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ANÈ GUTTER
Ane Gutter #Blog 14
19 Jun 2021, 10:33
FKLG 312:
#Blog 14:
Answer the following for a Blog Summary:
- Which different groups of hallucinogenic drugs are known?
- Name a few typical effects of the hallucinogenic drugs and discuss the clinical profile of a patient who had taken them.
- How is an over-dose of LSD dealt with?
- How is an over-dose of anticholinergic drugs dealt with?
Hallucinogens:
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Substances: |
Effects: |
Notes: |
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Phencyclidine “Angel dust”, PCP
Psychosis very common, lack of judgment leads to reckless behaviour.
Other hallucinogens: • LSD, mescaline (in peyote cactus), *psilocybin (*active ingredient of “shrooms”) |
Overdose: nystagmus (involuntary movement of eyes, slowly in one direction, fast in another), severe hypertension, convulsions, may be fatal.
5-HT2A agonists: sensory distortion, especially visual. Psychedelic, “mind revealing” effects.
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Ane Gutter #Blog 13
19 Jun 2021, 10:30
FKLG 312:
#Blog 13:
Answer the following for a Blog Summary:
Select one of the following assignments for elucidation in a 15 minute address to a certain target group:
- You (as a pharmacist) are invited by the local high school to address all the teachers and learners on the topic “Alcohol, what really is its effect on my body”. Focus on the effects, “pleasant” as well as “unpleasant”, how many glasses are safe? How do I know when I am starting to develop a problem? What should I then do? Throughout, keep the age of your target group (learners) in mind!
Alcohol, what does this really do to my body?
Alcohol reduces anxiety and has calming properties and therefore alcohol is often abused from a young age. According to SA's law, a person may not take in and manage more than 0,05g/dL of alcohol, which means that if you take in 2 drinks within 1 hour you are already on/over the limit. It takes the body about 1 hour (60 minutes) to metabolise 1 unit of alcohol.
By using alcohol it makes you less concerned with what is going on around you because you are relaxing. It is for this reason that many young people get into trouble, where their drinks are "spiked" and then they can't remember anything about what happened. Alcohol withdrawal syndrome is a huge risk if you are someone/ someone knows that uses a lot of alcohol. Alcohol withdrawal syndrome's seriously hyped degree depends on the duration and degree of alcohol use/misuse.
Symptoms can be experienced as quickly as 6 – 8 hours after stopping alcohol and getting better after 1-2 days. There are also out of cases where the withdrawal symptoms can lead to death and where it should be treated as soon as possible.
Alcohol use also causes central nervous system suppression and therefore acute overdoses can be as dangerous because respiratory and cardiovascular suppression results in and may lead to death.
Side effects associated with chronic alcohol use include, amongst others, the following:
- Develop toleration and dependence.
- Liver – absorption and lead to nutritional needs and increased risk for pancreatitis.
- Gastrointestinal effects – irritation, inflammation, bleeding and stomach wall damage.
- Endocrine and electrolyte imbalances – gynecomastia, testicides atrophy, endeem, and hypoglycaemia.
- Cardiovascular – hypertension, anaemia, heart attack.
- Immune system – reduced immunity leading to lung intuition and increase in appearance of skins other diseases and infections.
- It can also lead to cancer.
Tolerance = An increase of the original dose is required to bring about the same effects and usually occurs as a result of chronic drug use.
Dependency = Withdrawal syndrome occurs because there is persistent use of a certain drug and therefore body adapts to the persistent exposure.
Ane Gutter #Blog 13
29 May 2021, 12:49
Blog #13
Ané Gutter
31627706
Prepare a short “lecture” of not longer than 5 minutes (200 words), explaining to a patient what pain is, its possible causes, why different people experience pain differently and what the generally important principles of pain management and referral involve. The videos above will also be of value to complete this assignment.
- Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage = subjective experience
- Perception of pain is influenced by the patient's mood, morale and the meaning the pain has for the patient.
ACUTE VS CHRONIC PAIN:
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Acute: |
Chronic: |
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ACUTE – Fast pain
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CHRONIC – Slow pain
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Nerve pain is caused by pressure on nerves or the spinal cord, or by damage to nerves. It is also called neuropathic pain. People often describe nerve pain as burning, shooting, tingling, or as a feeling of something crawling under their skin. It can also occur after other cancer treatments such as radiotherapy or chemotherapy.
Bone pain : The cancer cells within the bone damage the bone tissue and cause the pain. People often describe this type of pain as aching, dull or throbbing.
Soft tissue pain from a body organ or muscle. For example, you may have pain in your back caused by tissue damage to the kidney. You can't always pinpoint this pain, but it is usually described as sharp, cramping, aching, or throbbing.
Phantom pain in a part of the body that has been removed. For example, pain in an arm or leg that has been removed due to sarcoma or osteosarcoma. Or pain in the breast area after removal of the breast (mastectomy). Phantom pain is very real and people sometimes describe it as unbearable.
Referred pain from an organ in the body may be felt in a different part of the body. This is called referred pain. For example, a swollen liver may cause pain in the right shoulder, even though the liver is under the ribs on the right side of the body. This is because the liver presses on nerves that end in the shoulder.
CANCER PAIN MANAGEMENT:
- Regular medication
- paracetamol or ibuprofen (anti-inflammatory)
- opioid drugs, chosen to suit each person and to minimise side effects.
- Combining medications
Radiotherapy, surgery, hormone therapy and chemotherapy – if successful in reducing tumour size – may also relieve pain.
Other techniques that may be helpful include relaxation therapies and acupuncture.
TREATMENT CHOICES:
- The location of the pain
- The severity of the pain
- The type of pain – such as sharp, tingling or aching.
- Whether the pain is persistent or comes and goes.
- What activities or events make the pain worse?
- What activities or events make the pain better?
- Current medications
- How much current medications ease the pain?
- The impact the pain has on lifestyle, such as poor quality of sleep or loss of appetite.
Mild to moderate pain:
- Non-opioid analgesic
- Aspirin, paracetamol or Ibuprofen.
- With or without adjuvant
persistent or worsening of pain:
Moderate pain:
- Weak opioid analgesic
- Codeine, dextropropoxyphene, tramadol or buprenorphine
- With or without a non-opioid
- Aspirin, paracetamol or Ibuprofen.
- With or without adjuvant
Severe pain:
- Strong opioid analgesic:
- Morphine, hydromorphone, oxycodone or trapentadol.
- With or without a non-opioid
- Aspirin, paracetamol or Ibuprofen.
- With or without adjuvant
Ané Gutter #Blog 12
14 May 2021, 18:48
FKLG 312:
Blog #12
Answer the following for a Blog Summary:
- Using your textbooks, draw up a classification of the drugs that are used as antidepressants.
- What do the existing drugs all have in common regarding their mechanisms of action?
- How long does it take for the antidepressive effects of these drugs to appear? What is the reason for this?
- How do the TADs and the selective serotonin reuptake inhibitors (SSRI’s) differ in respect of:
- efficacy
- side effects
- safety?
- What is the action of mirtazapine?
- What is the action of venlafaxine?
- What is the action of agomelatine?
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Tertiary amines: |
Secondary amines: |
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Re-uptake inhibitors that show preference for 5-HT re-uptake above NA re-uptake.
ANTI-CHOLINERGIC and ALIPHATIC (α1) EFFECTS (Includes involved receptor related side effects also)
I.e. NE such as: Impotence, blurred vision, midriasis, palpitations, tachycard, constipation, dry mouth, weight gain.
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Re-uptake inhibitors that show preference for NA re-uptake above 5-HT re-uptake.
ANTI-CHOLINERGIC and ALIFATIC (α1) EFFECTS (Includes involved receptor related side effects too) (Much more potent than the tertiary amines).NE = worse such as: Impotence, blurred vision, mydriasis, palpitations, tachycardia, constipation, dry mouth, weight gain.
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TAD structure-activity relationship:
- Higher affinity for re-uptake transport receptor than for specific R’s
- Uptake inhibitors
- (Tertiary: 5-HT selective)
- (Secondary: NA selective)
- Anti-cholinergic (Tertiary more potent)
- Alphalytic (Tertiary more potent)
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Quinidine-like (blocks heart conduction arrhythmia)These drugs are alternatives at:
Patients with psychomotor delay, Sleep Disorders, Poor appetite, Weight loss
OTHER INDICATIONS: TAD'S:
Enuresis (Children under the age of 6 years water their bed during REM sleep period. First try TAD (ESPECIALLY IMIPRAMINE) before considering surgery).Chronic pain: (RA, trigeminal neuralgia, cancer, migraine prophylaxis) amitriptyline in low doses Bipolar disorders (caution, can mania ppt) Acute Panic -IMIPRAMINE, Phobias- Imipramine.
Phobias – ESPECIALLY IMIPRAMINE
Chloramine: OCD
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TAD-Overdose: Very dangerous 10x daily dose can be fatal. Agitation, delirium, neuromuscular irritability, convulsions, coma, respiratory suppression, circulatory patches, hyperpyrexia, dysrhythmias Coma, Convulsions, Cardiotoxic
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Toxicity:
- Sedation (Due to H1 receptor blockade)
- Sympathomimetic: tremor, insomnia (Reduce the NA re-recording)
- Anticholinergic: vision disorders, dry mouth, constipation, urinary retention, confusion (M-blocking)
- CVS: orthostatic hypotension, dysrhythmias
- Psychoses, precipitating mania
- Convulsions
The tertiary amines:
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Substance: |
Indication: |
MOA: |
Notes: |
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Amitriptyline Imipramine Trimipramine Chlorimipramine (Clomipramine) Dothiepine Butriptyline |
Treatment of depression (major)
Amitriptyline: Chronic pain
Clomipramine especially also in OCD (Obsessive compulsive disorder).
FIRST CHOICES AT: - Phobias - Anxiety - Panic = SSRI'S THEN: Tertiary amines (NOT second amines).
Especially imipramine: Enuresis, acute panic, phobias.
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Reuptake inhibitors some preferred for 5-HT reuptake inhibition above NA reuptake inhibition.
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ANTI-CHOLINERGIC and ALIPHATIC (α1) EFFECTS (NE too) - (Much more potent than the secondary amines). |
The secondary amines:
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Substance: |
Indication: |
MOA: |
Note’s: |
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Nortriptyline Desimipramine (Metabolite of Imipramine). Amoxapine Maprotiline Lofepramine |
Treatment of depression (major)
Nortriptyline and BMI: Can be used in healthy elderly people). |
Reuptake inhibitors some preferred NA reuptake inhibition above 5-HT reuptake inhibition. |
ANTI-CHOLINERGIC and ALIPHATIC (α1) EFFECTS (NE too).
Maprotiline Toxicities: Like TAD's, dosage-related convulsions. (Caution in patients with epilepsy ) |
2. Monoamine oxidase inhibitors (MAOI’s):
Developed for the treatment of tuberculosis (iproniazide derivatives) - 1951.
• Inhibits break-down monoamines (NA, DA, 5-HT)
• MAO: Iso-enzymes
- MAO A (GIT)
- MAO B (striatum)
• Reversible (long duration of blockade, no covalent bonds), nonselective: Tranylcypromine (Parnate®)
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NB, Revise process in SU1! |
• Reversible, MAO A-selective: Moclobemide (Aurorix®)
Diet limitations:
Limitations:
- Cheese
- Yogurt
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Wine, beerToxicities:
Sleep disturbances, Postural hypotension
- Herring, sardines, caviar
- Yeast- and meat extracts (Marmite, Bovril)
- Liver, processed meat
- Ripe avocados
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Substance: |
Clinical indication: |
MOA: |
Notes: |
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Tranylcypromine |
Treatment of depression (ELECTIVE IN ATYPICAL DEPRESSION) - When the person's state of mind is low but there is not necessarily a lack of motivation.
Severe anxiety Phobias Hypochondriasis Panic |
Irreversible non-selective inhibitor of MAO-A+B with the result that fewer mono-amines (5-HT, DA and NA) are broken down and the concentrations increase. |
CAUSE CHEESE REACTION - Give the person recommendations on diet.
Effects still last for several weeks after withdrawal.
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Moclobemide: |
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Reversible inhibitor of MAO-A with the result that fewer mono-amines (NA, DA and 5-HT) are broken down and that lg. concentrations increase. |
Diet recommendations are therefore not necessary here unless the person is already experiencing blood pressure problems. |
3. Selective 5HT reuptake inhibitors (SSRI):
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Fluoxetine (Prozac®), Paroxetine (Aropax®), Fluvoxamine (Luvox®), Sertraline (Zoloft®), Citalopram (Cipramil®), Escitalopram (Cipralex®)
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TAD requires titration to minimum effective dosage while the SSRI's can usually begin immediately with full dosage. ALTHOUGH IT CAN PRESENT ANXIETY.
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Substance: |
Clinical indication: |
MOA: |
Notes: |
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Depression treatment (1st choice in the elderly)
FIRST CHOICES AT: - Phobias - Anxiety - Panic THEN: Tertiary amines (NOT second amines).
OCD (40mg/day plus)
Bulimia (80mg/day plus)
PMS
Resistant schizophrenia
Alcoholism (Not going to help an alcoholic, but will for a depressed person who drinks)
Bipolar disorder
Fluoxetine is the only AD approved in children. |
These drugs selectively block the serotonin re-uptake at the pre-synaptic neuron. |
Paroxetine has the most anti-cholinergic effects – exceptional because the other drugs have practically no anti-cholinergic effects, the drug also has a very short t1/2 and must be administered more than once p.d. – exceptional because the other drugs are only administered once a day. Especially severe withdrawal symptoms
The drugs are less cardiotoxic than the TAD's.
Possible association between fluoxetine and premature birth and delayed fetal growth rate.
The drugs have a better NE profile than many other drugs and are safer in acute overdosage. Can reduce appetite and result in weight loss.
Fluoxetine has a 5-week wash-out period |
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Toxicities: Insomnia, tremor, GIT disorders, headaches, ↓ libido, sexual dysfunction, anxiety (acute), EPS (Needles and pins/crayon/restless legs), withdrawal syndrome. The drugs can lower appetite and overweight patients can thereby lose weight. Remedies aren't sedating. HOW ACUTE ANXIETY AS TOXICITY AS SSRI'S IS USUALLY USED FOR IT. Initially, there is a sudden increase in the 5-HT levels in the brain that exacerbate anxiety, however, it later becomes better again.
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4. Serotonin and noradrenalin reuptake inhibitors (SNRI):
Blocks both 5-HT and NA re-uptake, more potent for 5-HT than for NA
- Venlafaxine (Efexor®)
- Duloxetine (Cymbalta®)
Also used in pain: neuralgia and fibromyalgia, GAD, vasomotor symptoms of menopause.
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Substance: |
Clinical indication: |
MOA: |
Notes: |
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Depression treatment
Severe anxiety and phobias
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Block both 5-HT and NA re-uptake, more potent for 5-HT than for NA. |
Venlafaxine toxicity: Nausea, sedation, dizziness, sweat, sexual disturbances, hypertension, anxiety.
Venlafaxine has less anti-cholinergic and cardiotoxic SE. |
5. Selective noradrenalin reuptake inhibitors (NARI):
Blocks re-uptake of NA
- Reboxetine (Edronax®)
- not cardiotoxic, no anti-cholinergic effects.
- no affinity for any NT R’s
- Used for Depression.
6. Tetracyclic and Unicyclic AD’s
- Mianserin (Ludiomil®)
- Mirtazepine (Remeron®)
- NaSSA (NA & specific serotonin AD)
- Blocks α2, 5-HT2A, 5-HT3
- Mirtazepine more potent than mianserin
- Also Blocks H1 (sedation, weight gain)
- Also Blocks α1 (postural hypotension)
- Mianserin: haematological reactions, (agranulocytosis), limited use
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Substance: |
Clinical indication: |
MOA: |
Notes: |
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Mianserin
Mirtazepine
Bupropione
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Treatment of depression.
Bupropion in lower doses: Nicotine withdrawal
Bupropion: Obesity
Bipolar disorder
Mirtazepine: Induce sedation
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Block α2, 5-HT2A and 5-HT3. Also block H1 and α1.
A naSSA – Noradrenaline and specific serotonin anti-depressant. Block α2 (Blockade of this inhibitory receptor promotes both NA (auto receptor) and 5-HT release (heteroreceptors)), 5-HT2A and 5-HT3. Also block H1 and α1. Also, indirect stimulation of 5-HT1A. Blockade of the inhibitory α2 receptors advance both NA (autoreceptors) & 5-HT release (heteroreceptors) •Indirect stimulation of 5-HT1A: anxiolytic •Blockade 5-HT3: anxiolytic, ↓ nausea •Blockade 5-HT2: anti-depressive effects
Block DA, as well as NA re-uptake. |
H1 blockade can cause sedation and mass gain. α1 blockade can cause postural hypotension. Causes blood disorders (agranulocytosis) – limited use.
Stimulation of 5-HT1A = anxiety myolities Blockade of 5-HT3 = anxiety insulating and lowers nausea. Blockade of 5-HT2A = Antidepressive Toxicities: Sedation, increased appetite and mass gain.
Alerting. May induce convulsions in certain patients. (Caution in epilepsy sufferers). •Lower dosages nicotine withdrawal (Zyban®
Fewer anti-cholinergic and cardiac effects.
Toxicities: Dizziness, dry mouth, sweating, tremor, psychoses, convulsions (high doses). |
5-HT receptor modulators:
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Substance: |
Clinical indication: |
MOA: |
Notes: |
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Trazodone (Molipaxin) |
• Effective initial and maintenance treatment for MDD (20 mg/d) • Well tolerated in older people • May have cognitive benefits, especially in older people • Considered as an alternative to other AD’s on market. |
5-HT2 antagonist • Weak 5-HT re-uptake inhibitor, weak α2 blocker • Trazodone also blocks H1 (severe sedation) & α1: (priapism) |
Currently: unlabeled hypnotic, highly sedating, not associated with tolerance or dependence |
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Vortioxetine (Brintellix ) |
Treatment of depression
Trazodone: Currently often used as hypnotic, due to severe sedative effects. (Not associated with tolerance/dependency).
Vortioxetine: Major depressive syndrome: effective + maintenance treatment. For beneficial cognitive effects (especially the elderly). Also helps for insomnia (a multimodal AD). Alternative to other ADs.
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• Block several 5-HT receptors (3, 7, 1D), agonist on 5-HT1A, partial agonist on 5-HT1B • Weak SERT inhibitor • MDD, Procognitive effects?? |
• Animal studies: Increase in extracellular levels: • NA, DA, Glutamate, ACh, Histamine in brain areas associated with depression, including the prefrontal cortex and hippocampus. • Additional in vivo testing is necessary to determine whether this multimodal action produces an additional clinical benefit
SE:
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SE: Most common: ü Nausea ü Headache ü Dry mouth ü Dizziness Also: • Sexual dysfunction • Weight gain • Hypertensive crisis • Increased risk of suicide • Pancreatitis Contra-indications/ Caution: § Other serotonergic drugs § Caution: NSAID’s, warfarin and anticoagulants § Bipolar disorder § Hyponatremia, elderly patients, and patients on diuretics at higher risk
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8. Circadian rhythm regulators: Agomelatine:
Synergism between melatonergic and 5-HT2c receptors:
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- 5-HT2c, MT1/MT2 receptors: High density in SCN Regulation of circadian rhythms
- MT1/MT2 agonism benefits sleep, but is not antidepressant.
- 5-HT2c agonism worsens sleep disturbances 5-HT2c antagonism improves sleep
- 5-HT2c antagonism benefits antidepressant action
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Substance: |
Clinical indication: |
MOA: |
Notes: |
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Agomelatine |
Major depression |
Restores the body's biorhythms. Primary agonist on melatonin 1+2 receptors and a m antagonist on 5-HT2C receptors.
MT1 and MT2 agonist and 5-HT2c antagonist • 5-HT2c-antagonism: disinhibition of DA and NA release in FC (Increase DA and NA release)
(Melatonin is a by-product of 5-HT. Responsible for directing biological beating (fatigue/body temperature etc.), melatonin therefore restores these rhythms because during depression these circadian rhythms are disturbed. Thus, depression affects melatonin secretion. |
S/E: Headache, dizziness, GIT discomfort, fatigue, liver enzyme increases
• CI: Hepatic impairment
• Valdoxane |
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THERE IS SINNERGISM BETWEEN MELATONIN RECEPTORS AND 5—HT RECEPTORS:
Higher density in SCN Regulation of circadian rhythms
For example, in the meantime, you cannot give someone only melatonin to totally alleviate depression, the insomnia that occurs in depression can be alleviated by a melatonin agonist.
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The non-specific receptors give rise to SEROTONIN SYNDROME: Life threatening response Severe muscle rigidity Myoclonus Hyperthermia CVS instability SSS stimulation (restlessness, convulsions) Treated: Anticonvulsants, muscle relaxants, cyproheptadine (5-HT2 antagonist)
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Pharmacokinetic principles of antidepressants:
- Liver metabolism
- Most AD’s long t½, 1/d dosage
- Exceptions: venlafaxine, Trazodone: 2 – 3x/d
- Active metabolites, some TAD’s, fluoxetine, venlafaxine, and other. •
- Norfluoxetine: t½ 7 – 9 days
- SSRI’s: inhibits certain cytP450 enzymes ⇒ Drug interactions
TAD’s side effects:
- Sedation
- Sympathomimetic: tremors, insomnia
- Anticholinergic: disturbed vision, dry mouth constipation, urinary retention, confusion • CVS: orthostatic hypotension, dysrhythmias • Psychosis, precipitates mania
- Convulsions
- Metabolic-endocrine: weight gain, sexual disturbances
TAD overdose:
- Very dangerous
- 10x daily dose can be fatal
- Agitation, delirium, neuromuscular irritability, convulsions, coma, respiratory suppression, circulatory collapse, hyperpyrexia, dysrhythmia
- Coma, Convulsions, Cardiotoxicity
- NB: Treatment: SAMF
Kry dit nie in die SAMF nie. Het die opgesoek:
- At 1 to 2 hours after ingestion, there is a rapid decline in mental and cardiovascular status. Diagnosis is established on clinical grounds and classic ECG changes (sinus tachycardia progressing to wide complex tachycardia and ventricular arrhythmias with increasing severity of intoxication).
- Hypertonic sodium bicarbonate improves conduction abnormalities and hypotension.
- Management of arrhythmias involves correction of acidosis, hypoxia, and electrolyte imbalance. Anti-arrhythmic drugs should generally be avoided.
- Hypotension usually responds to correction of hypoxia and administration of intravenous fluids and sodium bicarbonate.
- Treatment with vasopressors (such as norepinephrine [noradrenaline]) is controversial and should only be done in consultation with a medical toxicologist or intensive care specialist .
- Benzodiazepines are the first-line treatment for seizures.
Other AD’s side effects:
- MAOI’s: sleep disturbances, weight gain, postural hypotension, Drug/Food interactions
- Maprotiline: Like TAD, dose related convulsions
- Mirtazepine: sedation, ↑ appetite, weight gain
- Trazodone: sedation, nausea, insomnia, agitation, priapism
- Venlafaxine: nausea, sedation, sweat, light headedness, sexual disturbances, hypertension, anxiety
- SSRI’s: Insomnia, tremors, GIT-disturbances, headache, ↓ libido, sexual dysfunction, anxiety (acute), EPS, withdrawal syndrome
- Bupropion: light headedness, dry mouth, sweat, tremors, psychosis, convulsions (high doses)
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DRUG interactions dynamic and kinetic: v Fluoxetine, norfluoxetine, slow elimination: 5 week wash-out period before MAOI is started v Potentially deadly reactions with combination of any SSRI, TAD with MAOI (5-HT syndrome) v Combination of SSRI with carbamazepine: ↑ carbamazepine [plasma] + toxicity
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Summary of the SE of AD: |
MAO-inhibitors interactions:
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Hypertensive crisis
Symptoms of hypertensive crisis: Enlarged pupils, light sensitivity, severe headache, chest pains, arrhythmias, stiff neck, sweat, nausea, vomiting.
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Clinical use: general principles |
Treatment Resistant Depression |
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Other indications:
- TAD’s:
- Enuresis
- Chronic pain (RA, trigeminal neuralgia, cancer, migraine prophylaxis) (Amitriptyline low dosages)
- Bipolar disturbances (caution, can cause mania)
- Acute panic (especially Imipramine)
- Phobia’s (especially Imipramine)
- Chlorimipramine: OCD
- SSRI’s
- OCD (40 mg/d plus)
- Panic
- Social phobias
- Bulemia (80 mg/d plus)
- PMS
- Alcoholism (treatment of depression)
- Bupropion
- Nicotine withdrawal
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Elderly: |
Children, teenagers |
Pregnancy: |
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Ketamine: ü NMDA antagonist, glutamate involved in synaptic plasticity, MOA in depression unknown ü AD characteristics known for last 20 years • Rapid AD effect with max effect after 24 hours ü IV infusion arm, usually start with 3 infusions in first week, 2 in following week, 1/week for 3 weeks, maintenance 1/month • Effects last for 1 – 2 weeks after infusion, a longer-term effect is little reported ü Safety and tolerability at low single dose are generally good ü There is a lack of data concerning ketamine with repeated administration at higher doses ü Intranasal Esketamine in March 2019 by FDA approved,
ü Promising treatment in depressed patients with suicidal ideation
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FKLG 312:
Blog #12
Answer the following for a Blog Summary:
- Using your textbooks, draw up a classification of the drugs that are used as antidepressants.
- What do the existing drugs all have in common regarding their mechanisms of action?
- How long does it take for the antidepressive effects of these drugs to appear? What is the reason for this?
- How do the TADs and the selective serotonin reuptake inhibitors (SSRI’s) differ in respect of:
- efficacy
- side effects
- safety?
- What is the action of mirtazapine?
- What is the action of venlafaxine?
- What is the action of agomelatine?
|
Tertiary amines: |
Secondary amines: |
|
Re-uptake inhibitors that show preference for 5-HT re-uptake above NA re-uptake.
ANTI-CHOLINERGIC and ALIPHATIC (α1) EFFECTS (Includes involved receptor related side effects also)
I.e. NE such as: Impotence, blurred vision, midriasis, palpitations, tachycard, constipation, dry mouth, weight gain.
|
Re-uptake inhibitors that show preference for NA re-uptake above 5-HT re-uptake.
ANTI-CHOLINERGIC and ALIFATIC (α1) EFFECTS (Includes involved receptor related side effects too) (Much more potent than the tertiary amines).NE = worse such as: Impotence, blurred vision, mydriasis, palpitations, tachycardia, constipation, dry mouth, weight gain.
|
TAD structure-activity relationship:
- Higher affinity for re-uptake transport receptor than for specific R’s
- Uptake inhibitors
- (Tertiary: 5-HT selective)
- (Secondary: NA selective)
- Anti-cholinergic (Tertiary more potent)
- Alphalytic (Tertiary more potent)
-
Quinidine-like (blocks heart conduction arrhythmia)These drugs are alternatives at:
Patients with psychomotor delay, Sleep Disorders, Poor appetite, Weight loss
OTHER INDICATIONS: TAD'S:
Enuresis (Children under the age of 6 years water their bed during REM sleep period. First try TAD (ESPECIALLY IMIPRAMINE) before considering surgery).Chronic pain: (RA, trigeminal neuralgia, cancer, migraine prophylaxis) amitriptyline in low doses Bipolar disorders (caution, can mania ppt) Acute Panic -IMIPRAMINE, Phobias- Imipramine.
Phobias – ESPECIALLY IMIPRAMINE
Chloramine: OCD
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TAD-Overdose: Very dangerous 10x daily dose can be fatal. Agitation, delirium, neuromuscular irritability, convulsions, coma, respiratory suppression, circulatory patches, hyperpyrexia, dysrhythmias Coma, Convulsions, Cardiotoxic
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Toxicity:
- Sedation (Due to H1 receptor blockade)
- Sympathomimetic: tremor, insomnia (Reduce the NA re-recording)
- Anticholinergic: vision disorders, dry mouth, constipation, urinary retention, confusion (M-blocking)
- CVS: orthostatic hypotension, dysrhythmias
- Psychoses, precipitating mania
- Convulsions
The tertiary amines:
|
Substance: |
Indication: |
MOA: |
Notes: |
|
Amitriptyline Imipramine Trimipramine Chlorimipramine (Clomipramine) Dothiepine Butriptyline |
Treatment of depression (major)
Amitriptyline: Chronic pain
Clomipramine especially also in OCD (Obsessive compulsive disorder).
FIRST CHOICES AT: - Phobias - Anxiety - Panic = SSRI'S THEN: Tertiary amines (NOT second amines).
Especially imipramine: Enuresis, acute panic, phobias.
|
Reuptake inhibitors some preferred for 5-HT reuptake inhibition above NA reuptake inhibition.
|
ANTI-CHOLINERGIC and ALIPHATIC (α1) EFFECTS (NE too) - (Much more potent than the secondary amines). |
The secondary amines:
|
Substance: |
Indication: |
MOA: |
Note’s: |
|
Nortriptyline Desimipramine (Metabolite of Imipramine). Amoxapine Maprotiline Lofepramine |
Treatment of depression (major)
Nortriptyline and BMI: Can be used in healthy elderly people). |
Reuptake inhibitors some preferred NA reuptake inhibition above 5-HT reuptake inhibition. |
ANTI-CHOLINERGIC and ALIPHATIC (α1) EFFECTS (NE too).
Maprotiline Toxicities: Like TAD's, dosage-related convulsions. (Caution in patients with epilepsy ) |
2. Monoamine oxidase inhibitors (MAOI’s):
Developed for the treatment of tuberculosis (iproniazide derivatives) - 1951.
• Inhibits break-down monoamines (NA, DA, 5-HT)
• MAO: Iso-enzymes
- MAO A (GIT)
- MAO B (striatum)
• Reversible (long duration of blockade, no covalent bonds), nonselective: Tranylcypromine (Parnate®)
|
NB, Revise process in SU1! |
• Reversible, MAO A-selective: Moclobemide (Aurorix®)
Diet limitations:
Limitations:
- Cheese
- Yogurt
-
Wine, beerToxicities:
Sleep disturbances, Postural hypotension
- Herring, sardines, caviar
- Yeast- and meat extracts (Marmite, Bovril)
- Liver, processed meat
- Ripe avocados
|
Substance: |
Clinical indication: |
MOA: |
Notes: |
|
Tranylcypromine |
Treatment of depression (ELECTIVE IN ATYPICAL DEPRESSION) - When the person's state of mind is low but there is not necessarily a lack of motivation.
Severe anxiety Phobias Hypochondriasis Panic |
Irreversible non-selective inhibitor of MAO-A+B with the result that fewer mono-amines (5-HT, DA and NA) are broken down and the concentrations increase. |
CAUSE CHEESE REACTION - Give the person recommendations on diet.
Effects still last for several weeks after withdrawal.
|
|
Moclobemide: |
|
Reversible inhibitor of MAO-A with the result that fewer mono-amines (NA, DA and 5-HT) are broken down and that lg. concentrations increase. |
Diet recommendations are therefore not necessary here unless the person is already experiencing blood pressure problems. |
3. Selective 5HT reuptake inhibitors (SSRI):
|
Fluoxetine (Prozac®), Paroxetine (Aropax®), Fluvoxamine (Luvox®), Sertraline (Zoloft®), Citalopram (Cipramil®), Escitalopram (Cipralex®)
|
TAD requires titration to minimum effective dosage while the SSRI's can usually begin immediately with full dosage. ALTHOUGH IT CAN PRESENT ANXIETY.
|
Substance: |
Clinical indication: |
MOA: |
Notes: |
|
Depression treatment (1st choice in the elderly)
FIRST CHOICES AT: - Phobias - Anxiety - Panic THEN: Tertiary amines (NOT second amines).
OCD (40mg/day plus)
Bulimia (80mg/day plus)
PMS
Resistant schizophrenia
Alcoholism (Not going to help an alcoholic, but will for a depressed person who drinks)
Bipolar disorder
Fluoxetine is the only AD approved in children. |
These drugs selectively block the serotonin re-uptake at the pre-synaptic neuron. |
Paroxetine has the most anti-cholinergic effects – exceptional because the other drugs have practically no anti-cholinergic effects, the drug also has a very short t1/2 and must be administered more than once p.d. – exceptional because the other drugs are only administered once a day. Especially severe withdrawal symptoms
The drugs are less cardiotoxic than the TAD's.
Possible association between fluoxetine and premature birth and delayed fetal growth rate.
The drugs have a better NE profile than many other drugs and are safer in acute overdosage. Can reduce appetite and result in weight loss.
Fluoxetine has a 5-week wash-out period |
|
Toxicities: Insomnia, tremor, GIT disorders, headaches, ↓ libido, sexual dysfunction, anxiety (acute), EPS (Needles and pins/crayon/restless legs), withdrawal syndrome. The drugs can lower appetite and overweight patients can thereby lose weight. Remedies aren't sedating. HOW ACUTE ANXIETY AS TOXICITY AS SSRI'S IS USUALLY USED FOR IT. Initially, there is a sudden increase in the 5-HT levels in the brain that exacerbate anxiety, however, it later becomes better again.
|
4. Serotonin and noradrenalin reuptake inhibitors (SNRI):
Blocks both 5-HT and NA re-uptake, more potent for 5-HT than for NA
- Venlafaxine (Efexor®)
- Duloxetine (Cymbalta®)
Also used in pain: neuralgia and fibromyalgia, GAD, vasomotor symptoms of menopause.
|
Substance: |
Clinical indication: |
MOA: |
Notes: |
|
Depression treatment
Severe anxiety and phobias
|
Block both 5-HT and NA re-uptake, more potent for 5-HT than for NA. |
Venlafaxine toxicity: Nausea, sedation, dizziness, sweat, sexual disturbances, hypertension, anxiety.
Venlafaxine has less anti-cholinergic and cardiotoxic SE. |
5. Selective noradrenalin reuptake inhibitors (NARI):
Blocks re-uptake of NA
- Reboxetine (Edronax®)
- not cardiotoxic, no anti-cholinergic effects.
- no affinity for any NT R’s
- Used for Depression.
6. Tetracyclic and Unicyclic AD’s
- Mianserin (Ludiomil®)
- Mirtazepine (Remeron®)
- NaSSA (NA & specific serotonin AD)
- Blocks α2, 5-HT2A, 5-HT3
- Mirtazepine more potent than mianserin
- Also Blocks H1 (sedation, weight gain)
- Also Blocks α1 (postural hypotension)
- Mianserin: haematological reactions, (agranulocytosis), limited use
|
Substance: |
Clinical indication: |
MOA: |
Notes: |
|
Mianserin
Mirtazepine
Bupropione
|
Treatment of depression.
Bupropion in lower doses: Nicotine withdrawal
Bupropion: Obesity
Bipolar disorder
Mirtazepine: Induce sedation
|
Block α2, 5-HT2A and 5-HT3. Also block H1 and α1.
A naSSA – Noradrenaline and specific serotonin anti-depressant. Block α2 (Blockade of this inhibitory receptor promotes both NA (auto receptor) and 5-HT release (heteroreceptors)), 5-HT2A and 5-HT3. Also block H1 and α1. Also, indirect stimulation of 5-HT1A. Blockade of the inhibitory α2 receptors advance both NA (autoreceptors) & 5-HT release (heteroreceptors) •Indirect stimulation of 5-HT1A: anxiolytic •Blockade 5-HT3: anxiolytic, ↓ nausea •Blockade 5-HT2: anti-depressive effects
Block DA, as well as NA re-uptake. |
H1 blockade can cause sedation and mass gain. α1 blockade can cause postural hypotension. Causes blood disorders (agranulocytosis) – limited use.
Stimulation of 5-HT1A = anxiety myolities Blockade of 5-HT3 = anxiety insulating and lowers nausea. Blockade of 5-HT2A = Antidepressive Toxicities: Sedation, increased appetite and mass gain.
Alerting. May induce convulsions in certain patients. (Caution in epilepsy sufferers). •Lower dosages nicotine withdrawal (Zyban®
Fewer anti-cholinergic and cardiac effects.
Toxicities: Dizziness, dry mouth, sweating, tremor, psychoses, convulsions (high doses). |
5-HT receptor modulators:
|
Substance: |
Clinical indication: |
MOA: |
Notes: |
|
Trazodone (Molipaxin) |
• Effective initial and maintenance treatment for MDD (20 mg/d) • Well tolerated in older people • May have cognitive benefits, especially in older people • Considered as an alternative to other AD’s on market. |
5-HT2 antagonist • Weak 5-HT re-uptake inhibitor, weak α2 blocker • Trazodone also blocks H1 (severe sedation) & α1: (priapism) |
Currently: unlabeled hypnotic, highly sedating, not associated with tolerance or dependence |
|
Vortioxetine (Brintellix ) |
Treatment of depression
Trazodone: Currently often used as hypnotic, due to severe sedative effects. (Not associated with tolerance/dependency).
Vortioxetine: Major depressive syndrome: effective + maintenance treatment. For beneficial cognitive effects (especially the elderly). Also helps for insomnia (a multimodal AD). Alternative to other ADs.
|
• Block several 5-HT receptors (3, 7, 1D), agonist on 5-HT1A, partial agonist on 5-HT1B • Weak SERT inhibitor • MDD, Procognitive effects?? |
• Animal studies: Increase in extracellular levels: • NA, DA, Glutamate, ACh, Histamine in brain areas associated with depression, including the prefrontal cortex and hippocampus. • Additional in vivo testing is necessary to determine whether this multimodal action produces an additional clinical benefit
SE:
|
|
SE: Most common: ü Nausea ü Headache ü Dry mouth ü Dizziness Also: • Sexual dysfunction • Weight gain • Hypertensive crisis • Increased risk of suicide • Pancreatitis Contra-indications/ Caution: § Other serotonergic drugs § Caution: NSAID’s, warfarin and anticoagulants § Bipolar disorder § Hyponatremia, elderly patients, and patients on diuretics at higher risk
|
8. Circadian rhythm regulators: Agomelatine:
Synergism between melatonergic and 5-HT2c receptors:
-
- 5-HT2c, MT1/MT2 receptors: High density in SCN Regulation of circadian rhythms
- MT1/MT2 agonism benefits sleep, but is not antidepressant.
- 5-HT2c agonism worsens sleep disturbances 5-HT2c antagonism improves sleep
- 5-HT2c antagonism benefits antidepressant action
|
Substance: |
Clinical indication: |
MOA: |
Notes: |
|
Agomelatine |
Major depression |
Restores the body's biorhythms. Primary agonist on melatonin 1+2 receptors and a m antagonist on 5-HT2C receptors.
MT1 and MT2 agonist and 5-HT2c antagonist • 5-HT2c-antagonism: disinhibition of DA and NA release in FC (Increase DA and NA release)
(Melatonin is a by-product of 5-HT. Responsible for directing biological beating (fatigue/body temperature etc.), melatonin therefore restores these rhythms because during depression these circadian rhythms are disturbed. Thus, depression affects melatonin secretion. |
S/E: Headache, dizziness, GIT discomfort, fatigue, liver enzyme increases
• CI: Hepatic impairment
• Valdoxane |
|
THERE IS SINNERGISM BETWEEN MELATONIN RECEPTORS AND 5—HT RECEPTORS:
Higher density in SCN Regulation of circadian rhythms
For example, in the meantime, you cannot give someone only melatonin to totally alleviate depression, the insomnia that occurs in depression can be alleviated by a melatonin agonist.
|
|
The non-specific receptors give rise to SEROTONIN SYNDROME: Life threatening response Severe muscle rigidity Myoclonus Hyperthermia CVS instability SSS stimulation (restlessness, convulsions) Treated: Anticonvulsants, muscle relaxants, cyproheptadine (5-HT2 antagonist)
|
Pharmacokinetic principles of antidepressants:
- Liver metabolism
- Most AD’s long t½, 1/d dosage
- Exceptions: venlafaxine, Trazodone: 2 – 3x/d
- Active metabolites, some TAD’s, fluoxetine, venlafaxine, and other. •
- Norfluoxetine: t½ 7 – 9 days
- SSRI’s: inhibits certain cytP450 enzymes ⇒ Drug interactions
TAD’s side effects:
- Sedation
- Sympathomimetic: tremors, insomnia
- Anticholinergic: disturbed vision, dry mouth constipation, urinary retention, confusion • CVS: orthostatic hypotension, dysrhythmias • Psychosis, precipitates mania
- Convulsions
- Metabolic-endocrine: weight gain, sexual disturbances
TAD overdose:
- Very dangerous
- 10x daily dose can be fatal
- Agitation, delirium, neuromuscular irritability, convulsions, coma, respiratory suppression, circulatory collapse, hyperpyrexia, dysrhythmia
- Coma, Convulsions, Cardiotoxicity
- NB: Treatment: SAMF
Kry dit nie in die SAMF nie. Het die opgesoek:
- At 1 to 2 hours after ingestion, there is a rapid decline in mental and cardiovascular status. Diagnosis is established on clinical grounds and classic ECG changes (sinus tachycardia progressing to wide complex tachycardia and ventricular arrhythmias with increasing severity of intoxication).
- Hypertonic sodium bicarbonate improves conduction abnormalities and hypotension.
- Management of arrhythmias involves correction of acidosis, hypoxia, and electrolyte imbalance. Anti-arrhythmic drugs should generally be avoided.
- Hypotension usually responds to correction of hypoxia and administration of intravenous fluids and sodium bicarbonate.
- Treatment with vasopressors (such as norepinephrine [noradrenaline]) is controversial and should only be done in consultation with a medical toxicologist or intensive care specialist .
- Benzodiazepines are the first-line treatment for seizures.
Other AD’s side effects:
- MAOI’s: sleep disturbances, weight gain, postural hypotension, Drug/Food interactions
- Maprotiline: Like TAD, dose related convulsions
- Mirtazepine: sedation, ↑ appetite, weight gain
- Trazodone: sedation, nausea, insomnia, agitation, priapism
- Venlafaxine: nausea, sedation, sweat, light headedness, sexual disturbances, hypertension, anxiety
- SSRI’s: Insomnia, tremors, GIT-disturbances, headache, ↓ libido, sexual dysfunction, anxiety (acute), EPS, withdrawal syndrome
- Bupropion: light headedness, dry mouth, sweat, tremors, psychosis, convulsions (high doses)
|
DRUG interactions dynamic and kinetic: v Fluoxetine, norfluoxetine, slow elimination: 5 week wash-out period before MAOI is started v Potentially deadly reactions with combination of any SSRI, TAD with MAOI (5-HT syndrome) v Combination of SSRI with carbamazepine: ↑ carbamazepine [plasma] + toxicity
|
|
Summary of the SE of AD: |
MAO-inhibitors interactions:
|
Hypertensive crisis
Symptoms of hypertensive crisis: Enlarged pupils, light sensitivity, severe headache, chest pains, arrhythmias, stiff neck, sweat, nausea, vomiting.
|
|
Clinical use: general principles |
Treatment Resistant Depression |
|
|
Other indications:
- TAD’s:
- Enuresis
- Chronic pain (RA, trigeminal neuralgia, cancer, migraine prophylaxis) (Amitriptyline low dosages)
- Bipolar disturbances (caution, can cause mania)
- Acute panic (especially Imipramine)
- Phobia’s (especially Imipramine)
- Chlorimipramine: OCD
- SSRI’s
- OCD (40 mg/d plus)
- Panic
- Social phobias
- Bulemia (80 mg/d plus)
- PMS
- Alcoholism (treatment of depression)
- Bupropion
- Nicotine withdrawal
|
Elderly: |
Children, teenagers |
Pregnancy: |
|
|
|
|
Ketamine: ü NMDA antagonist, glutamate involved in synaptic plasticity, MOA in depression unknown ü AD characteristics known for last 20 years • Rapid AD effect with max effect after 24 hours ü IV infusion arm, usually start with 3 infusions in first week, 2 in following week, 1/week for 3 weeks, maintenance 1/month • Effects last for 1 – 2 weeks after infusion, a longer-term effect is little reported ü Safety and tolerability at low single dose are generally good ü There is a lack of data concerning ketamine with repeated administration at higher doses ü Intranasal Esketamine in March 2019 by FDA approved,
ü Promising treatment in depressed patients with suicidal ideation
|
Ane Gutter #Blog 13
02 May 2021, 11:23
Anè Gutter
31627706
#Blog 13:
Discuss the possible mechanisms of action of lithium.
- Mechanism of action: mediated by Li+
- Influences IP3 & DAG 2nd messenger systems by ↓ various enzymes which are very important for conversion and re-circulation of membrane phosphoinositides
- IP3 & DAG is NB in monoamine and cholinergic neurotransmission
What is the therapeutic index of lithium and what is its clinical significance?
The therapeutic index of lithium is 0,5-1.5mM > 2mM toxic. Li+has a very small index and thus the dosing of lithium should be done very carefully.Thw blood levels must be monitored very closely to prevent lithium toxicity that include:
- Tremors, sedation, ataxia, aphasia
- Muscle weakness, fatigue
- Polidypsia, poliuria, nocturia
- Nephrogenic diabetes insipidus (Li+ interferes with kidney’s ability to concentrate urine)
- Thyroid enlargement
- Leucocytosis
- Edema
- Weight gain, Acne, alopecia
- Sexual dysfunction
When is lithium used as single drug and in which cases and with which type of drugs is lithium combined?
Lithium is used as a monotherapy for the prophylaxis of manic and hypomanic episodes and treatment of an acute manic episodes. Lithium is used in combination with antidepressant for the treatment of resistant or recurrent unipolar depression, but you should be careful with the monotherapy because this can cause mania.
Name 3 clinically significant interactions lithium may have with other drugs. Illustrate your answer with suitable examples of drugs.
- Dehydration, diuretics (e.g. thiazides), NSAIM’s, ACE I’s & fluoxetine ↑ Li+ levels, toxicity
- Theophylline, caffeine ↑ renal excretion of Li+
- Neurotoxic combination with carbamazepine, Ca2+ blockers, losartan, methyldopa, metronidazole and phenytoin
- Traditional APD’s worse EPS in combination with Li+
Name the major side effects of lithium.
- Tremors, sedation, ataxia, aphasia
- Muscle weakness, fatigue
- Polidypsia, poliuria, nocturia
- Nephrogenic diabetes insipidus (Li+ interferes with kidney’s ability to concentrate urine)
- Thyroid enlargement
- Leucocytosis
- Edema
- Weight gain, Acne, alopecia
- Sexual dysfunction
What is the status of the use of lithium during pregnancy and lactation?
Lithium has been associated with an increased incidence of congenital cardiovascular abnormalities, but the incidence is very low and when the risk-benefit has been considered it may be continued. Lithium is excreted into the breastmilk in high concentrations and thus breastfeeding is not recommended.
Name three other important indications for lithium.
- Mood stabilizers
- lithium salts
- Valproate
- Carbamazepine
- Anti psychotic (acute mania)
- Anti-depressants (NB: can cause mania!)
- SSRI’s, Bupropion, MAOI’s, Lamotrigin
Evaluate the following case and fully motivate your recommendations:
Ms B. Polar (21 years, 60 kg) is a student and used the following medication for the past two months:
Camcolith 600mg bd. The plasma levels after two weeks were 0.8mmol/l. She sustained a muscle injury and has been using Indocid® 75mg nocte for the past 10 days. On questioning she reveals that “she had picked up a lot of weight” and is now using some of her mother’s “water pills” in the hope of losing a few of the extra kilos. However, she complains of fatigue, that she has difficulty in keeping her eyes open in class, remains thirsty and constantly feels shaky and nauseous.
- Indocid is an NSAIM (non-steroidal anti-inflammatory agent) and it will increase the lithium levels of the drug already given (CAMCOLIT), and the patient then has a risk for lithium toxicity.
- My recommendation will be to give another anti-inflammatory drug rather than an NSAIM to avoid toxicity. An indication that lithium toxicity is already present in the patient is her complaint of mass gain and because she drinks water pellets (diuretics) for it, lithium levels will increase further and her mass admissions will not be treated but exacerbate due to toxicity. The fatigue, thirsty feeling, nausea and tremors are all due lithium toxicity.
- My recommendation is to stop all current therapy and for now consider another drug for her bipolar disorder. A drug such as valproate will be recommended to treat bipolar disturbance in our patient with current lithium toxicity.
Ane Gutter #Blog 11
02 May 2021, 11:06
Anè Gutter
31627706
#Blog 11:
- Name an example of each of the three phenothiazine sub-families and state how they differ from one another in terms of potency and side effects.
Phenothiazine structure/ derivate:
- Aliphatic side-chain: Chlorpromazine (Largactil )
- Piperidine side-chain: periciazine (Neulactil )
- Piperazine side-chain: Fluphenazine (Modecate ), perphenazine, trifluoperazine, prochlorperazine.
Aliphatic and piperidine compounds:
- low potency, little EPS
- severe sedation
- strong anti-cholinergic effects,
- strong α-lytic effects (postural hypotension),
- cardiotoxic
Piperazine derivatives:
- high potency, more EPS,
- weaker anti-cholinergic side effects
- weaker α-lytic effects,
- less sedation
- less cardiovascular (CVS) side effects
- Which receptors in particular are blocked by the typical antipsychotic drugs?
Dopamine-2 receptors
- How does the mechanism of action of the atypical drugs differ from that of the typical drugs?
Atypical drugs:
- =Higher 5-HT receptor affinity.
- Block 5-HT2a receptors/inverse agonists on 5-HT2a and 5-HT2c more than DA 2 receptors.
- Block the constitution activity of h/d 5-HT2 receptors.
- h/d receptors modulate the release of DA, NA, Glutamate, GABA, AcH etc. in the cortex, limbic system and striatum.
- 5-HT2c stimulation inhibits DA release into the cortex and limbic system.
BETTER WORKING BUT MUCH MORE EXPENSIVE.
However, compared to the older drugs, these drugs then have fewer extra-pyramidal effects and prolactin effects, as well as less tardive disconnection.
(See only Risperidone and Paliperidone, )
- Most of the drugs act as a partial agonist on the 5-HT1A receptor that complements the 5-HT2A antagonism. (Synergism)
Typical drugs:
= NEUROLEPTICS
These drugs block mesolimbic DA 2 receptors.
Note:
These drugs also have anti-mimetic properties (Anti-vomiting) because the dopamine 2 receptors are blocked in the CESA.
- Which of the receptors blocked by the older drugs reduce the risk of extrapyramidal side effects?
Aliphatic (Chlorpromazine) and piperidine side chains (Periciazine)
- Which of the older drugs have a high incidence of extrapyramidal side effects? What is the reason for this?
Piperazine derivatives has a high potency, therefor more Extrapyramidal side effects.
- Because of which receptor(s) blockade do the aliphatic group of drugs have a high incidence of autonomic side effects?
If the nicotinic receptors is blocked.
Ane Gutter #Blog 10
07 Apr 2021, 12:27
FKLG 312:
SU 8:
Blog 10
- Which two main groups of drugs are important in the treatment of Parkinsonism?
Anticholinergic drugs
Dopamine agonists
- In what way does amantadine act as a antiparkinsonism drug?
Amantadine is an antiviral, NMDA antagonist and anticholinergic drug. Amantadine has the following mechanism of action to counter Parkinson's:
- Increase dopamine release.
- Increase dopamine synthesis.
- Inhibits the re-recording of dopamine.
- Discuss the mechanisms of action of the antiparkinsonism drugs that indirectly increase dopamine concentration.
Selective MAO – B inhibitors increase the dopamine concentration in an indirect manner through potent inhibition of MAO – B, thereby inhibiting the re-uptake of dopamine.
- Which of the dopamine agonists are ergot derivatives and which are not?
Ergot derivate = bromocriptine
Not ergot derivative = Pramipexole and Ropinirole
- List the specific dopamine receptors that are stimulated by each agonist.
Bromocriptine = D2 receptors (partial agonist)
Pramipexole = D3
Ropinirole = D2
- Which of these drugs are classified as neuron protecting drugs? What does this mean?
Pramipexole (Pexola) and selective MAO-B reuptakers are considered neuroprotective because it reduces affective symptoms and causes disease progression to decrease. Neuroprotective drugs meaning is that it reduces the symptoms of depression that can occur.
- What is the importance of monoamine oxidase B (MAO-B) selective drugs in the treatment of Parkinsonism?
MAO-B inhibitors increase dopamine concentration in the central nervous system in that it has a specific substrate for dopamine.
- How do the COMT-inhibitors act in Parkinsonism?
COMT inhibitors metabolizes L-dopa to 3-O-methyldopa (3OMD)
3OMD competes with L-dopa for active transport.
COMP prolongs L-dopa's duration of action, lowers metabolism, and promotes the bioavailability of L-dopa.
- How does istradephyline act?
Adenosine A2 antagonist – D2 function is inhibited by adenosine.
- Discuss the MOA of safinamide
Safinamide has two-pronged mechanisms.
- It Increases dopamine function by potent MAO-B inhibition and dopamine re-uptake inhibition.
- And it Lowers glutamate release.
Ane Gutter #Blog 9
07 Apr 2021, 12:13
FKLG 312:
SU 6:
Blog 9
- How does the sensitivity for blockade by a LA compare regarding the following types of fibres?
- myelinated fibres with unmyelinated fibres; and
Unmyelinated fibers and smaller myelinated fibers are blocked more efficiently by local anaesthetics than larger myelinated fibers. Thus, unmyelinated fibers are very sensitive to the effects of local anaesthetics.
- pressure/touch nerves with the dorsal nerves that transmit pain impulses?
The dorsal nerves, which lead impulses, are more sensitive to blockage/inhibition than pressure/touch nerves and will therefore be more easily inhibited.
- Make a list of the effects of LA on other tissues.
Heart: Class 1 anti-arrhythmic agents, Lidocaic (Class 1 drug) that block Sodium Channels at heart. This causes the action to shorten potential and extend the re-shelf period. Local anaesthetics affects the cardiovascular system by causing cardiac depression.
CNS: It also affects the central nervous system by producing light-headedness, visual and auditory disturbances.
Skeletal muscle: Poor blocking effect, no clinical application.
- What is the basis for the selection of a LA?
Clinical use, the type of process that is being done, and the duration of time necessary for the numbing effect that is needed in that tissue.
- Why are LA solutions sometimes saturated with CO2?
Because it will accelerate the onset of action of local anaesthetics. CO2 buffers the local anaesthetic. This then reduces the pain of injection and a faster onset of local anaesthetics is achieved. This will also raise the effective concentration of the nonionized form of the local anaesthetic, for only the nonionized form can cross the plasma membrane to have an effect, and thus the onset time of the regional block will be shortened.
- Which of the LA are typically used for surface anaesthesia?
Oxybuprocaine, benzocaine and cocaine.
Ane Gutter #Blog 8
26 Mar 2021, 08:45
FKLG 312:
SU 5.3
#Blog 8
Compile a table, listing the major effects on every system (cardiovascular, CNS, renal, hepatic and uterus) for all the inhalation anaesthetics. This table is important when it comes to the selection of drugs in certain individuals.
|
Substance: |
MOA: |
CI: |
Effects of substances:
|
|
Halothane |
Balance between strengthening inhibitory and weakening of excitatory circuits in SSS.
|
No longer often used due to hepatotoxicity and newer drugs. |
CNS: Rapid smooth induction, Stage 2 = absent, cerebral blood flow + increased intracranial pressure
Autonomic : Bradycardia
CVS: Blood pressure lowered, Sensitizes myocardium for arrhythmogenic effects of catecholamines.
Respiratory system : Not saliva-bronchial secretions or coughing.
Musculoskeletal: "MUSCLE TWITCHING" Skeletal muscle-relaxing effects Stage III Increase operation of non-depolarizing effects. Reduces action of depolarizing effects e.g. middle like succinylcholine) Post-operative → hypoxia
Uterus: Reduced muscle contraction that causes external turning of baby.
Liver : Hepatotoxic, is metabolized by the liver.( Rare and unpredictable)
|
|
Enflurane |
(Drugs strengthen the inhibitory lanes and weaken the excitatory lanes).
|
No longer use so often but use for maintenance. . |
CNS: Fast,smooth induction convulsions sometimes, NOT epileptics.
CVS: No sensitization of the myocardium, less ↓ than Halothane.
Respiratory: More↓ than Halothane
|
|
Isoflurane |
Drugs react with lipid component (Drugs are very lipid soluble ) of the cell membrane:
• Disturbance of membrane channels • Direct activation v GABA – A receptors
|
More ideal remedy than halothane and enflurane. Replaced the above 2 mainly. Not in patients who have to breathe spontaneously. Mainly maintenance |
CNS: Faster induction + recovery than Halothane.
CVS: Less ↓ than Halothane + Enflurane No sensitization of myocardium.
Respiratory: Potent ↓ effect. Strengthens because of potent skeletal muscle relaxing effect.
|
|
Desflurane |
Different neurons – different sensitivities:
E.g. Dorsal horn cells of the spinal cord are particularly sensitive to inhalation drugs, brain stem neurons are quite resistant against effects of drugs. |
Even more ideal than Isoflurane or sevoflurane. Potential to be used for various surgical procedures. Because of effect on resp. → NOT as induction. |
CNS: Even faster induction + recovery than Isoflurane, ↑ cerebral blood flow and intracranial pressure.
CVS: Less ↓ than Halothane + Enflurane.
Respiratory: Strong smell, irritate airways, if used as induction drug → cough, shortness of breath and laryngospasm. |
|
Sevoflurane |
|
Induction and maintenance. |
Effects similar to Desflurane, less irritation of airways Potentiate the effects of the non-depolarising muscle relaxants like the other halogenated ethers. Undergoes metabolism + chemically unstable |
|
N2O (Inorganic laugh gas) |
|
Status As additive drug in anaesthesia.
Single drug for short dental procedures e.g. extractions |
Inorganic gas
CNS Weak anaesthetic, potent analgesic, amnesia
CVS : No effect
Resp. : Pure N2O → hypoxia, always mix with O2 or air. Recovery phase: N2O fast diffusion from blood to alveoli, ↓ O2 pressure, → hypoxia
No skeletal muscle relaxation
|
|
Methoxyflurane |
|
|
|
Name the major acute toxic effects of the inhalation drugs.
- Nephrotoxicity
- Hematotoxicity
- Malignant hyperthermia
- Hepatotoxicity
Ane SU 4 #Blog 7
14 Mar 2021, 17:06
FKLG 312:
SU 4:
#Blog 7
- Which of the anti-epileptic drugs affect the metabolism of the Pill (oral contraceptive) and what are the implications of this? Which drugs are safe to use in combination with the Pill?
Anti-epileptic drugs that decrease the effectiveness of oral contraceptives :
- phenobarbitone
- phenytoin
- carbamazepine
- oxcarbazepine
- topiramate
The implications of this are that the female patient can have an unwanted pregnancy, or the patient’s hormone levels will not be regulated as it should because of the contraceptive not reaching therapeutic effective levels to prevent ovulation. It will decrease the Pill’s effectiveness.
Anti-epileptic drugs that are safe to use with oral contraceptives:
- valproate
- lamotrigine
- gabapentin
- levetiracetam
- vigabatrin.
- Can oral contraceptives also affect the effectivity of the anti-epileptic drugs?
Yes, Oral contraceptives can decrease lamotrigine and valproate serum levels.
- How does age affect the kinetics of these drugs (from neonates to old age)?
The metabolism of anti-epileptic drugs in neonates are slower than in an adult and the metabolism of these drugs in babies and children are faster than the metabolism in an adult. The metabolism of anti-epileptic drugs in geriatrics are also slower than in an adult, and you need to administer lower dosages.
- In which cases is plasma blood level monitoring indicated?
Blood plasma blood levels are used to see how the patient’s body tolerates the medicine. The blood tests help the doctor to identify the possible allergies, interactions, infections and other abnormalities that may affect the choice of appropriate anticonvulsant medication and helps to monitor the possible drug-induced side effects. Phenytoin can be used as an example, because Phenytoin starts off with 1st order kinetics and then zero order kinetics once the plasma concentration of phenytoin is > 10 ug/ml. The drug can then accumulate and then reach a toxicity level which is very dangerous.
