also antagonizes adenosine, a bronchoconstrictor. Increases respiratory muscle contractility and stimulates mucociliary clearance, thereby improving gas exchange and removal of secretions. Indications Chronic control and treatment of both chronic bronchitis and emphysema (COPD) Side Effects Nausea and vomiting Adverse Reactions - Vasodilation (flushing, headache, hypotension) - Excessive cardiac stimulation (arrhythmia, tachycardia, angina) - CNS effects (restlessness, insomnia, tremors, convulsions) Contraindications - Hypersensitivity Therapeutic Consideration Can be administered in combination with sympathomimetics if one drug is unable to control asthma alone. Caution in cardiovascular disease. Mucolytics, Decongestants & Expectorants Acetylcysteine Classification Mucolytic Mechanism of Action Contains sulfhydryl group that degrades glycoproteins in bronchial secretions, thus decreasing viscosity (thin, liquefy) and promoting easier mobilization and removal (by expectoration/coughing or suction apparatus). Indication Increased production and thickening of mucus that contributes to airway obstruction and interferes with normal respiration in various conditions, such as asthma, bronchitis, respiratory infections Side Effects Drowsiness Adverse Reactions - Vasodilation - Tachycardia - Hypotension - Bronchospasm Contraindications - Hypersensitivity Therapeutic Consideration To prevent bronchospasm, a bronchodilator is added to acetylcysteine inhalation mixture. Administration by nebulization, followed by postural drainage and tracheal suction if needed. Adequate hydration can help liquefy and mobilize secretions. Monitor for signs and symptoms of fluid overload (dyspnea, edema, increased BP) during therapy. Antidote for acetaminophen overdose. Pseudoephedrine Classification Non-selective adrenergic agonist Mechanism of Action Sympathomimetic drug constricts nasal blood vessels to produce nasal decongestion Indications Nasal congestion Side Effects Drowsiness or insomnia Adverse Reactions - Nervousness - Hallucinations - Seizures - Hypertension - Cardiovascular collapse - Respiratory difficulty Contraindications - Hypersensitivity - Hypertension - Monoamine oxidase (MAO) inhibitor therapy - ADHD - Drug abuse and rehab patients Therapeutic Considerations Avoid OTC cough and cold products while breast feeding or to children younger than 4 years old. Combination OTC preparations are available - with antihistaminics (cold and allergy), also with antitussives and analgesics. Federal laws regulates retail OTC sale of pseudoephedrine-containing drug products with purchase limits by any individual with photo identification required, placement out of direct customer access, and detailed recordkeeping of inventory and sales, as it is a precursor chemical used in illegal manufacture of methamphetamine and amphetamine (street-grade Schedule II drugs). Dextromethorphan Classification Opioid antitussive Mechanism of Action Suppresses the cough reflex (antitussive effect) produced by direct inhibition of coughing center in the medulla (does not cure underlying cause of irritation; decrease intensity and frequency of cough) the merely Indications Cough Side Effects Drowsiness or insomnia Adverse Reactions - Nervousness - Hallucinations - Seizures - Slow or fast heart rate - Breathing difficulty Contraindications - Hypersensitivity - Monoamine oxidase (MAO) inhibitor therapy (serotonin syndrome) - Concurrent opioid (respiratory depression) Therapeutic Consideration Avoid OTC cough and cold products while breast feeding or to children younger than 4 years old. Dextromethorphan is the only opioid that is not a scheduled drug. Lower addiction potential compared to other opioid analgesics when used in recommended doses for short periods. Potential for misuse in large doses causes dextromethorphan to act as dissociative anesthetic (sight/sounds distortion, detachment/dissociation from environment and self). Caution for history of drug abuse or drug-seeking behavior. Guaifenesin Classification Expectorant Mechanism of Action Increases respiratory secretions which lubricate/liquefy thickened mucus to facilitate its removal, thus reducing chest irritation and congestion. Indications Combined with antitussive drugs for relief of unproductive coughing in colds, bronchitis, other respiratory condition Side Effects Drowsiness or headache Therapeutic Considerations Adverse Reactions - Diarrhea - Vomiting Contraindications - Hypersensitivity Available OTC Most frequently used expectorant Antihistamines Diphenhydramine Classification Nonselective histamine-1 (H1) receptor antagonist (first generation antihistamine) Mechanism of Action Nonselective inhibition of peripheral and central (CNS) histamine-1 receptors to block histamine actions Blockade of sodium channel causes local anesthetic action Anticholinergic activity Indications Relief of allergy symptoms caused by histamine release including acute allergic reactions (itching and local surface pain of bites, stings, excoriations) and anaphylaxis, sedation, emesis. Side Effects Adverse Reactions Contraindications - Sedation Dry mouth (xerostomia) Paradoxical excitation in young children QT interval prolongation, but not associated with fatality - Hypersensitivity Cardiovascular disease Hypertension Prostate enlargement Urinary retention (due to anticholinergic activity) Therapeutic Consideration - Products are widely available OTC for relief of coughs, colds, flu, and allergy. Patients should be reminded to avoid alcohol and CNS depressants that could potentiate adverse effects. Available for parenteral administration. Pregnancy Category B. Loratadine Classification Selective histamine H1 receptor antagonist (second generation antihistamine) Mechanism of Action Selective inhibition of peripheral histamine-1 receptors to block peripheral histamine actions Indications Relief of allergy symptoms caused by histamine release in acute allergic reactions including urticaria, hay fever, insect bites, rhinitis, dermatitis Side Effects - Generally, well tolerated - Less sedating at recommended doses Therapeutic Consideration Adverse Reactions - Photosensitivity - Blurred vision Products are widely available OTC Pharmacology of the GI System Famotidine Classification Selective histamine H2 receptor antagonist Contraindications - Hypersensitivity Mechanism of Action Decreases gastric acid secretion and pepsin output from the stomach parietal selective blockade of H2 receptors (antisecretory), antiulcer action cells by Indications Gastric acid suppression in management of mild to moderate gastroesophageal reflux disease (GERD) Short-term treatment of active ulcers Maintenance therapy after ulcer healing Side Effects - Headache Adverse Reactions - Constipation Contraindications - Hypersensitivity Therapeutic Consideration Products are widely available OTC. Available for parenteral administration. These drugs are neither anticholinergic nor antispasmodic. Cigarette smoking has been shown to slow ulcer healing, increase risk of ulcer recurrence, and reverse anti-ulcer drug effectiveness. Omeprazole Classification proton-pump inhibitor Mechanism of Action directly inhibits ATPase exchange of hydrogen (H+) and potassium (K+) ions in parietal cells thereby inhibiting release of HCl the Indications Management of ulcers First line of therapy with antibiotics in the treatment of ulcers associated with H. pylori Side Effects - Headache - Nausea - Diarrhea/constipation Adverse Reactions - Clostridium difficile infection and pneumonia due to altered GI acidity and altered microflora (long-term/prolonged use) - Dementia - Renal dysfunction Contraindications - Hypersensitivity Therapeutics Considerations Drug of choice for ulcer healing and pain relief due to better acid suppression rate of than antisecretory H2-receptor antagonists. Cigarette smoking has been shown to slow ulcer healing, increase the risk of ulcer recurrence, and reverse antiulcer drug effectiveness. Loperamide Classification Antidiarrheal opioid derivative Mechanism of Action Peripheral opioid mu receptor agonist stimulates mu receptors in the myenteric to decrease peristalsis and constrict sphincters plexus Direct effect on circular smooth muscle of bowel prolongs GI transit time Indications Nonspecific (noninfection) diarrhea Acute and chronic diarrhea of irritable bowel syndrome (IBS) Rapid relief of traveler’s diarrhea (in combination with trimethoprimsulfamethoxazole) Side Effects - Constipation Adverse Reactions Relatively nontoxic Contraindications - Hypersensitivity Therapeutic Consideration Most antidiarrheals are relatively nontoxic to organs other than intestines because they are not absorbed into the general circulation. Loperamide is not a controlled substance and is available OTC and by prescription. If diarrhea persists, notify physician. Antidiarrheals should not be continued for more than 2 days. Chronic misuse can produce serious alterations in bowel function. Keep antidiarrheals out of reach of children - accidental ingestion may cause respiratory depression. Bismuth Subsalicylate Classification Antidiarrheal, antiulcer, adsorbent Mechanism of Action Does not act on specific receptors, acts in the intestinal lumen to adsorb (bind/attach to) irritating substances such as bacteria, digestive enzymes, toxins, and remove them by carrying them into the feces. Indications Nonspecific (non-infection) diarrhea Side Effects - Generally, well tolerated Therapeutic Consideration - - Adverse Reactions Constipation Contraindications - Hypersensitivity May temporarily cause stools and tongue to appear gray-black. Contains aspirin - discontinue bismuth subsalicylate with concurrent aspirin products if tinnitus (ringing in the ears) occurs. Adsorbents also complex with vitamins, minerals, other drugs, impairing their systemic absorption - should not be administered with meals or other medications. Bismuth should be avoided before GI radiologic procedures as it is radiopaque (may interfere with X-ray). If diarrhea persists, notify physician. Antidiarrheals should not be continued for more than 2 days. Keep antidiarrheals out of reach of children - accidental ingestion may cause respiratory depression. Docusate Classification Stool softener Mechanism of Action Promotes incorporation of water into stool, resulting in softer fecal mass and of stool passage Indications Short-term prevention of constipation (in patients who should avoid straining, after MI or rectal surgery) Side Effects Mild cramps Adverse Reactions Diarrhea such as Contraindications - Hypersensitivity Therapeutic Considerations Should not be taken when mineral oil is being used - potential to increase absorption of mineral oil UNIT 9: Pharmacology of Antibacterial, Antifungals and Antiviral (Chapters 41,42,44) Variables contributing to Various Infections Gram Positive vs Gram Negative While the body is equipped with a natural defense system, infections occur when there is a breach in this system. In this unit we will discuss the use of antibiotics (antibacterial) to kill or retard growth. The first step in doing so is Identifying and classifying the microbe. In order to do so recall the Gram stain will differentiate Gram + and Gram – organisms based on cell wall differences. Knowing the causative microbe will help when choosing an antibiotic. Some antibiotics have a narrow range while other have a broad spectrum. Recall that the source of most antibiotics are from nature, such as molds and bacteria. Classification Gram-Positive Bacteria - Methicillin Resistant Staphylococcus aureus Impetigo Septic Shock Syndrome Gastrointestinal Disorders Botulism Acne Meningitis Otitis media Sinusitis Endocarditis Gram-Negative Bacteria - Gastrointestinal disorders Meningitis Pneumonia Dog bites Sexually Transmitted Diseases Guillian Barre H. pylori infections Urinary tract infections Antibacterial Spectrum The antimicrobial spectrum of an antibiotic means the range of microorganisms it can inhibit. Spectrum: Antibiotics are generally categorized as either broad-spectrum or narrow spectrum antibiotics according to their spectrum of antimicrobial activity Broad Spectrum Antibiotics kill or Broad-spectrum antibiotics, such as doxycycline, azithromycin, amoxicillin and clavulanic acid, and fluoroquinolones, are effective against a wide range of bacteria (gram positive and gram negative bacteria). Narrow spectrum Antibiotics Narrow-spectrum antibiotics, such as vancomycin, only target limited types of clinically relevant bacteria. Bactericidal Kills bacteria Ex: fluoroquinolones Bacteriostatic Inhibits reproduction of bacteria Ex: tetracyclines Culture and Sensitivity Antibiotic Sensitivity Levofloxacin ++ - Amikacin Ciprofloxacin - Gentamicin +++ Ceftriaxone +++ Cefotaxime - Chloramphenicol - Cloxacillin - Amoxicillin & Clavulanic acid ++++ Enrofloxacin ++++ Moxiflox - Ceftriaxone & Salbactum - Cobactan ++++ URI: Amoxicillin Community-acquired pneumonia: Empiric therapy with a macrolide or doxycycline UTI- Nitrofurantoin or trimethoprim/sulfamethoxazole Gonococcal Infection- single intramuscular injection of ceftriaxone accompanied by either azithromycin, and oral doxycycline Syphilis- a single intramuscular injection of long acting benzathine penicillin G Chlamydial infections- single dose of azithromycin followed with doxycycline Systemic Fungal Infections Bloodstream infection or affecting the bones or lungs o Septicemia, endocarditis, and pulmonary and urinary tract infections (severe) Increased risk: o o o Patients following chemotherapy Persons immunocompromised Patients in intensive care Dermatophytic Infection Affecting the hair, nails or skin Organisms obtain nutrients from keratinized material Candida Albicans Infection Underlying pathologies like diabetes or immunocompromised states including pregnancy, predispose individuals to developing yeast infections Esophageal Candidiasis Esophageal candidiasis is most commonly diagnosed in patients with HIV , those receiving treatment with antibiotics , those using inhaled corticosteroids , or those receiving chemotherapy and immunocompromised patients." . Gaining insight Diabetes and pregnancy predispose individuals to developing yeast infections. Viral Infections Virus - Small infectious agent that must invade a living cell to reproduce. Influenza - Flu viruses Primarily affects the upper and lower respiratory tracts Spreads through sneezes and coughs of infected persons Family of viruses Types A, B, and C o Types A and B Infect humans Symptoms include headache, fever, intense fatigue, dry cough, muscle ache, and sensitivity to light Secondary bacterial infections can occur otitis media or bronchitis. Influenza Vaccine - Formulated each year Predicts which strains will be present the next year Recommended by the CDC for high risk persons or those who could transport the virus to them, such as health care providers RSV Respiratory syncytial virus, or RSV, is a common respiratory virus that usually causes mild, coldlike symptoms. It is very dangerous for babies and elderly. Herpes - - - Herpes simplex Virus (HSV) o Type 1 – Fever blister, cold sore o Type 2 – Genital Herpes Herpes zoster o Chickenpox o Shingles Vaccine available to patients over 60 Cytomegalovirus (CMV) Epstein Barr virus Herpesvirus 6 and 7 (Roseola), and 8 (Kaposi) AIDS/HIV HIV- Human Immunodeficiency virus damages immune system overtime and can cause aids Antibacterial Part 1 Penicillin V Potassium Classification Antibiotics Mechanism of Action Cell wall synthesis inhibitor Indications Gram positive and gram negative bacterial infections Syphilis Side Effects - N/V Abdominal pain Diarrhea Tongue discoloration Therapeutic Consideration Oral administration Penicillin G Benzathine Classification Antibiotics Adverse Reactions - Hemolytic anemia Clostridium difficile superinfection Contraindications Penicillin allergy Mechanism of Action Cell wall synthesis inhibitors Indications Diphtheria Neurosyphilis Syphilis Side Effects - Diarrhea Adverse Reactions - Hemolytic anemia - Clostridium difficile superinfection - Methemoglobinemia - Hallucinations Contraindications Penicillin allergy Therapeutics Considerations Intramuscular injection only. Not for intravenous use (US boxed warning); can cardiopulmonary arrest and death Penicillin G Procaine Classification Antibiotics Mechanism of Actions Cell wall synthesis inhibitor Inhibitors Diphtheria Neurosyphilis Syphilis cause Side Effects - Diarrhea Adverse Reactions - Methemoglobinemia - Hallucinations Contraindications Penicillin allergy Therapeutic Consideration Intramuscular injection only. Not the same as Penicillin G Benzathine Amoxicillin/Clavulanic Acid Classification Antibiotics Mechanism of Action Cell wall synthesis inhibitor clavulanic acid is a beta-lactamase inhibitor Indications Otitis Media Pneumonia Rhinosinusitis Side Effects - Nausea and vomitting - Diarrhea - Diaper rash in children Adverse Reactions - Hepatotoxicity - Pseudomembranous colitis - Stevens-Johnson syndrome Therapeutic Consideration Prolonged use may result in superinfection. Pregnancy category B Classification of Cephalosporins Contraindications - Penicillin allergy - Hepatic failure First Generation Cephalexin and cefazolin Used to treat gram-positive and -negative infections, especially K. pneumoniae Second Generation Cefaclor and cefoxitin Broader spectrum than first generation Indicated when first generation is not effective Used to treat B. fragilis, S. marcescens, H. influenzae, and N. gonorrhoeae Third Generation Cefixime, cefdinir, and ceftriaxone Broader spectrum than second generation Longer duration of action Used to treat serious gram-negative infections Cross the blood-brain barrier Fourth Generation Cefepime Greater resistance to beta-lactamase Cephalexin Classification Antibiotics Mechanism of Action Cell wall synthesis inhibitor Indications Cellulitis Streptococcal pharyngitis UTI Otitis media Respiratory tract infections Presurgical prophylaxis Side Effects - Nausea and vomiting Adverse Reactions - Hepatoxicity Contraindications - Hypersensivity - Diarrhea Abdominal pain - - Hemolytic anemia Disulfiram-like reaction StevenJohnson Syndrome C. diff superinfection - Use in caution with anaphylactic penicillin allergy Therapeutic Considerations May elevate INR, alternative for mild, non-anaphylactic penicilin allergy Vancomycin Classification Antibiotics Mechanism of Action Inhibits cell wall peptidogly can formation (bacteriostatic and bactericidal) Indications Sepsis C. Difficile infection Endocarditis Osteomyelitis Pneumonia (MRSA) Cellulitis (MRSA) Side Effects - Fatigue - Nausea and vomiting - Diarrhea - Flushing Adverse Reactions - Renal toxicity - Ototoxicity - Thrombophlebitis - Red-man syndrome Contraindications - Hypersensivity Therapeutic Consideration Individual dosing based on actual body weight and patient’s renal function. Only given orally for c. diff-not effective for systemic infections. US boxed warning for embryo-fetal toxicity. Polymyxin B Classification Antibiotics Mechanism of Action Disruption of cell membrane (bactericidal) Indications Meningitis and pseudomonal infections Ocular infections Side Effects - Facial flushing - Dizziness Adverse Reactions - C. difficile superinfection - Ototoxicity and teratogenic Contraindications - Pregnancy - Myasthenia gravis - Kidney failure Therapeutic Consideration Nephrotoxicity and neurotoxicity (boxed warning) Trimethoprim-sulfamethoxazole Classification Antibiotic-sulfonamide derivative Mechanism of Action Anti-metabolite (folic acid synthesis inhibitor) Indications UTI COPD exacerbations Travelers diarrhea Pneumocystis pneumonia (PCP) Intestinal infections Side Effects - Nausea or vomiting - Diarrhea - Lack of appetite Adverse Reactions - Stevens-johnson syndrome - Hyperkalemia - Hypoglycemia - Hyponatremia - C. diff - Hepatoxicity Contraindications - Hypersensitivity to sulfa medications - History of drug induced thrombocytopenia - Infants less than 2 months - Megaloblastic anemia - Severe hepatic or renal disease - Pregnancy and breastfeeding Therapeutic Consideration Use in caution in patients with thyroid dysfunction Ciprofloxacin Classification Antibiotics-fluoroquinolone Mechanism of Action Nucleic acid inhibitor Indications UTI Acute uncomplicated cystitis (reserve for patients with no alternative options) Bone and joint infections Typhoid fever Hospital acquired pneumonia Side Effects - Nausea or vomiting - Diarrhea - Myalgias Adverse Reactions Contraindications - Tendon rupture - Hypersensitivity - Depression, - Hepatoxicity - Renal toxicity - Hypoglycemia/hyperglycemia - C. diff Therapeutic Consideration US Boxed warning: Serious adverse effects including tendon rupture, peripheral neuropathy and CNS effects US Boxed warning: Exacerbation of myasthenia gravis Antibacterial Part III Azithromycin Classification Antibiotic- Macrolide Mechanism of Action Protein synthesis inhibitor Indications COPD exacerbation Otitis media pneumonia Streptococcal pharyngitis Urethritis/Cervicitis due to chlamydia or gonorrhea Side Effects - Abdominal pain - Nausea and vomiting - Headache Adverse Reactions - C. Diff - Vision changes - Hepatotoxicity - Stevens-johnson syndrome Contraindications - Hypersensitivity - Caution in history of cardiac arrythmias Therapeutic Considerations Prolonged use may result in fungal superinfection, less gastric irritation than macrolides other Doxycycline Classification Antibiotic-tetracycline Mechanism of Action Protein synthesis inhibitor Indications Cellulitis, MRSA C.diff Acne COPD Malaria Pneumonia Otitis media Anthrax Lyme disease Plague Rocky mountain spotted fever STIs including chlamydia, gonorrhea, and (syphilis, if PCN allergy) Side Effects GI disturbances Adverse Reactions - Hepatotoxicty - Pancreatitis - Steven-Johnsons syndrome Contraindications - Hepatotoxicty Therapeutic Considerations Inhibits bone growth in children under 8 years-old. Tetracyclines can cause permanent discoloration of teeth in children, and causes photosensitivity. (Use enhanced sun protection.) Gentamicin Classification Antibiotic-aminoglycoside Mechanism of Action Protein synthesis inhibitor Indications Severe gram-negative rod infections: Enterobacteriaceae family (e.g., Escherichia coli, Klebsiella pneumoniae, Serratia spp. and Enterobacter spp.) Pseudomonas aeruginosa, and some strains of Neisseria, Moraxella, and Haemophilus genera Side Effects - - Vertigo Nausea and vomiting Adverse Reactions - Nephrotoxic - Neuromuscular blockade - Ototoxic - Teratogenic Contraindications Myasthenia gravis Therapeutic Consideration The intravenous administration of calcium can overcome the neuromuscular blockade. Has a minimal gastrointestinal absorption, its administration is usually by parenteral routes. Clindamycin Classification Lincosamide Mechanism of Action Protein synthesis inhibitors Indications Osteomyelitis Gynecological infections Cellulitis Streptococcus Group A and B Septicemia Lower respiratory tract infections Side Effects - Abdominal pain - Diarrhea - Bad taste in mouth Adverse Reactions - C. diff - Stevens-Johnson syndrome - Hepatoxicity Contraindications - Hypersensitivity - Oral clindamycin in infants less than 30 days old Therapeutic Consideration (US Boxed Warning): Can cause severe and possibly fatal colitis. Antifungal Amphotericin B Classification Antifungal Mechanism of Action Membrane stability inhibitors Indications Systemic fungal infections (life-threatening) Side Effects - Nausea and vomiting - Diarrhea - Muscle/joint pain - Headache Adverse Reactions - Nephrotoxicity - Nepatoxicity Contraindications - Hypersensitivity Therapeutic Consideration This medication comes in both conventional and lipid-based formulations. US Boxed Warning: error prevention – risk of overdose with confusing the two formulations. US Boxed Warning: appropriate use – only for use in patients with progressive and potentially life-threatening fungal infections. Nystatin Classification Antifungal Mechanism of Action Membrane stability inhibitors Indications Oral candidiasis Cutaneous/mucocutaneous fungal infections (topical) Diaper rash Side Effects - Abdominal pain - Nausea and vomiting - Diarrhea Adverse Reactions - Mouth irritation - Tachycardia - Muscle pain - Severe skin irritation (topical) Contraindications - Hypersensitivity Therapeutic Consideration Available as an oral and topical medication. Can be used in powder formulations for skin fold infections Fluconazole Classification Antifungal Mechanism of Action Ergosterol Inhibitors Fluconazole binds to the lanosterol 14 alpha-demethylase. The magnification shows how it interacts with a heme group in the active site. Indications Candidiasis Cryptococcal meningitis Tinea fungal infections Side Effects - Headache - Nausea and vomiting - Abdominal pain - Change in taste Adverse Reactions - Cardiovascular effects - Hepatotoxicity - Dermatologic effects Therapeutic Consideration Pregnancy category D – Shown to cause fetal harm Antivirals Contraindications - Hypersensitivity - Other medications that may lead to arrhythmia (QT prolongation) Oseltamivir (Tamiflu) Classification Antiviral Mechanism of Action Viral release inhibitor/ neuraminidase inhibitor Indications Influenza A & B treatment and prophylaxis Side Effects - Diarrhea - Nausea and vomiting - Headache Adverse Reactions - Confusion - Tremors - Seizures - Stevens-Johnson syndrome Contraindications - Hypersensitivity - Not recommended for patients with end-stage renal disease - Caution: cardiovascular disease hepatic/renal impairment, respiratory disease Therapeutic Considerations Optimal response when administered within 24-48 hours of symptom onset. Limitations of use: does not replace annual influenza vaccine. Acyclovir Classification Antiviral Mechanism of Action Nucleoside (purine) analog Indications Herpes simplex virus (HSV) Herpes zoster (shingles) Varicella (chickenpox) Herpes simplex encephalitis Side Effects - Nausea and vomiting - Lethargy Adverse Reactions Contraindications - CNS effects (confusion, - Hypersensitivity behavioral/mood - changes, hallucinations, seizures) Nephrotoxicity Thrombotic thrombocytopenic purpura (TTP) Therapeutic Consideration IV formulation is an irritant Avoid extravasation Formulations include topical and oral Can decrease symptoms severity when used immediately after experiencing an outbreak Antivirals: HAART Therapy for HIV HAART Therapy - Highly active antiretroviral therapy (HAART) is a medication regimen used to manage and treat human immunodeficiency virus type 1 (HIV-1). Co-administration of multiple medications that inhibit viral replication by different mechanisms to inhibit the propagation of a virus and overcome resistance. The standard of care for most treatment-naïve patients is a combination of two nucleoside reverse transcriptase inhibitors (NRTI) plus one non-nucleoside reverse transcriptase inhibitor or integrase strand transfer inhibitor. Goals of HAART in Patients with HIV Infections Reduce morbidity and mortality (AIDS and non-AIDS associated causes) Improve the quality of life Reduce plasma viral RNA load Prevent transmission to others (sex partners, needle-sharing partners, mother to infant) Prevent drug resistance Improve immune function, such as CD4+ T-Helper cells Efavirenz Classification Antiretroviral Mechanism of Action Reverse transcriptase inhibitor HIV-1 reverse transcriptase (RT) complexed with efavirenz, a non nucleoside inhibitor (yellow). Indications HIV- 1 infection Side Effects Adverse Reactions Contraindications - Insomnia Abnormal dreams Fatigue - Infection CNS toxicity Fat redistribution Hepatoxicity Rash Increased cholesterol and triglycerides - Hypersensitivity Therapeutic Consideration Use in caution in patients with any hepatic impairment. Used as an alternative treatment option for pregnant patients. Monotherapy not recommended due to increased resistance. Raltegravir Classification Antiretroviral Mechanism of Action Integrase inhibitor Indications HIV-1 Infection Postexposure prophylaxis (off-label) Side Effects - Insomnia - Headache - Dizziness Adverse Reactions - Infection - Hepatotoxicity - Muscle/joint pain - Stevens-johnson syndrome Contraindications - Hypersensitivity Therapeutic Consideration Use in caution in patients with a history of rhabdomyolysis. Preferred integrase strand transfer inhibitor for HIV patients trying to conceive. Monotherapy not recommended due to increased resistance. Medications for Tuberculosis Rifampin Classification Antitubercular agent Mechanism of Action Nucleic acid inhibitor Indications Used in the treatment of tuberculosis Side Effects - Diarrhea - Fatigue - Headache - Nausea and vomiting - Body fluid discoloration - Hyperglycemia (caution in diabetic patients) - Disulfiram reaction Adverse Reactions - Coagulopathy (vitamin K disorders) - Hepatotoxicity - Dermatologic reactions (including steven-johnsons syndrome SJS) - Thrombocytopenia - Superinfection Contraindications Hepatic function impairment Therefore use caution in patients with hepatic impairment and alcoholism. Therapeutic Considerations Can cause staining of teeth (may be permanent), urine, feces, saliva, and tears. (Yellow, orange, red or brown). Remove contact lenses during therapy since permanent staining can occur. Isoniazid Classification Antitubercular agent Mechanism of Action Bacterial cell wall synthesis inhibitor Indications Active, latent, and prophylactic for TB infections Side Effects Nausea and vomiting Adverse Reactions - Hepatotoxicity - Pancreatitis - Hyperglycemia - Inflammatory response Contraindications Liver disease Therapeutic Consideration Recommended to take with pyridoxine (Vitamin B6 supplement) in any patient at risk for neuropathy and in pregnant/breastfeeding women. Do not take with food; avoid tyramine and/or histamine containing food. Avoid alcohol due to disulfiram effect. Miscellaneous Medications Metronidazole Classification Antibiotics, antiprotozoal, amebicide Mechanism of Action Interacts with DNA causing loss of helical structure resulting in inhibition of protein synthesis and cell death Amebiasis Anaerobic bacterial infections Surgical prophylaxis (colorectal surgery) Trichomoniasis Gastrointestinal infections Indications Side Effects - Nausea and vomiting - Joint pain - Decreased libido - Metallic taste Adverse Reactions - Hepatoxicity - CNS effects (peripheral neuropathy, seizures, encephalopathy, vertigo, aseptic meningitis, etc.) - Disulfram-like reactions Contraindications - Hypersensitivity, - Pregnancy (first trimester) - Use of alcohol during or within 3 days of therapy discontinuation - Active neurological disorders - History of blood dyscrasias - Hypothyroidism - Hypoadrenalism Therapeutic Consideration US boxed warning: carcinogenic in mice and rats UNIT 10: Pharmacology of Cancer (Chapters 45,46,30) Fundamentals of Cancer cells and cancer treatment Cancer: disease process that involves the development and reproduction of abnormal cells Cancerous cells o o Structural alteration accompanied by a loss of function Normal cell reproduction is controlled, whereas cancer cell reproduction is uncontrollable Malignancy refers to the life threatening growth of a cancerous tumor Hallmarks of Cancer Rapid growth Accelerated cell division. Invasive Spreading especially in a quick or aggressive manner. Metastatic Refers to the spread of cancer cells throughout the body from the primary site to secondary sites. Immortal With each cell division, telomeres shorten until eventually they become too short to protect the chromosomes and the cell dies. Cancers become immortal by reversing the normal telomere shortening process and instead lengthen their telomeres. This means they can divide an unlimited number of times. Types of Cancer treatment Targeted Therapy Cancer treatment that uses drugs to target specific involved in the growth and survival of cancer cells. genes and proteins that are Immune Modulation o o Actions or drugs that stimulate the activity of the immune system. Immunomodulating drugs are indicated for the treatment of various cancers, hepatitis, myelosuppression, and other conditions where increasing the activity of the immune system is beneficial. Boosting white blood cells of Hematopoiesis Enhance the production of red blood cells and platelets. Major Toxicities of Chemotherapy 1. Myelosuppression Suppression of bone marrow activity that interferes with the production of all blood cells This can reduce the number of: Red blood cells (anemia) - fatigue White blood cells (leukopenia) – increasing infections Platelets (thrombocytopenia) – bleeding problems Usually takes 1-2 weeks to develop 2. Ulcerations of the skin and GI tract are common 3. Alopecia – temporary loss of hair Because of these toxicities – chemo is administered in a series of treatments to allow a drug free period – 1-6 weeks between each. Cell cycle Cell-cycle specific (CCS) o Refers to cancer drugs that only act when the cell is actively dividing. Cell-cycle nonspecific (CCNS) o o Refers to cancer drugs that act in all phases of the cell cycle. Alkylating drugs are CCNS and interfere with cell growth in all phases whether the cell is actively dividing or in the resting stage. Cell cycle Nonspecific Medications for the Treatment of Cancer The Cell Cycle Cyclophosphamide Classification Antineoplastics (cell cycle nonspecific) Mechanism of Action Alkylating agent that irreversibly crosslinks DNA, immunosuppressant Indications Cancer Nephrotic syndrome Side Effects - Moderate to high emetic potential - Alopecia - Anorexia Adverse Reactions - Bone marrow suppression - Cardiotoxicity - Hepatoxicity - Hyponatremia - Bladder toxicity Contraindications - Urinary outflow obstruction - Severe renal or hepatic impairment Therapeutic Consideration Mesna may be required to prevent bladder toxicity – vigorously hydrate, may cause infertility Doxorubicin Classification Antineoplastic agent (cell cycle nonspecific) Mechanism of Action Antineoplastic agent (cell cycle nonspecific) Indications Cancer Side Effects - Discoloration of sweat, urine and tears (red) referred to as red devil - Moderate to high emetic potential - Alopecia Adverse Reactions - Cardiotoxicity - Infertility Contraindications - Recent MI - Severe persistent drug-related myelosuppression - Severe hepatic impairment Therapeutic Consideration US Boxed warning for cardiomyopathy, extravasation, secondary malignancy, and myelosuppression. Cell cycle specific medications for the treatment of cancer Fluorouracil Classification Antineoplastic (cell cycle specific) Mechanism of Action S phase inhibitor, pyrimidine antagonist, folic acid inhibitor (anti-metabolite) Indications Cancer Side Effects - Alopecia - Anorexia - Change in nails (including nail loss) Adverse Reactions - Cardiotoxicity - GI toxicity - Hand-foot syndrome - Neurotoxicity Contraindications - Hypersensitivity - Aplastic anemia - Nutritional deficiencies Therapeutic Consideration Antidote for toxicity – Uridine Triacetate. Patients should cycle off the drug for at least 6 months before planning a pregnancy. Vinblastine Classification Antineoplastic (cell cycle specific) Mechanism of Action Mitotic M phase inhibitor, binds to tubulin and inhibits microtubule formation Indications cancer Side Effects - Alopecia - Bone pain/jaw pain - Tinnitus Adverse Reactions - Myelosuppression - GI toxicity - Neurotoxicity - Pulmonary toxicity Contraindications - Granulocytopenia - Bacterial infections - Pregnancy Therapeutic Considerations US boxed warning: Extravasation and appropriate administration/experienced physician. IV only – can be fatal if administered through other routes. **Do not use intrathecally** Targeted Therapy - Rituximab : monoclonal antibody Bevacizumab: monoclonal antibody - angiogenesis inhibitor Imatinib: tyrosine kinase inhibitor Treatment for Lymphoma Treatment plan factors: - type of lymphoma - stage - symptoms - age - overall health - other factors Types: Chemotherapy, radiation therapy, targeted therapy, immunotherapy, and stem cell transplant. Rituximab Classification Antineoplastic (monoclonal antibody) Mechanism of Action Directed against CD20 antigen on the surface of B-lymphocytes (CD20 regulates cycle initiation). Also activates b-cell cytotoxicity cell Indications Cancer (lymphoid tissue cancer, Non-Hodgkin’s lymphoma), Rheumatoid arthritis Side Effects - Lethargy - Night sweats - Anemia - Flushing Adverse Reactions - Renal toxicity - Tumor lysis syndrome - Cardiotoxicity - Bowel obstructions Contraindications - Live vaccines - Severe infections Therapeutic Consideration US Boxed Warning: infusion-related reaction, mucocutaneous reactions, Hep B reactivation, progressive multifocal leukoencephalopathy (PML) Solid Tumors Colorectal Cancer Lung Cancer Cervical Cancer Bevacizumab Classification Antineoplastic (monoclonal antibody) Mechanism of Action Angiogenesis inhibitor Indications Cancer (solid tumors) Side Effects - Headache - Change in nails and taste - Change in voice Therapeutic Consideration Adverse Reactions - Hypertension - GI toxicity - Hemorrhage Contraindications - Hypersensitivity - Untreated CNS metastases Do not use with patients that have impaired wound healing, blood clots and hemorrhaging. Patients should cycle off the drug for at least 6 months before planning a pregnancy. Imatinib Classification Antineoplastic (tyrosine kinase inhibitor) Mechanism of Action Inhibits growth factors via tyrosine kinase Indications cancer Side Effects - Dizziness - Edema - Skin rash - Fluid retention Adverse Reactions - Hypertension - GI toxicity - Hemorrhage Contraindications - Interaction with grapefruit juice Therapeutic Consideration Monitor thyroid function testing. Can cause growth problems in children Hormones Understanding Breast Cancer Stages Treatments Surgery: Lumpectomy followed by radiation therapy Mastectomy followed by breast reconstruction Sentinel lymph node removal Complete axillary lymph node dissection Chemotherapy: drug therapy Radiation Therapy External beam radiation Internal radiation (brachytherapy) Intraoperative radiation Hormone Therapy Targeted Therapy Anastrozole Classification Antineoplastic (aromatase inhibitor) Mechanism of Action Inhibits aromatase to reduce peripheral conversion of androgens to estrogens Indications Breast cancer Side Effects - Hot flashes - Weight gain - Sweating Adverse Reactions - Hepatotoxicity - UTI - Bone mineral density loss (increased fracture risk) - Ischemic cardiovascular events - Musculoskeletal effect Contraindications - Hypersensitivity - Pregnancy/Lactation - Caution in premenopausal women Therapeutic Considerations First line of therapy in postmenopausal women with breast cancer Tamoxifen Classification Antineoplastic (selective estrogen receptor modulator (SERM)) Mechanism of Action Estrogen receptor antagonist at breast tissue, partial agonist at estrogen receptors in uterine tissue and bone Indications Treatment and prophylaxis of breast cancer Side Effects - Hot flashes - Insomnia - Back/bone/muscle/joint pain Adverse Reactions - Hypercalcemia - UTI - Blood clots - Ischemic heart disease - Decreased bone density Therapeutic Considerations US Boxed Warning: Increased risk of endometrial cancer and thromboembolic events (DVT/PE) Contraindications - Warfarin or history of DVT (deep vein thrombosis) /PE (pulmonary embolism) - History of stroke - Pregnancy - Uncontrolled hypertension Fulvestrant Classification Antineoplastic (estrogen receptor antagonist) Mechanism of Action Estrogen receptor antagonist Indications Breast cancer Side Effects - Hot flashes - Painful extremities - Throat irritation - Decreased blood glucose (caution in diabetic patients) - Anemia Therapeutic Consideration Adverse Reactions - UTI - Edema - Infections - Increased hepatic enzymes Contraindications - Pregnancy - Breastfeeding Caution in patients with a history of bleeding disorders. Patients should cycle off the drug for at least 1 year before planning a pregnancy. Immune Modulators/ Hematopoiesis Understanding CKD Anemia Symptoms: feeling tired/weak pale skin color headaches problems concentrating/thinking loss of appetite chest pain fast heartbeat feeling lightheaded shortness of breath CKD Anemia levels < 13g/dL (men) < 12g/dL (women) Epoetin Classification Hematopoietic agent Mechanism of Action Erythropoiesis- stimulating agent (ESA), colony stimulating factor Indications Anemia, Chronic kidney disease Side Effects - Cough - Joint/muscle pain - Mouth irritation and sores - Insomnia Adverse Reactions - Hyperglycemia (caution in diabetic patients) - Hypokalemia - Cutaneous reactions (Stevens Johnsons syndrome) - Seizures Therapeutic Considerations Contraindications Uncontrolled hypertension US Boxed Warning: Cardiovascular events, cancer, perisurgery Evaluate patient iron levels before and during treatment Filgrastim Classification Hematopoietic agent Mechanism of Action Chemo-induced myelosuppression Bone marrow transplantation AML Severe chronic neutropenia Side Effects - Cough - Joint/muscle pain - Mouth irritation and sores - Insomnia Therapeutic Considerations Adverse Reactions - Renal toxicity - Pulmonary toxicity - Thrombocytopenia - Enlarged and ruptured spleen Contraindications Hypersensitivity Do not administer 24 hours before or after cytotoxic chemotherapy UNIT 11: Special Use Medications Review of Pharmacological Classes and Indications Crash Cart Drugs Adenosine Drug Class: antiarrhythmic (emergent) Indication: paroxysmal supraventricular tachycardia (SVTs) Can also be given for pharmacological stress testing. Special Therapeutic considerations: ECG monitoring required during use. Not effective for conversion of atrial fibrillation, atrial flutter, or ventricular tachycardia – However – Can aid in the identification of the arrhythmia. Epinephrine Drug Class: adrenergic agonist Indication: anaphylaxis reactions, hypotension/shock, cardiac arrest (pulseless), symptomatic bradycardia Norepinephrine Drug Class: adrenergic agonist Indication: cardiogenic shock/hypovolemic shock, septic shock (treats low blood pressure) Special Therapeutic considerations: US boxed warning for extravasation: vesicant - antidote for extravasation ischemia is phentolamine Amiodarone Drug Class: antiarrhythmic agent Indication: ventricular arrhythmias Special Therapeutic considerations: CI in pulmonary fibrosis Dobutamine/Dopamine Drug Class: adrenergic agonist; inotrope Indication: cardiogenic shock Reversal Agents Calcium Chloride Drug Class: calcium salt Indication: cardiac arrest or cardiotoxicity in the presence of hyperkalemia, hypocalcemia, or hypermagnesemia Off label use for calcium channel and beta-blocker overdose Sodium Bicarbonate Drug Class: alkalinizing agent dissociates to provide bicarbonate ion which neutralizes hydrogen ion concentration and raises blood and urinary pH Indication: cardiac arrest (guided by arterial blood gases), metabolic acidosis, hyperkalemia Magnesium sulfate Drug Class: anticonvulsant Indication: Eclampsia/preeclampsia (seizure prophylaxis &treatment), hypomagnesemia, Torsades de pointes (off-label) Note: Magnesium is necessary for the movement of calcium, sodium, and potassium in and out of the cells, as well as stabilizing excitable membranes. Vasopressin Drug Class: antidiuretic hormone analog Indication: diabetes insipidus, shock (should be used if patient is hypotensive during or after fluid resuscitation to maintain MAP) – use in addition to norepinephrine Atropine Drug Class: anticholinergic agent Indication: bradycardia, organophosphate poisoning, circulatory collapse Antidote for muscarine-containing mushrooms, organophosphate, carbamate insecticide, and nerve agent poisoning
