01 PH Course Unit 5 PDF

[BSN] [PHARMACOLOGY] COURSE MODULE COURSE UNIT WEEK 1 5 5 Drugs Affecting the Body System and Nursing Considerations: CNS & ANS ü Read the course and unit objec...

[BSN] [PHARMACOLOGY] COURSE MODULE COURSE UNIT WEEK 1 5 5 Drugs Affecting the Body System and Nursing Considerations: CNS & ANS ü Read the course and unit objectives ü Read the study guide before class begins ü Read required reading materials and understand terminologies ü Participate in classroom discussion ü Participate in discussion board (Canvas) ü Answer and submit course unit tasks At the end of the course unit (CU), learners will be able to: Cognitive: 1. Review anatomy and physiology of the Nervous System 2. Understand the basic concept of diseases affecting the o Central Nervous System o Autonomic Nervous System 3. Classify Neurotransmitters that affect nervous function 4. Comprehend the basic impulse transmission in the nervous system to understand pharmacodynamics of drugs affecting the nervous system 5. Identify classifications of drugs affecting the CNS and ANS 6. Describe the specific actions of drugs and its adverse effects. 7. Understand the pharmacokinetics of drugs affecting the nervous system  8. Determine specific nursing considerations or precautions in safe drug administration 9. Provide appropriate health drug education related to drug therapy 10. Use available clinical evidence that can ensure safe medication administration Affective 1. Manifest professionalism in and excellence in planning for safe medication process 2. Listen attentively during discussion 3. Respect other’s opinion during discussion and tactfully make clarifications Psychomotor 1. Participate in an interactive discussion 2. Express suggestions, reactions and opinions in class ACTION POTENTIAL – this is a rapid change in the membrane potential that explains how impulses are conducted along the nerves ANXIETY – feeling of fear, tension or apprehension from known or unknown reasons DEPRESSION – affective disorders characterized by extreme sadness, hopelessness and disorganization MANIA – characterized by period of extreme over activity and excitement NEUROTRANSMITTERS – chemicals in the nervous system that help in the transmission of impulses PALLIATIVE TREATEMENT – control of signs and symptoms of the disease PARKINSON’S DISEASE – degenerative disease of the nervous system characterized by lack of neurotransmitter called Dopamine SCHIZOPHRENIA – most common type of psychotic disorder that may cause impairment o function of an individual I the society SEIZURE – abnormal and excessive impulse transmission in the brain SYNAPTIC TRANSMISSION – conduction of impulses across the junction between neurons REQUIRED READING Karch, A. M. (2019). Focus on nursing pharmacology. Lippincott Williams & Wilkins. Chapters on Drugs affecting CNS and ANS. All nursing considerations of the given CNS and ANS drugs Introduction Drugs affecting the nervous system alter its functions. A thorough review of the anatomy and physiology of the Central Nervous System and Autonomic System would help students understand the mechanisms of actions of drugs. The functional unit, neurons basic function is impulse transmission which happen by electrical and chemical process. Electrical transmission of impulses happen by action potential and chemical pocess make use of neurotransmitters to achieve its functions. Central Nervous System Brain & Spinal Cord – very important structure of the CNS is its protective mechanisms that not all chemicals can pass through it, this affects the pharmacodynamics of drugs because some of them cannot penetrate the CNS. One vital protective structure is the Blood Brain Barrier (BBB). This represents therapeutic challenge to drug treatment of brain related disorders because a large percentage of drugs are carried bound to plasma proteins and are unable to cross the brain. Peripheral Nervous System Autonomic Nervous System & Somatic Nervous System – Synapses made by the peripheral nervous system conduct impulses that is chemical in nature. These neurotransmitters have specific receptors in the neural membrane tos facilitate conduction of nerve impulses. Drugs may act in the nervous system to either stimulate or block the receptors to correct alterations in the nerovus functions. Neurons conduct impulses by Action Potential, the rapid change in the membran potential, this happens by movement of sodium into the cells causing depolarization and potassium out of the cells to cause repolarization. This movement of ions facilitated by channels in the cell membranes will be acted upon by drugs to correct changes in the nervous system causing disease process. Classifications of Drugs Affecting the CNS 1. Anxiolytic and Hypnotic Drugs Anxiety is a feeling of tension, nervousness, apprehension or fear that usually involves unpleasant reactions to a stimulus, whether acutal or unknown. Anxiety is classified as mild, moderate, severe and panic. Mild anxiety is normal as it helps the person to have wider perspective and focus on certain activities but increasing anxiety may cause restlessness and increase sympathetic stress reaction which may cause physical symptoms of the sympathetic stress reactions. When anxiety becomes moderate, there is a need for drug treatment. Sedation is the loss of awareness and reaction to environmental stimuli. Hypnosis is severe sedation. These conditons occur due to increase excitatory neurotansmitters causing rapid brain impulse conduction causing restlessness, irritability, loss of concentration, loss of mental focus and sympathetic responses like palpitations, tremors, diaphoresis, increase breathing and increase blood pressure. Drugs for anxiety are called Anxiolytic Drugs or Sedative Hypnotic Agents Mechanism of action – to enhance the effect of GABA (Gamma Amino Butyric Acid), an inhibitory neurotransmitter to decrease impulses in the synapses of the brain, therefore decreasing conduction of rapid impulses causing symptoms of anxiety. Drug Classifications o Barbiturates – drug action is to enhance GABA effect. This is used to be the drug of choice to manage anxiety but its depressant effect may cause severe respiratory depression that this is not primarily used for anxiety today § Pharmacokinetics: Barbiturates are absorbed well, reaching the peak levels in 20 to 60 minutes. It is metabolized in the liver and excreted in the urine § Contraindications and Cautions: Barbiturates are more addicting than other anxiolytic drugs. May cause severe CNS depression and respiratory dysfunction. Contraindicated in pregnant women and clients with heaptic and renal dysfunction § Adverse Effects: CNS depression, paradoxical excitement, anxiety and hallucinations. Gastrointestinal signs and symptoms like nausea, voimiting, constipation, diarrhea and epigastric pain. Cardiovascular effects include bradycardia, hypotension and syncope § Examples: Phenobarbital, Secobarbital, Amobarbital o Benzodiazepines – drug action is to enhance GABA effect to cause inhibition of impulse transmission. § Pharmacokinetics: this is well absorbed in the GIT with peak levels achieved in 30 minutes. This is lipid soluble and well distributed in the body crossing the BBB, placenta and breast milk. Metabolized in the liver and excreted in the urine § Contraindications and Cautions: Contraindicated in Clients with allergy to benzodiazepines, psychosis, clients with acute narrow angle glaucoma, shock, acute alcohol intoxication which may exacerbate the depressant effects of the drugs. Contraindicated in pregnancy as this is known to possible cause cleft lip or palate, inguinal hernia, cardiac defects, microcephaly or pyloric stenosis if taken during the first trimester. Caution should be used in the elderly or debilitated patients an those with hepatic and renal functions § Adverse Effects: Sedation,drowsiness, depression, lethargy, anticholinergic effects like drying of mount, constipation, orthostatic hypotension, urinary retention, dysrhythmias, blood dyscrasias and  phlebitis. Withdrawal syndrome may occur with abrupt cessation characterized by nausea, headache, vertigo, malaise and headache. § Examples: Diazepam, Lorazepam, Clonazepam o Non – Benzodiazepines – Other drugs used for anxiety that do not fall under Benzodiazepine DRUGS DESCRIPTIONS o Paraldehyde o Old drug used for Delerium Tremens, seizures, absorbed and metabolze in the liver. It has a distinctve odor and cannot be stored in plastic containers o Meprobamate o An old drug used to manage anxiety for 4 months, works in the limbic syste, metabolized in the liver and excreted in the urine o Chloral hydrate o Frequently used to produce nocturnal sedation or preoperative sedation. Unknown mechanis of action, absorned in the GIT, metabolized in the liver and excreted in the urine o Zolpidem o Used to treat insomnia, Metabolized in the liver and excreted in the urine o Anti histamines – o Used or its drowsiness effect in Diphenhydramine ( Benadryl) anxiety. With anticholinergic effect. Promethazine ( Phenergan Used during preoperatively or postoperatively to decrease use of narcotics o Buspirone o No sedative,anticonvulsant, or muscle relaxant properties, unknown mechanism of action, reduces anxiety without many CNS effects. Absorbed in the GIT, metabolized in the liver an excreted in the urine o Beta Blockers – o Decreasing sympathetic effect Propranolol to lessen signs nd symptoms of Metoprolol anxiety Nursing Considerations  o Do not administer intraarterially because of possible serius areriospasm and gangrene may develop o Don not mix IV drugs with other drugs o Give parenteral forms if oral forms are not feasible and switch to oral which is safer o Give IV drugs slowly to avoid hypotension effects o Promote safety measures o Monitor hepatic and kidney function o Taper dose of drugs gradually o Provide comfort measures to help patient tolerate the effects of drugs o Provide thorough health teaching about drug effects and adverse reactions o Offer support and encouragement o For overdose of Benzodiazepine, Flumazenil must be ready as its antidote. 2. Antidepressant Drugs Feelings of sadness is normal and expected after a tragic event in life. This is an expected response to a stressor. Since this is a normal process, many people experiencing severe sadness may develop a depressive disorder unrecognized. People fail to distiguish normal process of grieving with a major depressive disorder. Depression being an affective disorder is recognized by its clnical manifestations such as sleep disturbances, they have little energy, inability to perform daily activity. They may describe overwhelming feelings of sadness, despair, hopelessness and disorganization. Pharmacology explains depression by Biogenic Amine Theory. This theory explains that depression occurs due to decreasing neurotransmitters, norepinephrine, serotonin and dopamine. When impulses travel across the synapses, neurotransmitters are released into the symapse, they bind in the receptors in the post synpatic neural membrane and help impulse to be conducted. After which, neurotransmitters are removed by enzymes or they may go back to the presynaptic neuron: Refer to picture below In the limbic system which is the area responsible for over all emotion and behavior, there are three neurotransmitters being released, Norepinephrine, Serotonin and Dopamine. After impulse is transmitted across the synpase, and enzyme called Mono Amine Oxidase will remove them. Some however may go back to the pre synaptic neuron the process called reuptake of Neurotrnasmitters. If they are not available in the synapse, there will be no more impulse transmission. Let us go back to Biogenic Amine Theory which explains that depression results from decreasing neurotransmitter in the limbic system which may happen due possibly to: 1. Overused of neurotransmitters ( Norepinephrine, Dopamine and Serotonin) 2. Increase effect of Mono Amine Oxidase ( MAO ) enzyme 3. Increase reuptake of neurotransmitter back to presynaptinc neuron If we know the problem in the limbic system that is decreasing neurotransmitters, then we need to increase them and make them stay in the synaptic cleft. Drugs for hypertension may achieve its therapeutic effect within 2 – 4 weeks from its oral intake. Drugs for Depression are called Anti Depressant Drugs Mechanisms of action o Inhibit the enzyme Mono Amine Oxidase (MAO) o Inhibit Reuptake of Neurotransmitters Drug Classifications o Tricyclic Antidepressants (TCA) – inhibit presynaptic reuptake of neurotransmitter, norepinephrine and serotonin, which leads to accumulation of these neurotransmitters in the synaptic cleft and increased stimulation of post synpatic receptors § Pharmacokinetics: it is abosrbed in the gastrointestinal tract, reaching the peak in 2 to 4 hours. Widely distributed in the tissue including the  brain. Metabolized in the liver and excreted in the urine. They cross the placenta and the breast milk. § Contraindications and Caution: Contraindicated to those with known allergy to TCA. Clients with recent myocardial infarction because of its cardiovascular effects. Caution should be used in clients with Gastrointestinal and Genitourinary tract disorders. The presence of hepatic and renal impairment increases toxicity of the drugs. § Adverse Effects: CNS effects like sedation, hallucinations, fatigue, cardiovascular effects, unstable blood pressure, abnormal rhtyhms, myocaridal infarction, anticholinergic effects like drying of the mouth, constipation, urinary retention Remember Mnemonics C – Cardiovascular effects A – Anticholinergic effects S – Sedation H – Hyotension or Hypertension Clinically important drug – drug interactions: The effects of TCA may increase if combined with Ranitidine, Fluoxetine and Cimetidine especially the anticholinergic effects. Oral anticoagulant level may increase if combined with TCA and risk for bleeding increases. Increase effect with sympathomimetic drugs especially its cardiovascular effects Examples: Imipramine, Amitryptilline, Clomipramine o Mono Amine Oxidase Inhibitors – these drugs inactivate the enzyme MAO to increase the neurotransmitters in the synapses. Pharamacokinetics: absorbed in the GIT, reaching peak levels in 2 – 3 hours, metabolized in the liver and excreted in the urine. They pass the placenta and breast milk and not used in pregnancy. Contraindications and Cautions: Contraindicated in clients with cardiovascular disease, hepatic and renal disease. Caution should be used in psychiatric patients Adverse Effects: More adverse effects than other antidepressant drugs. Dizziness, excitement, nervousness, mania, hyperfexia, tremors, confusion, insomina, agitation and blurred vision. Liver toxicity, Cardiovascular toxicity. Anticholinergic effects Drug – Drug interaction: Drug interaction with other antidepressant drugs include hypertensive crisis, coma and severe convulsion. A period of 6 weeks should elapse after stopping SSRI and beginning MAOI. Drug – Food Interactions: Tyramine – rich food which normally broken down by MAO enzymes in the GIT amybe absorbed in high  concentration in the resence of MAOI and may cause hypertensive crisis. Examples: Isocarboxazid, Phenelzine, Tranylcypromine o Selective Serotonin Reuptake Inhibitors (SSRI) – these drug specifically block the reuptake of serotonin with little or no effect on Norepinpehrine. SSRIs do not have the many adverse effects of TCAs and MAOIs Indications: Depression, Obsessive Compulsive Disorders (OCD) Panic attacks, Bulemia, Post Traumatic Stress Disorder (PTSD) Pharmacokinetics: well absorbed in the GIT, metabolized in the liver and excreted in the urine or feces. SSRIs are associated with congenital abnormalities. They passed the placenta and the breastmilk Contraindication and Caution: Those with allergy to SSRIs, pregnancy and lactation. Adverse Effects: CNS effects like headache, drowsiness, dizziness, insomnia, anxiety, tremor, agitation and seizures. Anti cholinergic effects on the gastrointestinal tract and genitourinary tract. Examples: Fluoxetine, Sertraline, Paroxetine Nursing Considerations o Limit drug access to potentially suicidal patients to decrease the risk of overdose o Monitor the patient for 2 – 4 weeks to ascertain onset and full effects o Monitor blood pressure and orthostatic blood pressure carefully o Monitor liver function o Withold medication dose in client with severe headache that may due to severe hypertension and cerbrovascular effects o Have phentolamine or another adrenergic blocker for hypertensive crisis o Provide comfort measures to help the client tolerate drug effects o Privde list of food that is low or no tyramine to clients on MAOI therapy o Offer support and encouragement to help patients cope with the disease and drug regimen 3. Psychotherapeutic Drugs Mental disorders have several classifications. For this course, discussion include only drugs used for Schizophrenia and Mania, two of the most common psychiatric disorders. Schizophrenia is the most common type of osychotic disorders. This prevents an individual in functioning in the society. Some clinical manifestations include, hallucinations, delusions, paranoia, speech abnormalities and affcetive problems. Mania is associated with Bipolar illenss. Mania is characterized by periods of extreme overactivity and excitement Drugs for mental disorders are called Psychotherapeutic drugs. Drugs for Schizophrenia are called Anti Psychotic Drugs and for drugs for Mania are called Anti Manic Drugs Antipsychotic drugs Mechanisms of Action o Typical Antipsychotic drugs – block Dopamine receptors in the limbic system, in the reticular activating system and the brain. This group of antipsychotic may block all dopamine receptors including those not associated with psychoses o Atypical Antipsychotic drugs – block Dopamine and Serotonin receptors. This group will lock only the receptors of Dopamine and Serotinin which are responsible for occurrence of psychosis making them more specific drugs for Psychotic disorders Drug Classifications o Typical Antipsychotic drugs: Older drugs, they are less potent and associated with more adverse effects § Examples: Chlorpromazine, Fluphenazine, Thioridazine, Haloperidol o Typical Antipsychotic drugs: Older drugs, they are less potent and associated with more adverse effects § Examples: Chlorpromazine, Fluphenazine, Thioridazine, Haloperidol o Pharmacokinetics: Antipsychotic drugs are erratically absorbed in the GIT, metabolized in the liver and excreted in the bile and urine. Widely distributed in the tissues, being released up to 6 months after they are discontinued. Drugs cross the placenta and breast milk so they are not given to pregnant and lactating mothers o Contraindications and Cautions: Contraindicated in patients with Parkinson’s disease, cardiovascular disease, severe hypotension and bone marrow suppresion o Adverse Effects include Anti chlinergic effects like drying of the mouthe, constipation and urinary retention, Sedation effect, Orthostatic hypotension and extra pyramidal symptoms. Remember the mnemonics ASHE. These are the most common adverse effects of antipsychotic drugs which are manifesting more in typical antipsychotic than atypical antipsychotic drugs A – Anti cholinergic effect S – Sedation H – Hypotension E – Extra pyramidal Symptoms  Parkinson’s like syndrome, Dystonia, Akathisia, Tardive dyskinesia these adverse reactions happen because of dopmaine blocking effect in the basal ganglia altering its function of coordination and fine motor function. Other adverse effects may include respiratoy distress like laryngospasms, bronchospasms and dyspnea. Bone marrow suppresion and blood dyscrasia are seen in some patients Nursing Considerations o Do not allow patients to crush or chew the tablet as it decreases absorption of the drugs o Monitor for orthostatic hypotennsion o Consider warning the patient or the patient’s guardian on the risk of tardive dyskinesia o Monitor CBC to check signs of bone marrow suppression o Provide positioning of legs to decrease discomfort of dyskinesia o Provide sugarless candies for drying of the mouth o Encourage the patient to void before taking the dose if urinary retention is a problem o Provide safety measures such as side rails and assistance in ambulation if there are CNS effects o Provide vison examination to determine ocular changes o Conduct thorough health teaching on the effects and adverse effects of the drugs o Offer support and encouragement to help patients cope with their drug regimen Anti Manic Drug - LITHIUM Mechanism of Action – Lithium alters sodium transport in the nerve and muscle, inhibit the release of norepinephrine and dopamine slightly and decreases intraneuronal content of second messengers. The last action may modulate impulses to control hyperactive state in mania o Pharmacokinetics: Lithium is absorbed in the GIT. It slowly crosses the BBB. Dehydration and sodium depletion may cause the kidneys to reabsorb more Lithim thus increasing serum levels and toxicity. Lithium crosses the palcenta and breastmilk. o Contraindications and Cautions: Contraindicated to those with allergy to the drug, dehydration, hyponatremia and leukemia  o Adverse Effects: Toxicity associated with serum level of Lithium. ( Therapeutic level 0.6 – 1.2 mmol/L) o Serum level less than 1.5 mmol/L CNS problems including lethargy, slurred speech, muscle weakness, fine tremor; poluria, beginning gastric toxicity o Serum level 1.5 – 2 mmol/L Intensification of the above plus ECG changes o Serum levels of 2.0 – 2.5 mmol/LProgression of CNS symptoms to ataxia, hyperreflexia and seizure, hypotension o Serum levels more than 2.5 mmol/L complex multi organ toxicity and death Other drugs used for Mania o Aripiprazole – atypical antipsychotic drug o Lamotrigine – anti convulsive drug o Olanzapine – atypical antipsychotic drug o Quetiapine – atypical anti psychotic drug Nursing Considerations on administration of Lithium o Daily monitoring of lithium serum levels o Give the drug with food to alleviate GI irritation o Ensure that the patient have adequate intake of salt nd fluid o Monitor closely especially during the initial stage of therapy o Arrange for small and frequent meals with sugarless lozenges for drying of mouth o Provide safety measure like siderails and assistance with ambulation if CNS effects occur to prevent potential injury o Offer support and encouragement ot help patient cope with drug regimen 4. Anti – Seizure Drugs Seizure is a collection of different syndromes characterized by abnormal and excessive impulse transmission in the brain. Seizures may be primary or secondary. Primary seizure disorder has no known cause this is often called Epilepsy. Secondary Seizure may be caused by Cerebrovascular accident, Infections, Brain Tumor, Traumatic Brain Injury, Fever and a lot more conditions that may alter impulse transmission in the brain. Seizure and Convulsion are not synonymous. Convulsion is seizure manifesting motor symptoms like tonic clonic seizure. All convulsions are seizure but not all seizures are convulsions. Seizure is further classified into Generealized and Partial Seizure. Generalized seizure beigns in one area of the brain and rapidly spread to both hemispheres of the brain.  Examples of generalized seizure include Tonic – Clonic Seizure formerly known as Grand Mal Seizure. Partial seizures or focal seizures involve one area of the brain and do not spread throughout the entire organ. The presenting symptoms depend on exactly where the excessive electrical discharge is occurring in the brain. Samples include Partial Seizure and Complex Seizure. The problems of seizure is excessive impulse transmission in the brain, so the action of the drug is to decrease impulse transmission, anti seizure drugs cause CNS depression. Mechanisms of Action 1. Suppressing sodium influx or deporalarization in the neuron 2. Suppressing calcium influx, preventing electric current generated by calcium ions 3. Increasing the action of the Gamma Amino Butyric Acid ( GABA ) an inhibitory neurotransmitter in the brain Refer to the figure below: The figure shows how impulses are transmitted across the synapse. Action potential happen by sodium influx and potassium efflux, calcium channels open causing release of calcium that generate electrical activity and nurotransmitters both excitatory and inhibitory regulate impulse transmission. Excitatory neurotransmitters allow impulses to travel while inhibitory neurotransmitters stop impulses. The mechanisms of action of anti seizure drugs occur in the neuronal synapse. Drugs for Seizures are called Anti – seizure drugs or Anti – convulsive drugs (Anticonvulsant drugs) or Anti – Epileptic Drugs. Drug Classifications o Hydantoins – inhibit sodium influx or depolarization along the nerve fiber.  § Pharmacokinetics: Hydantoinsa are absorbed in the GIT.. It is higly protein bound up to 95%. A decrease in serum albumin or proteins increases free phenytois serum levels. Average half life is 24 hour. Hydantoins are metabolized to inactive metabolites and excreted in the liver. Hydantoins are less sedating than Barbiturates and Benzodiazepines. § Adverse Effects: Neurologic and psychiatric effect which include slurred speech, confusion, depression. Low platelet count and WBC may happen and gingival hyperplasia (overgrowth of gum tissue or reddened gums that easily bleeds). Hyperglycemia and less severe adverse effcts such as nausea, vomiting, constipation, drowsiness, headache and alopecia § Drug – Drug interactions: Hydantoins must not be taken with other anti seizure drugs because it may increase its CNS depressant effects. Increase effects of Hydantoins happen in combination with Aspirin, anticoagulants, Barbiturates, Rifampicin and chronic ingestion of ethanol. Decreased Hydantoins absorption occur when combined with Antacids, calcium preparations, sucralfate and some anti cancer drugs. § Examples: Phenytoin,Fosphenytoin, Ethotoin o Barbiturates - enhanced GABA effect. These drugs are highly sedating and they may cause severe CNS depression. ( Refer to Anxiolytic Drugs for detailed discussion ) § Indications: Anxiety, General Anesthesia and most commonly used for Generalized Tonic – Clonic Seizure o Benzodiazepines – enhanced GABA effect. (Refer to Anxiolytic Drugs for detailed discussion and examples) § Indications: For status epilepticus and benign febrile seizure. Diazepam is not used for long term treatment of seizure. Clonazepam is good for treatment of Petit Mal Seizure and Myoclonic Seizure o Succinimides – enhanced effect of GABA, an inhibitory neurotransmitter. Examples: Ethosuximide the drug of choice for Petit – Mal or Absence Seizure with relative few adverse effects than other anti seizure drugs. Methosuximide o Valproate or Valproic Acid – reduces electrical acivity by suppressing calclim influx and enhancing GABA effects the drug of choice for treating myoclonic seizure o Other anti- seizure drugs include Carbamazepine, Gabapentin, Lamotrigine, Levetiracetam. Topiramate. Some of these drugs used for partial seizure may also be used for treatment of neuropathic pain like Carbamazepine is used for treatment of Trigeminal Neuralgia. Nursing Considerations:  o Administer the drug with food to alleviate GI irritations o Monitor CBC to detect possible bone marriw suppresion o Evaluate therapeutic blood level to prevent toxicity o Provide safety measures o Provide thorough health teaching, including drug name, prescribed dosage and avoidance of adverse effects o Suggest that clients wear Medic Alert Bracelet to alert health care workers about the use of anti epiletpic drugs o Offer support and encouragement to help the partient cope with the drug regimen. 5. Anti – Parkinson’s Drugs Parkinson’s Disease is a degenrative disorder of the central nervous system. There is no known cause. This is common among elderly 60 years old and above. The disease is characterized by degeneration of the substantia nigra in the midbrain. A dopamine secreting neurons in the brain. Therefore there is tremendous decrease of dopamine in the brain especially affecting the basal ganglia. The basal ganglia is responsible for coordinating fine motor movement of the body. Alterations in the basal ganglia function results to lack of coordination, tremors, rigidity and bradykinesia. The neurons of the basal ganglia function normally when there is a balance between excitatory and inibitory neurotransmitters. Dopamine in the basal ganglia acts as the inhibitory neurotransmitter and Acetylcholine produced by higher neuron in the cerebral cortex act as excitatory neurotransmitter. In Parkinson’s disease an imbalance of neurotransmitters, decreased dopamine and increased acetylcholine results to clinical manifestions causing incoordination for unconscious muscle movements including those that control position, posture and movement Anti – Parkinson’s drugs should balance the effects of the neurotransmitters. To increase Dopamine effect and to decrease Acetylcholine effect should control symptoms of Parkinson’s Disease. These Drugs do not cure the disease but control the symptoms, hence the use is for palliative treatment. Mechanisms of Action 1. To increase dopamine effect 2. To supress acetylcholine effect Drug Classifications o Dopaminergic drugs – increase the effect of Dopamine at the receptor sites by increasing the levels of dopamine in the substantia nigra or directly stimulating the receptors § Pharmacokinetics: These drugs are absorbed in the GIT, metabolized in the liver and excreted in the urine. They cross the placenta and the breast milk § Contraidication and Caution: Contraindicated to clients with allergy to the drugs and glaucoma as the drug can exacerbate glaucoma. Caution should be used with any condition that could be exacerbated by dopamine receptor stimulation such as cardiovascular disease, bronchial asthma, peptic ulcer disease, urinary tract obstrution and psychiatric disorders. § Adverse Effects: CNS effects include anxiety, nervousness, headache, malaise, fatigue, confusion, mental changes, blurred vision, muscle twitching and ataxia. Peripheral effects include anorexia, nausea, vomiting, diarrhea, constipation, cardiac arrythmias, urinary retention and bone marrow suppresion § Drug – Drug interaction. Dopaminergic drugs combined with MAOI may increase hypertensive crisis. The combination of levodopa with Vitamin B6 and phenytoin and dopamine antagonists may lead to decrease effect of dopaminergic drugs. § Examples: Levodopa – a precursor of Dopamine. Once levodopa enters the BBB, it becomes dopamine and will replace the loss od dopamine. Dopamine itself cannot pass the BBB so a precursor called Levodopa is used. When this drug was develop, there was a dramatic reduction in the signs and symptoms of Parkinson’s disease, however it was found out later that levodopa can be destroyed by and enzyme called dopa decarboxylase before they cross the BBB resulting to decreasing the level of levodopa that may cross the BBB. This is the reason why another drug is combined with levodopa. This is Carbidopa. This drug cannot increase the level of dopamine in the brain but it inhibits the enzyme, dopa decarboxylase, therefore allowing more levodopa to pass the BBB. A combination of levodopa and carbidopa (Sinemet) is still the best drug for Parkinson’s disease. Amantadine is adrug that can increase the release of dopamine. This drug can be effective as long as there is a possibility of more dopamine release. Bromocriptine acts a direct dopamine agonists on dopamine receptor sites in the substantia nigra. o Anticholinergic drugs – oppose the effects of acetylcholine at receptor sites in the substantia nigra. These anticholinergic drugs have greater  affinity with the receptors of acetylcholine in the CNS than those in the periphery. However, they still block some receptors at the autonomic nervous sytem. Blocking the acetylcholine effect help to normalize the dopamine – acetylcholine imbalance in the basal ganglia. Pharmacokinetics: drugs absorbed in the GIT, metabolized in the liver and excreted by cellular pathways. They pass the placenta and the breast milk Contraindications and Cautions: Contraindicated in clients with Gastro intestinal or Genito urinary obstruction. Caution should be used in clients with cadiovascular conditions because of its blocking effect of parasympathetic nervous system Adverse Effects: Blocking CNS actylcholine may cause disorientation, confusion and memory loss. Peripheral anticholinergic effect include drying of the mouth, constipation, urinary retention and orthostatic hypotension. Drug – Drug interaction: These drugs should not be combined with other drugs with anti – cholinergic effects like anti – psychotic, anti – depressant drugs. Examples: Diphenhydramine ( Benadryl ), Benztropine ( Cogentin ), Biperiden ( Akineton ) Trihexyphenidyl ( Artane ) These drugs are famous by their brand names. Most often used for treatment of Parkinson’s like syndrome, an adverse effect of anti – psychotic drugs. Nursing Considerations o Provide sugarless lozenges to relieve drying of the mouth o Give the drugs with caution in hot weather or with exposure to hot environemtn because of increase risk for heat prostration o Give drugs with meals as they may cause GI irritation o Monitor bowel functions o Establish safety precautions o Ensure that the patient voids before taking the drugs if urinary retention is a problem o Provide thorough patient teaching about topics such as the drug name and prescribed dosage, measures help to avoid averse effects, warning signs that may indicate problems and need for pwriodic monitoring and evaluation to enhance patient knowledge about drug therapy and to promote compliance o Offer support and encouragement to help the patient cope up with the disease and drug regimen AUTONOMIC NERVOUS SYSTEM The division of the peripheral nervous system that supply involuntary muscles, glands and other effectors not innervated by the somatic nervous system. Autonomic nervous system is responsible for all involuntary actions of the body that the person is not aware of. This is divided into two divisions: PARASYMPATHETIC NERVOUS SYSTEM Parasympathetic nervous system (PNS) comes from the cranio – sacral outflow of the peripheral nervous system. Cranial nerve X, IX, VII, III participate in the cranial flow. Majority of the PNS comes from cranial nerve X ( Vagus nerve ). This is the only cranial nerves that extend up to the thorax and abdomen to supply majority of parasympathetic innervation, so a vagal stimulation is synanymous with parsympathetic innervation. Sacral nerves also participate in the PNS to supply mostly the effectors in the pelvic area like urinary bladder. The ganglia of the PNS are located near the organ of innervation. The neurons therefore of the PNS are pre – ganglionic neuron, the neuron from the Cranio – sacral outflow to the ganglia and the post – ganglionic neuron, the neuron from the ganglia to the organ of innervations. PNS is responsible for “REST AND DIGEST” involuntary responses of the body Impulses transmitted across the synapses of the ganglia are mediated also by the neurotransmitters. In the PNS, the neurotransmitter is Acetylcholine. Receptors for acetylcholine are located in the post synaptic neuronal membrane. These receptors are called cholinergic receptors. There are 2 tyoes of cholinergic receptors 1. Nicotinic Receptors 2. Muscarinic receptors SYMPATHETIC NERVOUS SYSTEM The division of the autonomic nervous system, Sympathetic nervous system (SNS) from the thoraco- lumbar outflow, spinal nerves from this region send nerve fibers to the sympathetic ganglia located near the CNS, then post ganglionic neurons send innervation to the involuntary muscles and glands and other effectors mostly assoicated with involuntary process in the body. The preganglionic neuron of the SNS is shorter than PNS and the post ganglionic neuron is longer than PNS. SNS is responsile for “FIGHT OR FLIGHT” involuntary responses of the body. Impulses transmitted across the synapses also are mediated by the  neurotransmitters. There are two neurotransmitters in the SNS. Actylcholine and Epinephrine and Norepinpehrine ( Catecholamines ) Actylcholine is released by the preganglionic neurons, while epinephrine and norepinephrine are the neurotransmitters released by the post ganglionic neurons, except for those post ganglionc neurons innervating adrenal medulla, pilo arector muscles, sweat glands and some smooth muscles of the blood vessels, they have sympathetic innervations but the neurotransmitter in at the postganglionic neurons is Acetylcholine Epinephrine and Norepinephrine may also be called Adrenalin and Noradrenaline respectively or they are being refered to as catecholamines. Their receptors are called Adrenergic Receptors. There are 2 types of adrenergic receptors 1. Alpha receptors 2. Beta receptors Drugs affecting the Autonomic Nervous System are called Autonomic Drugs Classifications of Autonomic Drugs Drugs affecting the PNS are called Cholinergic Drugs Drugs affecting the SNS are called Adrenergic Drugs In the study of pharmacodynamics, one action of the drugs is its binding with the receptors that may stimulate the receptors (drugs are called agonist) and drugs that may block the receptors (drugs are called antagonists). If a student is aware of the responses of the PNS and SNS, it would be easier to remember drug actions, they would either stimulate the receptors and produce the same effect or block the receptors or inhibit the effects. Most of the effectors are innervated by both sympathetic and parasympathetic and in such case the response of the body is opposite. See examples below: Effectors SNS PNS Heart Increase HR Decrease HR Lungs Bronchodilate Bronchoconstrict Blood vessels Vasoconstrict Vasodilate Therefore, if a drug stimulates the receptors for PNS, it is called cholinergic agonist, enhancing PNS effect so such drug is also referred to as parasympathomimetic drug. A drug that blocks the cholinergic receptors is called cholinergic antagonist, also called anticholinergic drugs, inhibiting PNS response and such drug may also be referred to as parasympatholytic drug If a drug stimulates receptors for SNS, it is called adrenergic agonist, increasing SNS effect so such drug is also referred to as sympathomimetic drugs. A drug that blocks the adrenergic receptors decreases SNS responses called adrenergic agonist or it is also called sympatholytic drugs. Remember, knowing the responses of the PNS and SNS is very important to understand actions of autonomic drugs, because these drugs would only stimulate or block the receptors. Cholinergic drugs – majority of these drugs affect the PNS. o Direct acting cholinergic agonist – directly stimulates the cholinergic receptors to increase its effects § Pharmacokinetics: well absorbed with relatively short half – life. Metabolism and excretion may occur at the synaptic level but exact mechanism is unknown § Contraindications and Cautions: These drugs enhance parasympathetic effect so must not be given to patients with hypotension, bradycardia or heart block, intestinal obstruction and urinary retention. § Adverse effects: These are related to increase parasympathetic responses such as bradycardia, diarrhea, urinary incontinence. Increase sweating may happen because of the acetylcholine present in the sweat glands. § Drug – Drug interaction: Effects of these drugs maybe increase if combined with anticholinesterase drugs or the indirect acting cholinergic agonists. § Examples 1. Bethanecol – indicated for non – obstructive urinary retention like in neurogenic bladder 2. Carbachol – indicated for glaucoma, causing pupillary constriction 3. Pilocarpine – indicated for glaucoma, causing pupillary constriction o Indirect acting cholinergic agonist – this drug increases acetylcholine effect by inhibiting the action of acetylcholinesterase (an enzyme that removes acetylcholine in the synapse. If acetylcholinesterase is not removed in the synaptic cleft, more acetylcholine stays in the synapse stimulating more  receptors, thus enhancing their effects. These drugs are used for treatment of Myasthenia gravis and Alzheimer’s disease Myasthenia gravis is an autoimmune disease of the neuromuscular junction (NMJ). This is characterized by destruction of cholinergic receptors at the NMJ that will slow down impulses going to the skeletal muscles. This disease is characterized by the development of muscle weakness and paralysis. To increase junctional transmission, indirect acting cholinergic agonist inhibits acetylcholinesterase making more acetylcholine present in the junction to improve impulse transmission and muscle function. These drugs are also called anticholinesterase drugs. Anticholinesterase drugs for Myasthenia gravis include: Edrophonium HCL (Tensilon) – short acting anticholinesterase drug used to diagnose the disease. The action lasts for 10 to 20 minutes. Neostigmine, Physostigmine, Pyridostigmine – long acting anticholinesterase drugs used for therapeutic purposes. The onset of action starts 20 to 30 minutes and may last for 3 – 6 hours. Alzheimer’s Disease is a degenerative disease of the CNS characterized by loss of neurons in the CNS which may slow down impulse transmission across the synapses of the CNS. One important cause of this is explained by loss of acetylcholine receptors in the post synaptic neurons, like myasthenia gravis, less receptors mean lesser impulse transmission. So anticholinesterase drugs that inhibit acetylcholinesterase enzyme will increase acetylcholine effect and promote impulse transmission in the CNS. Can drugs for myasthenia gravis be used to patients with Alzheimer’s disease? The answer is no simply because those drugs cannot pass the BBB. Therefore, Alzheimer’s disease will have its own anticholinesterase drugs. Acetylcholinesterase drugs used for Alzheimer’s disease are called Anti Alzheimer’s drugs which include Rivastigmine Donepezil Tacrine  Pharmacokinetics: These drugs are well absorbed and distributed in the body. Drugs for myasthenia do not pass the BBB. The drugs are metabolized in the liver and excreted in the urine. Contraindications and Cautions: The drugs are not given to those with known allergy to the drugs. The drugs may exacerbate bradycardia, diarrhea and urinary incontinence Adverse effects: Exacerbation of parasympathetic effects may be seen in the patient such as bradycardia, hypotension and incontinence Nursing Considerations o Properly administer eye medication o Slow IV administration to avoid severe cholinergic effects o Cholinergic agonist oral preparation must be taken with an empty stomach to decrease nausea and vomiting o Closely monitor vital signs and exacerbation of parasympathetic effects o Provide safety measures o Monitor patients with Alzeimer’s disease for progression of the disease. Drugs will not cure the disease o Monitor patients with Myasthenia gravis for underside or overdose of medication o Provide health teaching on the name of drugs, its action and adverse effects to promote client’s understanding and compliance o Provide emotional support and encouragement to help the patient cope with drug regimen o Cholinergic antagonist also being referred to as anticholinergic drug or parasympatholytic. The drugs act to block the cholinergic receptors in the PNS. The drugs may also block some cholinergic receptors present in the SNS. § Pharmacokinetics: The drugs are well absorbed and distributed. Drugs pass the BBB, placenta and breastmilk. The drugs are excreted in the urine. § Contraindications and Cautions: The drugs are not given to patients with known allergy to the drugs. Should not be used in clients with cardiovascular, gastrointestinal or genitourinary conditions because they may exacerbate anticholinergic effect add worsen the conditions. Contraindicated in client with glaucoma as the drug may cause pupillary dilation and further increase intraocular pressure. Caution is used to patients with hepatic or urinary impairment. § Adverse effects: These are associated with anticholinergic effects of drugs such as drying o the mouth, constipation, urinary retention,  tachycardia, mydriasis. Drowsiness, confusion and insomnia are all related to the CNS effects of anticholinergic drugs § Examples: Atropine – indicated to decrease secretions, treat bradycardia, pylorospams, ureteral colic, cause pupil dilation (mydriasis) indicated as preop drug for cataract extraction. Use as antidote for cholinergic crisis Dicyclomine – use for hyperactive bowel in adults Scopolamine – use in motion sickness, indicated to decrease secretion, pupil dilation Adrenergic drugs these drugs act to either stimulate or block the adrenergic receptors in the SNS o Adrenergic agonist – stimulate the receptors to increase sympathetic effect and is also referred to as sympathomimetic drugs o Adrenergic antagonist – block the receptors to decrease sympathetic effect and is also referred to as sympatholytic drugs Adrenergic receptors have 2 types and subtypes. Classification is based on their actual locations in the body. Below are some adrenergic receptor sites and their specific locations in the body Types of the Adrenergic Receptors 1. Alpha receptors a. Alpha 1 receptors b. Alpha 2 receptors 2. Beta receptor a. Beta 1 receptors b. Beta 2 receptors Study the table below for some important locations of the receptors RECEPTORS LOCATION Alpha 1 receptors Vascular smooth muscles, iris, visceral smooth muscles like the urinary bladder and iris Alpha 2 receptors CNS neurons, pancreatic islets Beta 1 receptors Myocardium, Kidneys, CNS neurons Beta 2 receptors Visceral smooth muscles like in the lungs, some vascular smooth muscles, CNS neurons For the sake of the discussion and the given examples of drugs, the effects of some of drugs in particular receptors will be discussed first. Alpha 1 receptors when stimulated will cause vasoconstriction, pupillary dilation and closure of urinary bladder sphincter causing urinary retention. When the receptors are block? What would be the expected effects? Alpha 2 receptors in the CNS neurons when stimulated will decrease norepinephrine flow from the CNS to the SNS therefore decreasing sympathetic response. Take note that this is the drug that stimulate adrenergic receptors but decreasing SNS effect because the receptors being stimulated are located in the CNS. Beta 1 receptors in the heart when stimulated will increase heart rate. When we use a drug that blocks the receptor, what is the effect? Beta 2 are located in the lungs, if we use a drug that stimulates receptors, the effect is bronchodilation, what is the effect if we block the receptor? Classifications of Adrenergic Agonist Drugs 1. Alpha and Beta adrenergic drugs ( Sympathomimetic drugs ) – these drugs stimulate all adrenergic receptors to enhance their effects. Pharmacokinetics: these drugs are rapidly absorbed, metabolized in the liver and excreted in the urine. These drugs may cross the placenta and breastmilk Contraindications and Cautions: Should not be given in client with allergy to these drugs and to patients with pheochromocytoma as the drugs may exacerbate the signs and symptoms Adverse effects: These are all related to increase SNS response like tachycardia, hypertension, constipation, urinary retention, pupillary dilation Examples o Epinephrine – the drug of choice during CPR, indicated for treatment of shock o Dobutamine – used for treatment of congestive heart failure o Dopamine – usually given for congestive heart failure and cardiogenic shock o Norepinephrine – like epinephrine, may be indicated for cardiac arrest 2. Alpha specific adrenergic agonist – these drugs specifically stimulate only the alpha receptors and not the beta receptors Pharmacokinetics: these drugs are well absorbed and distributed, reach peak levels in 20 to 45 minutes. These drugs are metabolized in the liver and excreted in the urine  Contraindications and Cautions: these drugs are not indicated to clients with allergy to the drugs, those with hypertension and close angle glaucoma. Caution is used in clients with cardiovascular disease. Adverse effects: these are related to the overdose of drugs that may increase sympathetic effects like hypertension, gastrointestinal depression and genitourinary effects like urinary retention Examples o Alpha 1 adrenergic agonist – Phenylephrine used for treatment of common colds and allergy. This drug causes vasoconstriction to lessen congestion in the nose therefore called decongestants. o Alpha 2 adrenergic agonist – Clonidine better known for its brand name as Catapres acting on the CNS neurons to decrease norepinephrine flow. This drug is indicated for treatment of hypertension. 3. Beta specific adrenergic agonist – these drugs specifically stimulate the beta receptors and not the alpha receptors. Pharmacokinetics: well absorbed and distributed in the body, metabolized in the liver and excreted in the urine. The drugs pass the placenta and breastmilk, use in pregnancy and lactation only if benefits outweigh the risks Contraindications and Cautions: The drugs are contraindicated in clients with allergy to the drugs. Caution is used in clients with cardiovascular disease like hypertension and tachycardia. Adverse effects: These are related to the primary effects of drugs which will increase sympathetic effects like hypertension and tachycardia. Examples o Isoproterenol – for treatment of cardiogenic shock and heartblock in transplanted heart. o Salbutamol – for treatment of obstructive respiratory disease like COPD and bronchial asthma Nursing Considerations o Avoid sudden withdrawal of the drug because it may cause rebound hypertension, arrhythmias and flushing o Monitor vital signs especially blood pressure and heart rate o Avoid comfort measures including rest and environmental control to decrease CNS irritation. o Provide adequate health teaching on the name of drug, prescribed dosage, effects and adverse effects to increase patient’s knowledge and subsequent compliance. Classifications of Adrenergic Antagonist Drugs (Sympatholytic drugs) 1. Alpha and Beta adrenergic antagonist – these drugs block all adrenergic receptors  Pharmacokinetics: these drugs are well absorbed and distributed in the body, metabolized in the liver and excreted in the urine and the feces. Contraindications and Cautions: These drugs should not be given to clients with allergy to the drugs. To those with hypotension and bradycardia. Caution is used in clients with cardiovascular disease and obstructive lung disorders Adverse effects: these mainly on the effects of the drugs in the lungs like bronchospasm, blood vessels causing vasodilation and hypotension. Examples o Carvedilol o Labetalol § Both examples maybe indicated to clients with severe hypertension caused by pheochromocytoma 2. Alpha adrenergic antagonist – these drugs block only the alpha receptors, specific drugs act on the alpha 1 and alpha 2 receptors. Pharmacokinetics: these drugs are well absorbed and distributed, metabolized in the liver and excreted in the urine. Contraindications and Cautions: The drugs should not be given to clients with hypotension and urinary incontinence Adverse effects: related to the primary action of the drug causing vasodilation and hypotension Examples o Phentolamine – more specific drug hypertension in pheochromocytoma, that will have less adverse effects. 3. Alpha 1 selective adrenergic antagonist – these drugs block only the alpha receptors, specific drugs act on the alpha receptors on the blood vessels and urinary bladder to case vasodilation for treatment of hypertension and bladder emptying for treatment of urinary retention. Although some drugs may act in both blood vessels and urinary bladder at the same time Pharmacokinetics: drugs are absorbed in the GIT, metabolized in the liver and excreted in the urine. Contraindications and Cautions: Contraindicated in clients with allergy to the drugs. This may exacerbate hypotension and urinary incontinence. Caution is used to clients with cardiovascular disease, gastrointestinal and genitourinary conditions Adverse effects: related to the sympatholytic effect of drugs causing hypotension and urinary incontinence. Examples o Prazosin – indicated for treatment of hypertension o Terazosin – indicated for treatment of hypertension and BPH causing urinary retention o Doxazosin – indicated for treatment of hypertension and BPH causing urinary retention  o Alfuzosin indicated for treatment of BPH o Tamsulosin – indicated for treatment of BPH 4. Beta adrenergic antagonists – these drugs block both beta 1 and beta 2 receptors, particularly affecting both the heart and the lungs, these drugs increase heart rate and bronchoconstriction of the lungs 5. Beta 1 specific adrenergic antagonist these drugs block specifically beta 1 receptors in the heart. These drugs are most commonly known as beta blockers. These drugs are indicated to clients with hypertension, dysrhythmias, angina and use to support cardiac function in clients with congestive heart failure Pharmacokinetics: these drugs are absorbed in the gastrointestinal tract and undergo hepatic metabolism. The presence of food may increase the bioavailability of some beta blockers. These drugs are known teratogenic in animals as it passes the placenta and breast milk Contraindications and Cautions: Contraindicated in clients with allergy to the drugs. Caution should be used in clients with bradycardia and heart block as well on patients with obstructive lung diseases like COPD and bronchial asthma Adverse effects: these are related to the bradycardia and bronchoconstriction effect of the drug. Gastrointestinal effects like nausea and vomiting, genitourinary symptoms may be disturbing to clients as well. Examples Beta adrenergic antagonists or Beta blockers o Propranolol o Pindolol Beta 1 specific adrenergic antagonists or Beta 1 blockers o Metoprolol o Atenolol Nursing considerations o Avoid sudden withdrawal of the drug because it may cause rebound hypertension, arrhythmias and flushing o Monitor vital signs especially blood pressure and heart rate o Monitor ECG o Avoid comfort measures including rest and environmental control to decrease CNS irritation. o Provide adequate health teaching on the name of drug, prescribed dosage, effects and adverse effects to increase patient’s knowledge and subsequent compliance. Karch, A. M. (2019). Focus on nursing pharmacology. Lippincott Williams & Wilkins. Kee, Joyce Le Fuer and Hayer, Evelyn R., Pharmacology: A Nursing Process Approach, 5th Edition, 2006, by Elsevier (Singapore) PTE LTD Lilley, Linda lane & Harrington, Scott, Pharmacology and the Nursing Process, 5th Edition, by Elsevier (Singapore) PTE LTD Rizzo, D. C. (2016) Fundamentals of Anatomy and Physiology 4th edition. Cengage (A picture depicting a synapse showing neurotransmitters from the presynaptic neurons and receptors at the post synaptic neuron) Retrieved from https://www.ck12.org/biology/nerve-impulse/lesson/Nerve- Cells-and-Nerve-Impulses-MS-LS/ Onyekwelu, Kenechukwu (2019) Neuron-neuron interaction-transmission of impulse across the synapse. (Ethanol) Retrieved from https://www.researchgate.net/figure/Neuron-neuron-interaction- transmission-of-impulse-across-the-synapse_fig2_330564807 Lilley, Linda lane & Harrington, Scott, Pharmacology and the Nursing Process, 5th Edition, by Elsevier (Singapore) PTE LTD Rizzo, D. C. (2016) Fundamentals of Anatomy and Physiology 4th edition. Cengage Make a drug study on the individual drugs discussed in this course unit. Write them in an ½ index card and compile them. Search new 2 drugs for each classification of CNS and ANS drugs not discussed in this course unit and include them in the drug study. Drug study: DRUG DOSAGE THERAPEUTIC ADVERSE CONTRAINDICATION NURSING ACTION EFFECTS CONSIDERATIONS