RXRS-302 Study Guide Midterm 2 PDF

Week 4: Introduction to Drug Discovery and Development The Pharma Value Chain: The many entities and organizational, operational, and value-adding activities involved in developing and delivering pharmaceutical products to the market. Stakeholders include: pharmaceutical manufacturers tha research, develop, and produce drugs. Before target discovery, a library of gene/protein/metabolites (genome, proteome, metabolome) sequences to explore for information. E.g APOE4 gene increased cases of Alzheimer’s Identifying a Drug Target: Drug target - specific macromolecule, or biological system, which the drug will interact with. E.g. FPR2 receptor. Sometimes this can happen through incidental observation Target sites: What is the source of the issue? How can I reach it? E.g target in the liver, oral meds, 1st pass metabolism. Liver (hepatocyte): mTORC1 (controls protein synthesis) → Triglyceride lipid accumulation → NAFLD Heart (cardiomyocyte): mTORC1 → Hypercholesterolemia impaired autophagy → Cardiac Disease Arterial wall (macrophage): mTORC1 → Lipid burden chronic inflammation → Atherosclerosis Side effect is due to hitting other targets. Selectivity: Similar targets may be present (homologous & closely aligned) specificity that it can hit the target. If other targets/receptors are reached, there will be more side effects. E.g targeting a bacterial enzyme, which isn’t present in mammals or which has significant structural differences from the corresponding enzyme in mammals Target Discovery: Comparing control vs disease, is the differential proteins or mRNA or metabolites expressed/not expressed. ○ Genes and gene modification associated with a disease ○ Proteins or protein modifications associated with a disease ○ Regulatory pathways required for disease processes Look for gene/proteins/metabolites essential for infectious agents and distinct from the host. Target validation: Molecular level: ○ Screen enzyme inhibitors or activators Cellular level: ○ Verify the involvement of the protein in the disease state (often use gene silencing siRNAs) ○ Understanding the protein pathways and interactions Organism level: ○ Verify critical nature of target and uniqueness Lead discovery: Discover leads that affect the target gene, protein or pathway: ○ Inhibit/activate a defective protein ○ inhibit/activate expression of a protein/pathway ○ Stimulate protein modifications or cellular location Evaluate leads to ‘cure’ of the problem: ○ Replace missing or defective protein with gene therapy ○ Antisense or siRNA to prevent protein expression ○ Antibody to remove or inhibit protein target ○ Simulation of synthesis to replace or activate proteins ○ Simulate protein modification or location Drug discovery methods: Screening natural products Screening synthetic banks Enhance a side effect use structural similarity to a natural ligand Computer assisted drug design Serendipity Screening natural compound: Plans, microbes, the marine world, and animals all provide a rich source of structurally complex natural products. E.g aspirin, Atropine, caffeine, codeine, morphine Screening synthetic banks: Pharmaceutical companies have prepared thousands of companies These are stored in the freezer and cataloged and screened on new targets as these new targets are identified. “Which of the following can inhibit/enhance this target?” Computer assisted drug design: If one knows the precise molecular structure of the target molecular structure of the target, then one can use a computer to design a perfectly fitting ligand. Drawbacks: ○ Most programs don't allow conformational movement in the target (as ligand is being designed and or docked into the active site ○ Cannot evaluate intrinsic activities ○ Thus most programs are somewhat inaccurate Enhance a side effect: Sulphanilamide: antibacterial with side effect of lowering glucose levels in blood also diuretic activity Tolbutamide: compound which has been optimized to only lower blood glucose levels. Useful in treatment of type II diabetes Chlorothiazide: a compound which has been optimized to only display diuretic activity Structural similarity to natural ligand: 5-hydroxytryptamine (5-HT): serotonin (a natural neurotransmitter synthesized in certain neurons in the CNS) ○ Natural drugs in our body are endogenous molecules Sumatriptan (Imitrex): Used to treat migraine headaches, known to be a 5-H1 agonist, similar structure to serotonin Serendipity: A chance occurrence: Accidental discovery by an experimentalist: ○ Understands the big picture and is not solely focused on his/her immediate research goal ○ Open mind toward unexpected results ○ Use deductive logic in the explanation of such results ○ E.g penicillin and viagra for ED. Lead Identification: At this state, validated hits would be tested to determine factors such as: ○ Selectivity vs a panel of other receptors (target) ○ Physicochemical characteristics (e.g hydrophilic/lipophilic. Lipophilic will have a higher volume of distribution, can it pass through the BBB?) Indication of administration ○ Drug-like properties ○ Metabolic properties (half-life, etc) ○ Those molecules with acceptable potency, physical, and ADME properties can be advanced through lead optimisation. ○ Dose likely to be unknown at this point Those molecules fulfilling the lead identification criteria can go to molecular finishing school ○ At this stage, medicinal chemistry conduct extensive SARs to improve potency and selectivity ○ Also, this is the opportunity to improve physicochemical and drug like properties Involves molecular bioscientist, medicinal chemist, pharmacokinetics group, formulation group, clinical researchers, marketers among others. Structure-activity-relationship (SAR): Once a lead has been discovered, it is important to understand precisely which structural features are responsible for its biological activity (i.e. to identify the “pharmacophore”) The pharmacophore is the precise section of the molecule that is responsible for biological activity, which cannot be touched Lead discovery: Modification may be done through synthetic modifications ○ Yield more active molecules ○ Eliminate “excessive” functionality ○ Reduce toxicity and cost of production of the active material Example: ○ R-OH can be converted through R-OCH3 to see if O-H is involved in an important interaction ○ R-NH2 can be converted to R-NH-COR’ to see if interaction with positive charge on protonated amine is an important interaction Applications: ○ When the field has been narrowed down after being tested against the target. the best molecules are advanced to animal models and preliminary toxicology. Selecting the best candidate: ○ The smaller your EC50, the more potential the drug has ADMET: Ideal properties of drugs: Absorption: passes GI tract into the bloodstream Distribution: gets to target tissue (BBB) Metabolism: Not readily metabolized Excretion: Not readily excreted Toxicity: Not toxic to other cells or tissues Lipinski’s rule of five: Doesn’t apply to neuro drugs Fewer than 5H bond donors (which can be estimated by counting the total number of OH and NH groups in the molecule Fewer than 5H bond acceptors (estimated by the total of N and O atoms in the molecule) A molecular weight of less than 500 A partitioning coefficient (logP) of less than 5 ○ Partition coefficient measures how hydrophilic or hydrophobic a chemical substance is ○ The greater the solubility of a substance, the higher its partition coefficient, and the higher the partition coefficient, the higher the permeability of the membrane to that particular substance. Candidate Selection: At this stage, those optimized leads are scrutinized for their properties: ○ Potency ○ Selectivity ○ Bioavailability ○ Intellectual property (IP) position ○ Safety ○ Scale up potential (can you make enough of it cheaply enough?) ○ The data on the successful candidate will then be submitted to the appropriate health authorities to get permission to conduct clinical investigation. Anti Inflammatory drugs act on COX The case of AA Pathway: ○ LXA4 and NAP1051 ○ Lots of similarities, difference is NAP1051 has a longer half-life and anti-inflammatory A drug on the market was modified Implications: uses for arthritis, and antiinflammatory ○ Should we expect differences in PK/PD? Less soluble in water so it can’t be put in solution. Within oil an injected intravascular or topical Good drug but consider the device to deliver it. Strategies for dealing with drug solubility: Common strategies to address low drug solubility: ○ Co-solvents ○ Salts: e.g ziprasidone HCL and diclofenac sodium ○ Surfants ○ Cyclodextrins ○ Particle size reduction ○ Lipid-based systems ○ Co-crystals ○ Amorphous solid dispersions Cyclodextrin and drug solubility ○ Cyclists are very soluble in water, but the inner part of the bucket is very lipophilic, outside hydrophilic ○ Bucket structure allows lipid drug to be included in hydrophobic cavity while outside improves solubility in water. ○ Formation of inclusion complexes with cyclodextrins or calixarenes can enhance drug solubility through several mechanisms: Increased surface area: The inclusion complex increases the SA available for drug dissolution, allowing more efficient interaction with the surrounding solvent. Disruption of drug aggregation: Poorly soluble drugs often tend to aggregate, reducing their solubility. Inclusion complexes disrupt drug aggregation and keep the drug molecules dispersed, enhancing solubility. Facilitated transport: Inclusion complexes can enhance the transport of drug molecules across biological membranes, such as the intestinal epithelium, leading to improved absorption and bioavailability. Choosing the bioassay: Drug testing may be conducted in these systems: ○ In vitro: in an artificial environment, such as in a test tube or culture media ○ In vivo: in the living body. Referring to tests conducting in living animals ○ Ex vivo: refers to doing the test on a tissue taken from living organism In Vitro Testing Benefit: speed, requires relatively small amounts of compound Speed may be increased to the point where it is possible to analyze several hundred compounds in a single day (high throughput screening) Results may not translate to living animals In Vivo Testing: More expensive May cause suffering to animals Results may be clouded by interference with other biological systems Determine toxicity and efficacy in animal models Mouse vs pig vs dog: can control genetics of a mouse, ability to control the system/environment. Mice are smaller and easier to manage. Indication, which animals have similarities with humans? Rabbit → eye. Disease model. Preclinical Testing: These questions should be answered: ○ Is the drug safe ○ Affects other body systems? ○ Effective dose range? ○ Pharmacodynamics? ○ Pharmacokinetics ○ Is the drug a carcinogen? ○ Is the drug a teratogen? ○ Long term animal studies confirm cancer or birth defects Investigational New Drug: Investigational new drug (IND): application for permission to administer a new drug to humans Outlines the proposal to use the new drug for human testing in clinical trials Studies in humans can only begin after IND is reviewed and approved by the FDA and Institutional Review Board (IRB) Good Laboratory Practices: GLP are laws that are intended to support appropriate practice in research and development They pertain to processes and conditions under which clinical and nonclinical research of pharmaceuticals, devices, and biologics for humans and animals should be planned and connected. Handle testing facility and enforces the principles They discuss how the studies should be monitored and reported, and how the record from these studies should be stored. They discuss how facilities in which clinical and nonclinical studies are conducted should be maintained However, they do not pertain to the manufacturer of products Good manufacturing practices: This ensures that pharmaceuticals, divides, and biologics are produced according to: ○ Consistent standard ○ Good quality and ○ Appropriateness for intended use GMP requires pharmaceutical companies to have processes that assure the adequate manufacturing control. Good Clinical practice: Universally recognized international standards/guidelines on the design and conduct of clinical trials Protects the rights, safety, and well-being of trial participants Describes the responsibilities of everyone who conducts clinical trials Covers the conduct and monitoring of clinical trials Describes reporting of data and records retention. Definition of GCP: a standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are protected.” Quality Data + Ethics = GCP Data and Reported Results are Credible, and Accurate = Quality data Rights, Integrity, and Confidentiality of Trial Subjects are Protected = Ethics Clinical Trial: Research studies that test a medical, surgical or behavior intervention in people Involves a team of investigators Who’s involved: Investigators, coordinators/project managers, nurses, clinical officers, fieldworkers, pharmacists, data manager and entry clerks, monitor/QA, laboratory staff and possibly data safety and monitoring board, clinical trial steering committee. Different types of clinical trials: Treatment trials: test new treatment, new combinations of drugs, or new approaches to treat a disease Prevention trials: test for better ways to prevent disease in people who’ve never had the disease or to prevent a disease from returning Screening trials: test the best way to detect certain diseases or health conditions Diagnostic: how can new tests or procedures ID disease Quality of life trials/supportive care: explore ways to improve comfort and quality of life for individuals with a chronic illness Phases of clinical trial: Phase 1: 20-100 healthy volunteers: ○ Is the drug safe? ○ Are there any serious side effects? ○ How does the drug dose relate to any side effects ○ Is the vaccine causing an immune response? Phase 2: Several hundred volunteers ○ What are the most common short term side effects ○ What is the body’s immune response? ○ Are there signs that the vaccine is protective? Phase 3: 1000+ volunteers: ○ How do disease rates compare between people who get the vaccine and those who do not? How well can the vaccine protect people from the disease Phase 4: Vaccine approved ○ FDA approve a vaccine only if it’s safe, effective and benefits outweigh the risks ○ Researchers continue to collect data on the vaccine long-term benefits and side effects Phase I: Is the drug safe and tolerable? Does the PK differ much from animal to man? → linearity Does it show proper absorption, bioavailability? Can we detect effects unrelated to the expected action? Is there any predictable toxicity? Subject considerations: ○ First in a small group of 12 to 25 ○ Inclusion criteria (informed consent is a must) ○ Healthy volunteers, expect for toxic drug, e.g Anti HIV, anti-cancer ○ Exclusion: women of child-bearing age, children Start with a dose about 1/10 - ⅕ tolerated animal dose Slowly increase the dose to find a safe tolerated dose No blinding Centre has emergency care and facility for kinetics study performed in a single center Takes 3-6 months - 70% success rate. Phase 2: First in patient (diff from healthy volunteer) Early phase 20-100 patients with relevant disease ○ Therapeutics benefits and ADRs evaluated establish a dose range to be used in late phase ○ Comparison with standard drug Late phase 50-100 patients ○ Double blind ○ Compared with a placebo or standard drug ○ Outcomes: Assesses efficacy against a defined therapeutic endpoint Detailed PK and PD data Establishes a dose and a dosage form for future trials Takes 6 month to 2 years 35% acceptance rate Phase III: Large scale, randomized, controlled trials About 250 - 20,000 patients Performed by clinicians in the hospital Minimises errors of phase I and II Effectiveness of the new treatment against effectiveness of current treatments Methods: ○ Multicentric → ensures geographic and ethnic variations ○ Different patient subgroups e.g pediatric, geriatric, renal impaired ○ Randomized allocation of test drug/placebo/standard drug ○ Double blinded: Document all adverse drug reactions Rigorous statistical evaluation of all clinical data ○ Takes a long time: up to 5 years: 25% success Phase IV or post marketing surveillance: No fixed duration/patient population Starts immediately after marketing Ensure it is yielding the required effects Report all ADRs Helps to detect: ○ Rare ADRs ○ Drug interactions ○ Also new uses [sometimes called phase V] Week 6 - Pharmacotherapy considerations in the Elderly Trends in aging: Decline in premature death in the elderly and their overall better health are likely due to: ○ Public health measures affecting all age groups, such as expanding immunizations and good prenatal care ○ Advances in medical technology ○ Promotion of a healthy lifestyle ○ Improvements in living conditions ○ Improved public health campaigns and screening ○ Behavior changes (smoking cessation) Trends in geriatric care: US expenditures for healthcare are already the highest among developed nations, but are expected to rise further as chronic disease affect growing number of geriatric patients Among healthcare costs for older americans 95% are for chronic diseases The cost of providing healthcare for one person aged 65 or older is 3-5 times higher than the cost for someone younger By 2030 healthcare spending will increase by 25%, as the population ages, this estimate does not take into account inflation and the highest costs of new technologies. Medication related problems: Older adults account for 49.8% if hospital admissions due to adverse drug events – rate is greatest for age 85+ years Adults age 50+ account for 51.1% of ED admissions for adverse drug events Hospital readmissions (hospice) Preventable medication errors: ○ Renal and hepatic function ○ Drug interactions ○ Lack of individualized therapy Age associated Issues: Physiologic changes affect both pharmacokinetics and pharmacodynamics Reduced physiologic reserve narrows the margin for error Polymedicine increases the risk for adverse reactions and drug interactions Multiple providers and self-care both increase the risk for inappropriate medication use. Changes in geriatric patients: Increase in body fat (25-30%) reduces plasma levels of lipid soluble drugs Decrease total body water by 25% increases concentration of water soluble drugs and intensity of response, greater risk for dehydration Decrease concentration of serum albumin: ma;nourishment decrease albumin and results in increased drug levels Decreased metabolism: hepatic functions in elderly and drug levels increase (diazepam, theophylline) Changes in Geriatric Patients: Stomach pH increases, blood flow decreases, decrease in gut motility (slow onset) In the elderly muscle decreases by 25% Excretion: decline (40-50% of renal functions in elderly may lead to higher serum drug levels and longer drug half-life. Reduced renal clearance of active metabolites may enhance therapeutic effect or risk of toxicity (digoxin, lithium, aminoglycosides, vancomycin). Age associated changes: Area Change Function General Decreased height, weight Increased fat Decreased total body water Altered drug distribution Cardiovascular Tortuosity of arteries Arterial thickening Arterial fibrosis Sclerosis of heart valves Decrease CO Decrease HR response Decreased arterial compliance Renal Abnormal glomeruli Decreased RBF, ClCr Decreased max urine osmolality Skin Wrinkling Sweat gland atrophy Altered thermoregulation Lung Decreased elasticity Decreased ciliary activity Decreased vital capacity Decreased maxim O2 uptake Decreased cough reflex GI tract Decreased HCl, saliva flow Fewer taste buds Decreased cholinergic activity Altered absorption Reduced taste sensation Decreased bowel motility Eyes Decreased pupil size Growth of lens Decreased accommodation and acuity Decreased color sensitivity Decreased depth perception Hearing Ossicle degeneration Eustatian tube obstruction Atrophy of external ear and cochlear hair cells Loss of auditory neurons Decreased high frequency hearing Decreased pitch discrimination Nervous system Decreased brain weight Decreased cortical cell count Decreased transmission speed Receptor alterations Immune system Decreased T-cell activity Drug Distribution: Factors leading to altered distribution ○ Decreased: Lean body mass Total body water Serum albumin Cardiac output ○ Increased: Total body fat Alpha1-acid glycoprotein Factors leading to altered metabolism: Reduced liver mass and volume Decreased hepatic blood flow Altered enzyme activity ○ Sex and genetic differences ○ Age associated declines ○ Drug interactions Nutrition and health status Decreased Decreased/Unchanged Unchanged CYP1A2 CYP2C19 CYP2A CYP2C9 CYP3A4 CYP2D6 Other factors: ○ Induction - smoking/alcohol ○ Induction/Inhibition - drugs ○ Variable: Diet ○ Inhibition, if severe: Malnutrition ○ Inhibition: Frailty CNS Changes: Reduced blood flow and oxygenation Increased MAO levels Decreased norepinephrine, dopamine More sensitive to sedating agents Greater sensitivity to anticholinergic agents Increased permeability of the BBB Cardiovascular changes: Decreased response to catecholamines (hormones made from adrenal glands) ○ Primarily affects beta receptors Increased circulating norepinephrine Reduced cardiac output Increased peripheral resistance Less responsive baroreceptors (a type of mechanoreceptors allowing for relaying information derived from blood pressure within the autonomic nervous system) Endocrine Changes: Impaired glucose tolerance Decreased renal response to hypoglycemia (low blood glucose) Decreased production of sex hormones Decreased thyroid hormone production Prescribing guidelines: Beers criteria ○ Originally targeted to long-term care START criteria ○ Frequently underutilized treatments/meds STOPP criteria ○ Potentially inappropriate medications Therapeutic Malfunction: Hepler and Strand have used the term ‘drug related morbidity’ to describe the phenomenon ○ Therapeutic malfunction: the failure of a therapeutic agent to produce the intended therapeutic outcome ○ Encompasses both treatment failure and the production of new medical problems Appropriate initiation of therapy require the recognition and assessment of the patient’s signs and symptoms to generate an appropriate diagnosis and therapeutic plan Adverse drug reactions in geriatrics: Seven times more likely in elderly ○ 16% of hospital admissions and 50% of all medical related deaths Drug accumulation secondary to reduced renal function Polypharmacy: dangerous practice (drug-drug interactions) Greater severity of illness Presence of multiple pathologies Increased individual variation inadequate supervision of long-term therapy Poor patient compliance Assess: Appreciate, effectiveness, safety, adherence Problems with initiation of therapy: Patient doesn’t report s/sx that may have medications to help treat ○ Problem may be asymptomatic ○ Lack an understanding of significance or meaning symptoms ○ Distrust of providers ○ Lack of access to healthcare due to an inability to pay for services or geographic barriers ○ Selection of starting a drug is challenging Clinically appropriate/effective Const and non clinical challenges Problems in monitoring and managing drug therapy: ‘Clinical inertia’: failure of healthcare providers to initiate or intensify therapy when indicated Clinical inertia due to at least three problems: ○ Overstimulation of care provided ○ Use of soft reasons to avoid intensification of therapy ○ Practice organization not being designed for achieving therapeutic goals ○ Several studies have noted that physicians overestimate their care provided for chronic illness ○ Overestimation of the extent to which they screened and monitored Problems with information flow: Poor flow of information throughout the pharmaceutical care system Clinicians need ○ Timely access to objective and subjective data ○ Evaluate the appropriateness of a prescribed drug via diagnosis, weight, and other medications. Patients need proper communications ○ Therapeutic goals, how to appropriately use the medication, how to self-monitor for side effects and therapeutic effectiveness, and how and when to contact various clinicians Prescribing cascades Best practices for pharmacotherapy: Simplify regimen (once or twice daily dosing) Consolidate medications Use of blister packs, pill boxes, calendars, watches, other reminders Reduce costs (e.g., generics, pill splitting) Summary: Age-associated changes in pharmacokinetics and pharmacodynamics present therapeutic challenges Interpatient variability makes it difficult to predict clinical effects with certainty Disease, nutrition, adherence, other drugs complicate the picture Patients benefit from a “risk management” approach Week 6: Psychotropic Pharmacology Central Nervous System Stimulants Neuron antoi: Direct message travels 85 billion neurons Dendrites, where neurons receive most of the information (input) conduct action potential then response via axon terminal. Receive messages, cascade down electric potential down to the axon covered by myelin sheaths. Methamphetamine is a neurotoxin, axon needs myelin insulation for proper conduction Synaptic cleft: Presynaptic neuron: signal is initiated ○ synthesis , packaging, release of NT Postsynaptic neuron: Signal is received Neurotransmitters act as first messengers in signal transduction Reuptake through transporters Termination of monoamines are done though monoamine oxidase (main metabolizers) an inhibitor would prolong the life spain of those below ○ Dopamine, norepinephrine, and serotonin Neurotransmitter is the first messenger Psychotropic medication: Medication that is prescribed for the treatment of symptoms of psychosis or another mental, emotional, or behavior disorder Exert an effect on the central nervous system to influence and modify behavior, cognition, or affective state. Term includes the following categories: ○ Psychomotor stimulants (for anxiety and depression) ○ Antidepressants ○ Antipsychotics (hallucinations, delusions, paranoia, mood stabilizers) ○ Agents for control of mania or depression (lithium) ○ Antianxiety agents ○ Sedatives, hypnotics or other sleep promoting medications Affect: perceivable action/signs which demonstrate their mood Class of psychotropic medications: Antidepressants: treats depression Antipsychotics: treats psychosis Stimulants: targets problems for those with low concentration, controlling actions , and remaining still or quiet (used for ADHD) ○ ADD - attention deficit disorder (used to be a separate diagnosis) Mood stabilizers: prevents cycling between manic and depression Antianxiety agents: treats signs of symptoms of anxiety Anatomy of the CNS stimulation: Activity is regulated by check and balances system: ○ Excitatory (dopamine, norepinephrine, serotonin) and inhibitory (GABA) neurotransmitters and corresponding receptors in the brain and spinal cord Stimulants act by stimulating the excitatory neurons in the brain (stimulatory ligands to the neurons to control the release and activities of neurotransmitters). Neurotransmitters: Primary monoamines combined with carbonyl group Dopamine: ○ Metabolic precursor of norepinephrine ○ Control of muscle tone and movement (markingson’s) reward, motivation, memory and attention Norepinephrine: ○ Neurotransmitters of sympathetic nervous system ○ Responsible for activity and arousal as well as anxiety learning and pleasure Serotonin: ○ Monoamine neurotransmitter ○ mood , behavior, movement, pain, appreciation, sexual activity, appetite, endocrine secretions, cardiac function, and sleep wake cycle. ADHD low dopamine activity or depression CNS Stimulants: ADHD symptoms: ○ Short attention span, inability to stay still, being impulsive Stimulants may be short acting or long acting: ○ Short acting: fast onset, short duration (15-30 minutes twice a day) ○ Long acting: take longer to act but last longer (once per day for moderate to severe symptoms) Some may need both long acting and short acting to cover school day Long acting in the morning, no stimulants at night time For those with faster metabolism, add a shorter acting one and wears off around 9-10 Stimulants: Short acting: ○ Amphetamine (adderall) ○ Dexmethylphenidate (Focalin) ○ Methylphenidate (ritalin, metadate, methylin) ○ Dextroamphetamine (Dedrine, dextrostat) Long acting: ○ Amphetamine (adderall XR) ○ Dexmethylphenidate (Focalin XR) ○ Methylphenidate (Concerta) ○ Lisdexamfetamine (Vyvanse) (prodrug) Stimulant Use: 2016 CDC: around 9% of children 2-17 6.1 mil have been diagnosed with ADHD ○ Among the children with ADHD, 6/10 were taking ADHD medication ○ Lifetime prevalence of ADHD has been estimated to be as high as 8.1% ○ Methylphenidate. Atomoxetine, amphetamine top 3 of 5 treatments for children under 18 Psychomotor stimulants: Psychomotor stimulants are drugs that produce behavioral activation → behavior activation is usually accompanies by the following: Increased arousal, increased alertness, increased motor activity Acute Effects of Stimulants: Increases in ability to focus/concentration, sociability, libido, mood elevation Euphoria, vigor, decrease the need for sleep, ergogenic effects (Increases in power output) Neurocognitive enhancing effects in healthy individuals Cocaine - Schedule II drug: Cocaine derived from the leaves of the coca plant Erythroxylon coca Coca chewing originated in peru ○ Used to sustain the performance of laborers in the peruvian silver mines Travel medicine ○ Utilized in peru to prevent high altitude sickness Once a component of Coca Cola ○ Contained approx 60mg of cocaine per 8 oz serving Initially manufacturing and marketing as “intellectual beverage” and “brain tonic” Cocaine was removed from all beverages in 1903 Mechanisms of action: ○ Less potent than amphetamines but both refer to the dopamine reuptake transporters (DAT) when the presynaptic neuron releases dopamine vesicles into the synaptic cleft. ○ Dopamine will bind to postsynaptic receptors such as D1-D5 either stimulatory or inhibitory. ○ Afterwards dopamine dissociates and is reuptake back into the presynaptic neuron where monoamine oxidase will metabolize it, destroying the dopamine. ○ If cocaine blocks the activity of that, the DAT will be prevented from reuptake dopamine and instead it will bind to the postsynaptic neuron at a different site. Indirect sympathomimetic, not directly binding to receptors, binding to dopamine transporters which indirectly affects level of dopamine. Behavior effects – Cocaine and amphetamines: Recreational doses of amphetamines and cocaine: ○ Enhanced stimulation, coordination and performance ○ Increased strength and endurance ○ Increased mental and physical activation ○ Enhanced performance in simple cognitive tasks Adverse Effects: Because both cocaine and amphetamines bind to the DAT and NAT, there’s an increase in activity of norepinephrine. ○ Increase in BP, heart rate Cardiac effects, increases SBP/DBP 2-14mmHg ○ Decrease glandular secretions ○ Rare: psychosis, mood disturbance, and severe anxiety or panic attacks ○ Adolescents with a history or signs of drug misuse use non stimulant or stimulant with less abuse potential (lisdexamfetamine) in combination with behavior therapy Physiological effects — Cocaine and Amphetamines: Autonomic effects: indirect release norepinephrine and epinephrine ○ Increase systolic and diastolic blood pressure ○ Increased heart rate ○ Bronchial dilation ○ Pupillary dilation ○ Decrease glandular secretions Amphetamines: First synthesized in 1887 in Germany Therapeutics: ○ Treatment of narcolepsy disorders ○ D-amphetamine was sold OTC in Europe until 1960s ○ Methamphetamineis the methylated derivative of amphetamine and was first synthesized in Japan in 1893 ○ The methyl group increases the drug’s ability to cross the BBB (increase bioavailability) Neurons can be demyelinated over long term use Domaine Receptors: All GPCRs w/ 7 transmembrane domains D1-like receptors: Gs coupled (D1 and D5) D2 like receptors: Gi coupled (D2, D3, D4) Therapeutics: L and D isomers of amphetamine: D-amphetamine is more psychoactive ○ Adderall (contains D and L salts in 3:1 ratio) used to treat ADHD and narcolepsy ○ L isomer is still the active ingredient in nasal decongestant inhalers ○ Vicks vapor inhaler Lisdexamfetamine: Dextroamphetamine + lysine group Hydrolyzed to D-amphetamine in the GI tract and it goes to the BBB (prodrug) Therapeutic actions: 13-14 Used for ADHD and binge eating disorder in adults No significant mean changes in systolic or diastolic blood pressure Minor increases in heart rate Similar ADRs as mixed-salt amphetamine and methylphenidate Lower abuse potential Methylxanthines: Caffeine → paraxanthine (84%), theobromine (12%) [in chocolate and stimulatory], theophylline (4%) Trimethylxanthine that antagonized adenosine receptor (slows down heart rate), which lead to downstream secondary effects on multiple neurotransmitters Indirect catecholamine (epinephrine and dopamine) enhancement Mechanism of action: Non-selective inhibition of phosphodiesterase ○ Increase in cyclic adenosine monophosphate and cyclic guanosine monophosphate ○ Adenosine receptor antagonist ○ Caffeine activates noradrenaline neurons and seems to affect the local release of dopamine. Dosage and effect: ○ Caffeine 100-200mg: decrease in fatigue, increased mental status, alertness ○ Caffeine 1.5g: anxiety, tremors ○ Caffeine 10g: cardiac arrhythmias Use for attention and alertness: Leon (2000) - 19 studies ○ Some benefits of caffeine, and using it was better than providing no treatment at all ○ Decreasing impulsivity, aggression, and parents' and teachers’ perceptions of children’s symptom severity ○ Also compared with methylphenidate/amphetamines Moderate intake can help adults become better able to remain on task Increase speed of reaction time, and enhance the ability to perform complex, intense tasks, like performance in a flight simulator Adverse effects: Cardiovascular effects: positive inotropic, positive chronotropic Diuretic effects: increases the excretion of sodium, chlorine, and potassium Gastric: stimulates secretion of gastric acid Do stimulants inhibit growth? May be related to poor nutrition, lack of appetite, inhibitory effects of increased DA on growth hormones. Evidence varies ○ 2010 prospective study found no association ○ Other studies have demonstrated an association Modafinil and Armodafinil: Treatment for narcolepsy Racemic mixture (modafinil) and as R-enantiomer (armodafinil) Weak inhibitor of DA and NE reuptake transporter but binds to both in vivo at therapeutic doses ○ Requires DA transporter and intact alpha I adrenergic receptors for activity Activities in the locus coeruleus ○ Active orexin-releasing neurons in lateral hypothalamus Pharmacological effects; ○ Armodafinil causes small but significant increase in blood pressure, no sleep rebound, low abuse potential, boosts alertness and performance to levels similar to caffeine ○ ADRs: Headache, nausea, dizziness, insomnia Possible side effects of stimulants: Side effects: decreased appetite, weight loss, headaches, stomachaches, trouble getting to sleep, jitteriness, social withdrawal, tics, sudden repetitive movements or sounds, aggressive behavior or hostility, psychotic or manic symptoms Adverse reactions: ○ Sudden death in children with pre-existing serious heart problems Choosing the initial Psychotropics: Factors to consider in selecting psychotropics: ○ History of prior response (family or family member) ○ Safety in overdose ○ Adverse effect profiles ○ Patient age ○ Concurrent medical psychiatric conditions ○ Concurrent medications (e.g potential for drug interactions) ○ Convenience (e.g minimal titration, once-daily dosing ○ Cost ○ Patient preference Antidepressants: ○ MAO (inhibitors, phenelzine, selegiline, tranylcypromine) ○ Tricyclic antidepressants (amitriptyline, clomipramine, imipramine) ○ Heterocyclic antidepressants (amoxapine, bupropion, mirtazapine) ○ 5-HT-NE reuptake inhibitors (duloxetine, venlafaxine) ○ 5-HT antagonists (nefazodone, trazodone) ○ Selective serotonin reuptake inhibitors (escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) Week 7 - Clinical Management of Attention Deficit Hyperactivity Disorder ADHD vs ADD: Attention deficit disorder (ADD) is the odd name for ADHD Officially changed in the 1990s but some people still use both names Definition: A mental health disorder sometimes referred to as a brain disorder or neurobehavioral disorder that includes a combination of persistent problems such as: ○ Hyperactivity (sitting still), inattentive (difficulty paying attention, and impulsive behavior (lacking control) Happens in children and teens, but will continue to adulthood ○ Adult ADHD can lead to unstable relationships, poor work or school performance, low self-esteem, and other problems ○ Usually diagnosed first in childhood and often lasts into adulthood. Children don’t grow out of these behaviors ○ A neurodevelopmental condition with the brain and nervous system that affects attention, impulsivity and activity levels. ADHD Facts: Typical age onset of 3-7 11% of children and 5% of adults More common in males than in females Symptoms may persist into adolescence 68% or adulthood 20-50% Adults with ADHD may be at risks for other psychiatric disorders Potential causes for ADHD: Unknown exact specific causes Genetic components 20-30% ADHD tend to run in families, family studies have identified some genes that appear to play a role in the development of ADHD (Dopamine receptor genes RDR2, DRD4, DRD5, etc). Brain chemicals: these may be out of balance with ADHD (biochemical) Brain changes: areas of the brain that control attention are less active in children with ADHD The brain of people with ADHD: Looks like a behavior problem is actually a brain disorder that affects both structure and function of the brain Research shows that the brain of people with ADHD are smaller in certain areas especially in the frontal lobe, affecting impulse control, concentration, and inhibition Brain development is slower in people with ADHD the neural pathways wont connect and mature at the same rate making it harder to pay attention and focus. This can impair executive function which handles organization and routine tasks Brain chemistry of neurotransmitters in ADHD: Dopamine sends signals throughout the nervous system, helps regulate movement, sleep, emotions, memory, the brain’s reward mechanisms, attention, and learning High dopamine levels may lead to the following symptoms: ○ Hyperactivity, anxiety and agitation, insomnia, delusions, depression, schizo, psychosis. ○ Not to be confused with inattentive and a ADHD diagnosis ○ Unmedicated people with ADHD have a higher concentration of DA transporters. Which lead to lower DA levels in the brain Norepinephrine helps the body respond to stress, involved in mood regulation and the ability to concentrate Noradrenaline high levels cause panic attacks, hyperactivity Low levels cause lethargy, depression, ADHD Affects in the brain: Brain regions smaller in ADHD children: ○ Prefrontal cortex, hippocampus, cerebellum and amygdala. Brain growth of ADHD children catches up to brain growth of normal by late adolescence to early adulthood (matures more slowly) Neurological basis of ADHD: Neuroanatomy: frontal lobes (prefrontal and striatal areas) ○ Neurotransmitters: Norepinephrine, dopamine, serotonin (less degree) Dopamine helps the brain to reinforce rewarding behaviors, norepinephrine affects heart rate, blood vessels, blood pressure and breathing. In the PET scan, the brain of the ADHD patient shows less activity, mainly in the frontal areas ADHD Risk Factors: Some which may affect a baby’s brain development during pregnancy are: ○ Poor nutrition, infections, smoking, drinking, substance abuse, exposure to toxins such as lead Child’s brain development risk factors after birth are: ○ Being born prematurely, toxins exposure, damage or injury to the front of the brain, called the frontal lobe, can cause problems controlling impulses and emotions. Nutritional deficiencies, especially diets low in fiber and omega-e-fatty acids have a greater change of ADHD Research shows eating too much sugars, watching TV, stressful home life, poor parenting, poor schools, food allergies doesn’t cause ADHD Common symptoms in preschool age: Motor restlessness Difficulty completing development tasks (potty training) Decreased or restless sleep Insatiable curiosity Family difficulties (obtaining/keeping babysitters or preschool placement) Vigorous and often destructive play Demanding Of parental attention, argumentative Delays in motor or language development Excessive temper tantrums (more severe and frequent) Low levels of compliances (especially in boys) Warning signs ages 6-12: Easily distracted Unable to sustain attention Homework is disorganized, sloppy, incomplete, careless errors Blurts out answers before question competed (disruptive) Perception of immaturity Symptoms in adolescent ages 13-18: Excessive motor activity tends to decrease Sense of inner restlessness School work disorganized and shows poorly follow through and fails to work independently Engaging in risky behaviors Difficult with authority figures Poor self-esteem Poor peer relationships, anger, emotional liability Symptoms in adulthood: Highly distractible Disorganized, fails to plan ahead Forgetful, loses things Difficulty in initiating and finishing projects or tasks misjudges available time, commonly late Makes impulsive decisions ○ Spending money, travel, jobs or social plans Poor anger control “bottle rocket temper” Job instability and marital difficulties Problems at work Low self esteem, mood swings, anxiety, depression, substance use and abuse Procrastination and trouble concentrating when reading, often bored Subtypes: Inattentive type Hyperactive-impulsive type Combined type Inattentive type: Disorganized or difficult to finish a task, or pay attention to detail or follow instructions or conversations. Easily distracted or forgets details or daily routines In children too. Often daydreaming. Occurs equal in both genders Hyperactive-impulsive type: Fidgets and talks a lot. Hard to sit still for long. Restless and has trouble with impulsivity Being impulsive means to interrupt others a lot, grab things from people, or speak at inappropriate times Hard for the person to wait their turn In children: squirms, fidgets, or bounces when sitting, staying quiet, always moving Occurs 2-9 times more frequent in boys Combined type: Symptoms of both other types which are equally present in the person Greater than 6 criteria of each impulse and inattentive type Diagnosis tests: Medical and social history of child and family Physical exam and neurological assessment including screening of vision, hearing and verbal and motor skills to rule out physical issues Neuropsychiatric EEG-based assessment AID (NEBA) system: ○ Measures THETA and BETA brain waves. The theta/beta ratio has been shown to be higher in children and adolescents with ADHD. ○ American psychiatric association’s diagnostic and statistical manual 5th edition (DSM-5) to diagnose ADHD DSM-5 diagnosis of inattentive type: Inattention to detail Difficulty to sustain attention Seems to not listen Fails to finish tasks Difficulty organizing Avoids taste that require sustained attention Loses things Easily distracted Forgetful Age younger than 17 but have greater than 6 criteria, older than 17, needs 5 to diagnose ADHD DSM-5 diagnosis of impulsivity type: Impulsivity: ○ Blurts out answer before finished ○ Difficulty awaiting turn ○ Interrupts or intrudes on others Hyperactivity: ○ Fidgets – hands, feet, squirms ○ Unable to stay seated ○ Runs about or climbs excessively ○ Has difficulty playing quietly ○ On the go, driven by motor ○ Talks excessively Age younger than 17 but have greater than 6 criteria, older than 17, needs 5 to diagnose ADHD ADHD rating scale in Children: Evaluation of intelligence, aptitude, personality traits, or processing skills. These are often done with input from the parents and teachers Vanderbilt assessment scale: parents and teachers answer questions on symptoms of ADHD. also looks for other conditions such as conduct disorder, anxiety, depression Conners rating scale: diff depending on age, children, teens, and adults. Questionnaire regarding behavior, work, and social life Behavior assessment system for children (BASC): ○ Exams hyperactivity, aggression and conduct problems, anxiety, depression, attention and learning problems Child behavior checklist/teacher report from (CBCL): scale looks at problem behavior in children ADHD rating scale in adults: Adult ADHD clinical diagnostic scale: ACDS: a doctor, therapist, or other health care worker ask 18 questions about a patient’s symptoms during an interview Conners rating scale: answer a questionnaire about themselves and may ask a spouse, co-worker, or close friend to do one as well Brown ADD symptom assessment scale (BADDS) for adults: 40 questions, looks for problems with things like attention memory and mood Comorbidity: Accompanied by other disorders Conduct disorder, tourette's syndrome, anxiety disorders, major depression, bipolar disorder, schizophrenia, schizoaffective disorder Types: ○ ADHD (inattentive) and depression: 25% of children, chronic sadness. Increased activity in thalamus and hypothalamus, decreased activity in prefrontal cortex. ○ ADHD and anxiety: great friend, very loyal, always worried, obsessive and inflexible.Medication treatment options: Stimulants such as ritalin or adderall Non-stimulants such as strattera Norepinephrine reuptake inhibitor Antidepressants Alpha-2 noradrenergic agonists Stimulants: May be effective up to 80-90% appropriately diagnosed patients with ADHD DEA class II controlled substances Therapeutics uses: attention deficit, weight loss, narcolepsy ○ Improve attention span ○ Increase ability to follow directions ○ Decrease distractibility ○ Decrease impulsivity aggression and stubbornness Psychostimulants have rapid onset of therapeutic effects (1 hour) Act on brain chemicals dopamine and norepinephrine, control hyperactivity and impulsive behavior and attention span May make psychiatric conditions like depression or anxiety worse or psychotic reaction Higher risk of heart problems and death in children with heart disease Controversy about overuse, stimulants most prescribed Stimulants: pharmacological/monitoring issues: Baseline and on at least quarterly CBC Weight, height Blood pressure, heart rate Mechanism of action between stimulants varies slightly response to each may be different Approx 20-25% who do not response to one medication will response to another Less than 45 of children discontinue due to adverse effect Growth impairment drug holidays on weekends and summer, if feasible. Current belief, however, is drug holidays are not necessary because they catch ip in late adolescence/ Each person must have the dose titrated maintained at lowest effective dose Managing stimulants SEs: Stomach ache, headache, anxiety, jitteriness, addictive, abuse potential Anorexia/weight loss can be managed by giving medication after breakfast, but high fat foods can delay the onset and increase pK concentrations on some medications Poor growth can be managed with drug holidays Dizziness monitor BP, make sure they have adequate fluid intake insomnia/nightmares: establish a bedtime routine and good sleep hygiene habits: omit/reduce last dose Tics: make sure if its drug related to reconsider risk vs benefits Psychosis: make sure dose and medication is appropriate, refer to mental health specialist Mood lability: Occurs at peak concentrations ○ Reduce the dose or switching to a LA preparation ○ Irritability, sadness, and increased activity as the medication wears off is common when a medication is used on a BID schedule, try adding an afternoon dose or switching to LA form ○ Emotions that shift quickie, uncontrollably, drastically Rebond: refers to symptoms or adverse effects that occur as the medication is wearing off ○ Rebound effects may improve by stepping down the dose at the end of the day (increasing dose of the LA agent administered in the morning or adding a smaller dose of short-acting medication at the end of the day Optimal Stimulant Selection: Choose between the two stimulant molecules: ○ Amphetamines: FDA approved for children age 3 No hepatic metabolism Less rebond Both isomers are effective Twice as potent 35% have preferential response ○ Methylphenidate: FDA approved for children age 6 Heavily metabolized in gut/liver Rebond is common Only right isomer is effective Half as potent 26% have preferential response Initially selected immediate release as first choice of treatment Choose among available delivery systems: ○ Time release amphetamine: Adderall XR Dexedrine spansules ○ Time release methylphenidate: Methylin ER Metadate ER Concerta Metadate CD Ritalin LA Focalin XR Amphetamine mechanism of action Once dopamine/norepinephrine gets released it goes into the synapse. In ADHD, they don’t have much DA or NE. The goal is to maintain it in synapse as long as possible Amphetamine blocks DA or NE uptake into vesicle, AMPH diffuses into vesicle causing DA release into cytoplasm AMPH is taken up into the cell causing DA release into synapse AMPH reverses the flow of DA and NE transporters by blocking DA and NE reuptake Potential side effects of stimulants: Constricted blood vessels cause cold hands and feet due to lack of circulation. Nervousness, restlessness, headaches, dizziness, hoarseness, slowed speech, changes in vision, irritability, increased heart rate, limb numbness due to constriction of blood vessels Amphetamine mixture: Formulation: ○ Adderall: 5-15, increments of 2.5, 20, 30 mg ○ Adderall XR: 5-30 mg increments of 5 mg Properties: single-entity of mixed amphetamine salts including dextroamphetamine sulfate and saccharate as well as amphetamine sulfate and aspartate Pharmacokinetics (dosage, adverse effects, and drug drug interactions): dextroamphetamine sulfate Administration of immediate release: with or without food. Last dose should be given 6 hours prior to bedtime. May be crushed or chewed Administration of sustained release: capsule may be taken whole or opened and sprinkled on spoonful of “cold” applesauce Beads should not be chewed Withdraw: If medication is being misused or overused withdrawal symptoms can occur Symptoms: feeling uneasy, insomnia, too sleepy, hunger, panic attacks, phobias, anxiety, irritability, fatigue, lack of energy, depression, suicidal thoughts No current treatment for withdraw May last few days to few weeks Health Canada suspending Adderall XR due to risk of sudden death, heart-related death and stroke in children and adults taking recommended doses ○ 20 international reports of sudden death in patients taking Adderall or Adderall XR ○ Deaths not associated with overdose, misuse or abuse ○ FDA response did not withdraw, recommended not to use adderall with patients with structural cardiac abnormalities Vyvanse (lisdexamfetamine): New long acting ADHD medication that provides consistent ADHD symptoms control for up to 12 hours, fro school time to homework and family time MOA CNS stimulant, blocks reuptake of DA and norepinephrine Prodrug to dextroamphetamine Medication not recommended for children 3 and under ADR: abdominal pain, dry mouth, N/V Appetite/weight, dizziness, insomnia, irritability Dose: start at 30 mg daily in AM, increase by 20 mg/day up to 70 mg day (max recommended) Dosage is based on medical conditions and response to treatment Black Box warning - cardiac sudden death, misuse and abuse of amphetamines Methylphenidate (Ritalin): Blocks dopamine and norepinephrine transporters Thus, Da and Ne accumulate in synapse Blocks neurotransmitters to go back into the presynaptic neuron Forces it to stay in the synapse Side Effects: Common: ○ Loss of appetite ○ Insomnia (difficulty sleeping) ○ Nervousness or restlessness ○ Headache ○ Stomachache or abdominal pain ○ Nausea or vomiting ○ Weight loss ○ Increased heart rate ○ Increased blood pressure ○ Dizziness or lightheadedness ○ Dry mouth ○ Sweating Uncommon: ○ Mood changes, including irritability or anxiety ○ Agitation or aggression ○ Depression or sadness ○ Suicidal thoughts or behaviors (rare but serious) ○ Hallucinations or psychosis (rare but serious) ○ Skin rash or itching ○ Allergic reactions such as swelling, difficulty breathing, or hives (rare but serious) ○ Seizures (rare but serious) ○ Blurred vision or other visual disturbances ○ Difficulty urinating ○ Priapism (prolonged and painful erection) - extremely rare but considered a medical emergency ○ Steven johnson syndrome Dosage, immediate release: Dosage: 5 to 60mg/day Initiate: 0.3/kg/dose Weekly by 0.1 mg/kg/dose or by 5-10mg/day to a max of 2 mg/kg/day or 60 mg/day ion two to 3 divided doses Administration: ○ 30 minutes before meal ○ Last dose should be given prior to 6pm ○ May crush immediate release tablets Dosage, long acting (ritalin, ritalin SR, ritalin LA) Formulations: ○ 5, 10, 20 mg tablets ○ 10, 20 mg extended-release tablets ○ 20, 30, 40 mg extended release capsules PK: ○ Immediate release: onset 30-60 minutes; tmax - 2 hours, t1/2 - 2 to 3 hours; duration 3-5 hours ○ Sustained release tablets: tmax - 4 to 7 hours; duration 7- 9 hours ○ Sustained release capsules: tmax - 1 to 3 hours; duration 7 to 10 hours, bioavailability (1st pass) 30 to 80%, hepatic - 80% ○ Extended release: given once daily; administration 30 minutes before meal; must be swallowed whole; capsules - swallowed own or sprinkled, never crush or chew Other ADHD drugs: Dextroamphetamine: ○ Administration: immediate release, sustained release: do not crush or chew ○ Adverse effects: more anorexia or weight loss ○ Drug interactions: similar to methylphenidate expect hepatic interactions Metabolism inhibited by methylphenidate: adrenergic blockers, phenobarbital Metabolism induced by methylphenidate: warfarin, monoamine oxidase inhibitors, opioids, TCA Metabolism can be induced by other drugs: alkalinizing agents, tricyclic antidepressants (TCA) Medications to avoid: oral suspensions/antibiotics, vitamin C (inhibits the drug) ionize stimulants prevent the absorption of the stimulant from the GI tract Foods to avoid: citrus fruits, fruit juices, soft drinks, lemonade Drug interactions: ○ Decongestants (hard on heart) ○ Caffeine ○ Weight loss products ○ Systemic steroids ○ Asthma medications containing albuterol (increase heart rate) Daytrana patches effective two hours after applied to hip, weekly until there’s an appropriate effect Quillichew ER: oral suspension; onset 45 minutes; duration 12 hours Possible stimulant drug-drug interactions: Certain antidepressants, blood pressure medications, seizure medications, decongestants, stomach acid medications (antacids) Required by law depending on stimulant meds: Boxed warning Medication guide and warning of serious side effects and risk of suicide Non-stimulant treatments for ADHD Resistance to stimulant therapy include comorbidity disorder Stimulant failure 15-20% or stimulant stigma Side effects experienced with stimulants are intolerable which limits compliant Prescribed 6 years or older: medications include atomoxetine (strattera), clonidine (catapres), guanfacine (intuniv) NE reuptake inhibitor (atomoxetine): Atomoxetine (strattera): selectively blocks NE transporters, therefore leading to an increase of NE in the synapse. Slow onset of therapeutic effect (2-4 weeks) Atomoxetine side effects; Nausea, tachycardia, hypertension, fatigue, sedation Can cause liver damage ADHD medications - antidepressants: SSRIs Bupropion (wellbutrin) Blocks DA and NE transporter, allowing for an increase of DA and NE in the synapse Venlafaxine effexor blocks NE reuptake, causing increase of NE in the synapse Side effects: anxiety, upset stomach, trouble sleeping, most are minor Tricyclic antidepressants Alpha-2 adrenergic agonist ADHD behavioral treatment: Behavioral therapy Social skills training Organizational training Used in conjunction with meds Psychotherapy Cognitive behavior ○ Goal setting, role playing, modeling good peers, self monitoring Educational interventions ○ Environmental control noise, visual stimulation, coating Parent training ○ Reward token system ○ Highly structured ○ Well-defined limits EEG biofeedback ○ Brain games Diet ○ Megavitamins, fish oil, gluten free, antioxidants Therapy for ADHD focus on changing behavior: Special education helps a child learn at school Behavior modification teaches ways to replace bad behavior with good ones Psychotherapy helps learn ways to handle emotions, frustrations, and improve self-esteem Social skills training teach behavior such as sharing and taking turns Living with ADHD & lifestyle changes: Eat a diet with lots of fruits, veggies, whole gains and lean protein Some exercise daily Limit time spent on electronics Plenty of sleep Simplify child's room design to lessen distractions and improve organization Week 7 - Antidepressants Pharmacology What is depression: Common yet serious mood disorder Greatly impacts daily activities, including sleeping and eating Often co-occurs with other health conditions Affects 17.3 million american adults and 1.9 million children More prevalent in women vs women Key neurotransmitters in depression (each affect mood): Noradrenaline: alertness, energy, vigilance, concentration, anxiety, irritability, attention, motivation Serotonin: repetitive and stereotypical behavior, compulsion, impulse, sleep, memory, sex, appetite, aggression Dopamine: pleasure, reward seeking, drive Symptoms: DSIGECAPS Depressed mood Sleep changes Interest lost Guilt Energy loss cognition/concentration Appetite Psychomotor Suicidal ideation Risk factors: Can be generic, biological, environmental, psychological Often begins in adulthood Certain medical illnesses (cancer, diabetes, heart disease thyroid disease) and medications Family history of depression Major life changes, trauma, stress Diagnosis: Subjective information ○ Symptoms and their context, suicide risk, medical history, family history, social history (substance use) Objective information ○ Mental status exam (mood issues), physical exam (appearance), screening tools for progression (PHQ-9) PHQ-9 (patient health questionnaire-9): Gives you a number to tell now severe depression may be Assessing Severity;: Minor vs major depression Spectrum based on symptoms, number of episodes, extent of psychosocial or physical impairments, recurrences Diagnosis of major depression: 5+ symptoms (D SIG E CAPS) ○ At least 1 is depressed mood or lost of interest/pleasure Present for at least two weeks Causes significant distress or impairment in functioning Cannot be explained by any other psychotic disorders Differential diagnosis: Ruling out other factors ○ General medical illness, sadness, burnout, complicated grief, ADHD, bipolar disorder, schizophrenia, substance/medication induced, premenstrual dysphoric disorder Treatment: Goals of treatment: ○ Response: 50% or greater improvement on a depression rating scale ○ Remission: resolution of depressive syndrome, defined by scores within normal range of the scale Pharmacotherapy: antidepressants Psychotherapy: Cognitive behavioral therapy (CBT), family/couples therapy, interpersonal psychotherapy, etc Antidepressants: First line: ○ Selective serotonin reuptake inhibitors (SSRIs) ○ Serotonin-norepinephrine reuptake inhibitors (SNRIs) Atypical antidepressants Tricyclic antidepressants (TCAs) Monoamine oxidase inhibitors (MAOIs) Factors influencing selection: Safety, side effects, (risk for low blood pressure or dizziness) Specific depressive symptoms (loss of energy, struggling with sleep, target these symptoms) Comorbid illness Current medications and potential drug interactions Ease of use Patient preferences Costs Previous family history of response to antidepressants SSRIs and SNRIs: Generally first-line therapy based on efficacy and tolerability SSRI: acts on serotonin pathways SNRI: Acts on serotonin and norepinephrine pathways Common side effects: weight gain, sedation, dizziness, insomnia, stomach upset, sexual problems Atypicals: Bupropion (wellbutrin XL): ○ Acts on dopamine and norephedrine pathways ○ Benefits: no sexual effects, weight loss, stimulating, ○ Common side effects, insomnia, nausea, anxiety, dry mouth Mirtazapine (remeron) ○ Increased appetite, sedation ○ Common side effects: weight gain, dry mouth, drowsiness TCAs and MAOIs (oldest meds, now generally avoided) Generally avoided to safety concerns ○ Broad spectrum: act on a lot of receptors and neurotransmitters, ‘dirty drugs’, constellation of negative side effects Risk of overdose Other safety concerns: ○ Heart complications, seizure, confusion, sedation, drug interactions Serotonin syndrome: Increased risk for MAOIs and being on multiple agents that work on serotonin pathways Life threatening drug reaction due to too much serotonin Signs and symptoms: sweating, hyperthermia, vomiting, diarrhea, stuff muscles Hyperreflexia: hyperactive stretch reflexes of the muscles Counseling Pearls: Set realistic expectations (min 4 weeks to work) Discuss side effects and how to manage them Importance of adherence and following up Avoidance of alcohol and other substances Healthy lifestyle recommendations Resources for support groups, hotlines, etc Empowerment Use of antidepressants in other conditions: Can be used to treat a range of conditions including anxiety, OCD, PTSD, bipolar disorder, certain chronic pain conditions, migraine prevention Challenges: Special populations: geriatric patients at risk of falls, pediatric patients age limits with meds, pregnancy Managing side effects: some side effects can be pros and or cons, creating new issues Resistance to medications: some patients may have no response to multiple medications, exploration of options, timely, frustrating to some patients Suicide risk: takes weeks or months to see improvement in mood ○ Physical improvements occur in two weeks but not mood, hence they have motivation to go through with suicide Week 8 - Clinical Management of Major Depressive Disorder Major depression: Serious mood disorder Persistent feelings of sadness, lost of interest in activities they once enjoyed Can be present with physical symptoms such as chronic pain or digestive issues Can’t simply “snap out of it” May require long-term treatment and medication Symptoms: Sadness, angry outbursts, anxiety, reduced appetite or weight gain, tiredness, sleep disturbances, slow thought processes, lost of interest in pleasure or normal activities, unexplained physical problems, frequent thoughts of death Statistics: 29% of americans affected at some point, 17.8% current MDD 10% of adults More common in younger populations More common in caucasians Women nearly twice as likely Adults with depressive disorder have a 64% greater risk of developing coronary artery disease 35% don’t receive treatment Causes: Genetics or family history Changes in body’s balance of hormones, pregnancy, postpartum Traumatic life events Health conditions: diabetes, anemia, pain conditions, thyroid disorders, etc Medication causes: opiates (pain relievers), benzodiazepines, beta blockers Neurotransmitters in causing depression: Chemical messengers that the human body cannot function without Scientists know at least 100 neurotransmitters Job is to help nerve cells communicate with each other Carry chemical messages from 1 neuron to the next target cell (nerve cell, muscle or gland) Located in axon terminal between neurons Stored within thin walled sacs called synaptic vesicles Each synaptic vesicle contains thousands of neurotransmitter molecules that are re;eased into the synapse (which is less than 400 nm) Cause of depression: imbalance of neurotransmitters: Monoamine neurotransmitters affected by depression: serotonin, norepinephrine, dopamine Increased levels of MAO-A (monoamine oxidase A) enzyme breaks down key neurotransmitters 5-HTP chemical that the body makes from tryptophan then changed into serotonin (5-HT) ○ Serotonin regulates mood, sleep, appetite and depression Serotonin: Produced bio-chemically from amino acid tryptophan Stores in GI, thrombocytes aka platelets and CNS Within GI tract it regulates intestinal movements, bidirectional communication between brain and GI tract Microbes in gut communicate with cognitive and emotional centers in the brain Platelets aid in healing of wounds, serotonin stimulates vasoconstriction (reducing blood flow to wound) Removed by synaptic cleft via reuptake by serotonin transporter Reuptake is inhibited by SSRIs Foods containing Tryptophan: L-tryptophan is essential amino acid that can’t be synthesized by humans, found in plant and animal protein foods US recommended 250mg - 425 mg per day Found in milk, canned tuna, turkey, chicken, nuts, speeds, oats, fruits, bread Enters CNS via L-type amino acid transporter (LAT1) which shuttles amino acids past BBB Diagnosis: Rating scales: PHQ-9, HAM-D, mental status exam (MSE), DSM-5 ○ Clinician and patient rated ○ Depends on setting and cognitive/mental state of patients PHQ-9: ○ 9 questions ○ Max score is 27 ○ Minimal is 1-4 MSE: ○ More of a physical exam, objective assessment of mental functioning ○ Verbal and non-verbal communication ○ Appearance ○ Behavior and attitude ○ Speech DSM-5: ○ 5 of which have occurred in the following two weeks ○ Does it affect speed or energy, suicide, insomnia, depressed mood or lost of interest ○ functional/impairment ○ D SIG E CAPS Phases of depressive illness: Defined by present or absence of symptoms rather than time frames Symptoms not in remission when illness is acute When patient reaches remission, the continuation phase begins Maintenance phase is identical to continuation phase although its meant to indicate indefinite use of antidepressants due to previous episodes Continuation and maintenance: Continuation: therapy should continue for 4-9 months at the dose required to achieve remission. ○ Risk of relapse increases with shorter treatment duration. If relapse, address potential causes such as adherence, substance use, psychosocial stressors Maintenance: recommended for chronic depression or history of three or more depressive episodes: ○ May require indefinite therapy, additional considerations are residual symptoms, psychosocial stressor, maximization of non-pharmacotherapy approaches Response vs Remission: Response: 50% reduction in depression symptoms measured by validated depression symptom rating scale Remission: absence of depression symptoms (scale depended cutoff is less than 5 PHQ-9) ○ Remission is more robust marker of illness improvement than response Treatments: Selecting an antidepressant: ○ Severity and type of depression and symptoms, previous response or familial response, patient preference, financial consideration, side effet profile, age, comorbidities (substance abuse, medical disorders), concomitant drugs, suicidal ideation Pharmacologic (antidepressants): ○ SSRIs and SNRIs, atypical antidepressants, tricyclic, MOAIs, augmentation agents Nonpharmacologic: ○ Psychotherapy: Cognitive behavioral therapy (CBT), interpersonal therapy ○ Interventional: Electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation, vagal nerve stimulation, bright light therapy Patient education about antidepressants: Response is delayed, must be taken for at least 7-12 months Antidepressant medications are not addictive substances, taken at the same time daily May experience side effects initially Acute phase of improvement: 1-2 weeks, full benefit 4-12 weeks Continuation phase 4-9 months All SSRIs and SNRIs should be gradually titrated down on discontinuation of therapy Don’t discontinue therapy during times of life stressors and monitor for recurrence of depressive symptoms SSRIs: Fluoxetine (Prozac), Sertraline (Zoloft), Paroxetine (Paxil, Pexeva), Fluvoxamine (Luvox), Citalopram (Celexa), Escitalopram (Lexapro), Vilazodone (Viibryd), Vortioxetine (Trintellix) Considered first line antidepressants Boost serotonin levels by preventing reabsorbing serotonin, leaving more to pass messages between nerve cells Inhibits presynaptic reuptake of serotonin rom synaptic cleft Weekly affect norepinephrine and dopamine Side effects: ○ CNS effects: sedation insomnia, headaches, vivid dreams, nightmares, anxiety, mania ○ GI effects: N/V, diarrhea, constipation, anorexia ○ ○ Dry mouth Sexual disfunction, bleeding/anemia due to platelet depletion, sweating,weight gain, suicidal ideation SSRI dosing considerations ○ Administered once daily, initial dose can be maintenance dose, if needs to be increased, titrate 3-5 days if tolerable ○ Increased sedation when taken with alcohol and other sedating drugs ○ Safer in overdose (less toxicity ○ Useful for anxiety, OCD, eating disorder, menstrual cycle SNRIs: Venlafaxine (Effexor, Effexor XR, Venlafaxine ER), Duloxetine (Cymbalta; recent approval of generic), Desvenlafaxine (Pristiq), Levomilnacipran (Fetzima) Increases serotonin and norepinephrine reuptake Adverse effects: ○ GI effects (nausea, constipation, diarrhea), insomnia, drowsiness, dizziness, dry mouth, sweating, sexual dysfunction Certain SNRIs have different adverse effects: Effexor can cause hypertension dose related withdraw, Duloxetine can cause hepatitis and jaundice Dosing: Effexor requires titration, Duloxetine doesn’t Treats depression, anxiety, chronic pain, fibromyalgia Atypical Antidepressants: Serotonin receptor antagonists (SARIs): ○ Phenylpiperidines: Nefazodone (Serzone), Trazodone, Trazodone XR (Desyrel, Oleptro), Mirtazapine (Remeron, Remeron SolTab) ○ Adverse effects: CNS (sedation, dizziness, confusion, cardiovascular (orthostatic), priapism, anxiety/panic attacks, weight gain ○ Dosing required due to orthostatic and sedation Bupropion (Wellbutrin, Wellbutrin XL, Aplenzin, Forfivo XL) ○ Blocks reuptake of NE and DO, non competitive antagonist of nicotinic receptors ○ Clinical uses: depression, smoking cessation, neuropathic pain, weight gain, ADHD ○ AE: insomnia, headache, jitteriness, agitation, nausea, rash, increased BF, causes less sexual dysfunction and can be used with SSRI and SNRI without risk of serotonin syndrome Others: Vortioxetine (Trintellix), Esketamine (Spravato) Tricyclic Antidepressants (TCAs): Blocks serotonin and norepinephrine reuptake Amitriptyline (Elavil), Doxepin (Sinequan). Imipramine (Tofranil), Trimipramine (Surmontil), Clomipramine (Anafranil), Desipramine (Norpramin), Nortriptyline (Pamelor) Effective for depression, pain syndromes, anxiety disorders Side effects: ○ Neuro side effects: sedation, mental status changes, respiratory depression, lethargy, confusion, lower seizure threshold, blurred vision ○ GI side effects: constipation, weight gain, dry mouth, urinary retention ○ CV side effects: Orthostasis, tachycardia, cardiac arrhythmias, sudden deaths Sexual dysfunction Discovered in 1950’s as an antihistamine, marketed in 1960’s as antidepressant Different types Tertiary, Secondary Not preferable in patients with suicidal ideation or past suicide attempts, risk of overdose Monoamine Oxidase Inhibitors (MAOIs): 1st clinically effective antidepressant (1940-1950’s), prevents the enzyme called monoamine oxidase from removing serotonin, norepinephrine, dopamine Nardil and Parnate used for depression and Eldepryl (selegiline) used to treat Parkinson’s disease Side effects: ○ CNS adverse effects: sedation/insomnia, headache, disorientation, switch from depression to mania ○ CV adverse effects: Orthostatic hypotension, decreased HR, hypertensive crisis ○ Sexual impotence ○ GI/GU: Dry mouth, constipation, urinary hesitancy, weight gain Food interactions: ○ Dietary restriction of foods containing tyramine ○ Definitely avoid: Beer, red wine, aged cheeses, sauerkraut, dry sausage, fava or ○ Italian green bean pods, smoked fish, liver, soy sauce, and soy products, yeast extract ○ May be problematic: Ripe avocado/bananas, yogurt, alcohol, caffeine, sour cream, chocolate, peanuts ○ Combination may lead to hypertensive crisis, severe headache Many drug Contraindications Augmentation Therapy: Addition of second antidepressant to initial therapy Appropriate if failed or partially responded after 4 to 8 weeks of antidepressant therapy at adequate dose May be preferable if partial response observed to initial treatment Not always an antidepressant: (adjunctive strategies) ○ Antipsychotics (Risperdal, Zyprexa, Seroquel) ○ Lithium (great in reducing suicidality) ○ Bupropion, Mirtazapine ○ Thyroid supplementation ○ CNS stimulants ○ Ketamine (single IM dose) historically an anesthetic and analgesic, helps with individuals in self-injurious behavior oral/sublingual, IN, IM, IV routes ○ Psilocybin (psychedelic treatment) Selecting and antidepressant medication based on side effect profile: Patients with primarily low energy and anhedonia use an antidepressant with NE effects (duloxetine, venlafaxine) or bupropion. ○ Avoid sedating meds like Paxil (SSRI) or mirtazapine Patients who are anxious and irritable use an antidepressant with serotonergic activity (SSRI). ○ Avoid meds that can increase anxiety initially (SNRI, bupropion), but can be used later if other options fail Patients who do not want sexual dysfunction use Bupropion, mirtazapine. ○ Avoid SSRIs (especially Paxil or Prozac) Patients who do not want weight gain (obese) use Bupropion. Avoid Paxil, mirtazapine, MAOIs, and TCA’s Patients with comorbidities: hypertension, cerebrovascular disease Avoid Effexor, TCA’s, MAOIs. Seizures avoid bupropion, TCA’s. Parkinson’s use bupropion (because increases dopamine), avoid antipsychotics American Psychiatric Association Practice Guidelines 2010: Therapeutic trial = 4 to 6 weeks (optimized dose) If no response to mono therapy then switch within or between pharmacological class Cross-taper (most common) often used when switching to an antidepressant with a difference mechanism of action SSRI to SNRI Direct switch doesn’t require washout period can be done by direct switch, SSRI to SSRI Washout period, stop 1st drug and then start new drug (MAOIs and drugs that may interact with it) If partial response to monotherapy (optimized dose) start augmentation with psychotherapy, and/or start augmentation with non-MAOI antidepressant or non-antidepressant medication Switching Drugs: Appropriate if failed 4 to 8 weeks of antidepressant therapy of adequate dose May switch to agent within same class or different class (SSRI to SSRI) or (SSRI to SNRI) Switching drugs is high risk because it can introduce risk of side effects, withdrawal, or decompensation Two strategies: Direct Switch may be used when switching between SSRIs ○ Cross Taper: Gradual reduction of one agent with gradual introduction of new agent (usually over 1 to 2 weeks). This will minimize risk of mood decompensation and symptom exacerbation. This will minimize risk of withdrawal. May increase the risk of additive serotonergic side effects Serotonin Syndrome: Can occur when multiple serotonergic medications given (SSRIs, SNRIs, TCAs, MAOIs, tramadol, meperidine, sumatriptan, St. John’s wort, cocaine, amphetamines, MDMA) Symptoms: ○ Mild: GI (abdominal cramping, N/V/D), nervousness, dilated pupils, tremor ○ Moderate: Agitation, restlessness, muscle twitching, involuntary muscle contractions, muscle spasms, muscle rigidity, sweating, fever, shivering, abnormal eye movements ○ Severe: Confusion, disorientation, delirium, rapid heart rate, high blood pressure, seizures, abnormal heartbeat, fainting Potentially life-threatening condition due to excessive serotonin levels Can develop quickly over hours, common within 24 hours Avoid foods that have tryptophan (turkey, soy, eggs, pumpkin seeds, peanuts, some cheeses) Treat this: stop the offending medication resolves syndrome usually Activation Syndrome: Severe adverse effect caused by antidepressants (SSRI’s mainly Paxil) Symptoms: Anxiety, agitation, panic attacks, insomnia, irritability, akathisia (the inability to remain still), mania Can emerge after the first few weeks of anti-depression treatment or a dose increase Resolves with dose reduction or cessation or treatment Sometimes suicidal Serotonin Withdrawal Syndrome: Due to abrupt discontinuation of medications, especially meds with short half-lives (doxepin, amitriptyline, imipramine, desipramine, paroxetine, fluvoxamine, venlafaxine) Symptoms: flu-like symptoms, dizziness, insomnia, nausea, shooting pains in extremities, anxiety, lethargy, insomnia, cholinergic symptoms, not life-threatening Onset around 48 hours after last dose Duration 3 days to 2 weeks but may be longer 56% of patients may experience withdrawal upon discontinuing antidepressants Neuroleptic malignant syndrome: Usually reported with antipsychotics or dopamine antagonists (i.e. Reglan, Compazine, Inapsine, Phenergan, Thorazine, Haldol) Reported in some cases with SSRI and SNRI alone or in combination with triptans, MAOIs, antipsychotics/dopamine antagonists Symptoms: lead-pipe rigidity, unstable blood pressure, tachycardia, fever, mental status changes, rhabdomyolysis, renal failure Can be life-threatening Black Box Warnings: The highest safety-related warning that medications can have assigned by the Food and Drug Administration These warnings are intended to bring the consumer’s attention to the major risks of the drug Draws attention to a medication’s serious or life-threatening side effects or risks The boldfaced text appears at the beginning of the package insert accompanying each prescription: warning that antidepressant usage for children and adolescents may increase risk of suicidality. Medication Guides are required to be dispensed with every antidepressant prescription to alert patients and caregivers to the risk of suicidal thinking and behavior. It also includes information on precautions that may be taken ○ Medication Guide is a paper handout that comes with many prescription medicines to help avoid serious adverse events Treatment Refractory Depression: Generally defined by failure of two adequate antidepressant trials usually many more in clinical practice Estimated prevalence of 10% to 30% in depressed patients Treatment modalities: Electroconvulsive therapy (ECT) Repetitive Transcranial Magnetic Stimulation (rTMS) Vagal Nerve Stimulation: Deep brain stimulation, Trigeminal nerve stimulation Ketamine Psilocybin-assisted psychotherapy Non-pharmacological treatment: Psychotherapy: Cognitive Behavioral Therapy ○ Treatment effect not seen for months, expensive, time investment, poor quality control Electroconvulsive Therapy: ○ High response rate, well tolerated, rapid onset, delivered in controlled environment, patients asleep during treatment, seizure induced after administering premedications. ○ Indications for severe vegetative symptoms, psychotic depression, catatonia, intractable mania. ○ Adverse effects are sedation, confusion, usually retrograde amnesia, long term memory loss very rare Repetitive Transcranial Magnetic Stimulation administers repetitive sub-convulsive magnetic stimulation to dorsolateral prefrontal cortex Vagal Nerve Stimulation an implant to treat chronic depression, previously indicated in epilepsy. ○ Used for adjunctive long-term treatment of chronic or recurrent depression. ○ Black box warning that device is permanent. May cause temporary hoarseness, cough, feeling of SOB on exertion Bright light Therapy which uses blue wavelength of light may be effective for suppressing melatonin Complementary and Alternative Therapies (supplements) St. John’s Wort S-adenosylmethionine (SAMe) Omega 3 fatty acids Folate Acupuncture Summary and Conclusions: Depression is a common and treatable mental illness that too often leads to suicide Antidepressants have evolved over time to improve adverse effects and overdose safety profiles There is significant heterogeneity in treatment response to various antidepressant medications Patient specific factors in conjunction with guideline recommendations should guide treatment choices Being proactive with counseling, reaching out, offering support, and being an empathetic listener can have a profound impact on the life of another

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