Vasograin tablets

Indications

• Psychoses
• Schizophrenia
• Severe anxiety
• Nausea and vomiting
• Prevention of nausea and vomiting in migraine
• Labyrinthine disorders

Dosage

Adults: For psychosis, 12.5 mg by deep intramuscular injection as required; orally, initially 4 mg daily adjusted according to response, then increased by 2-4 mg at intervals of not less than 1 week, maximum 16 mg per day. For nausea and vomiting

Mechanism of action

Prochlorperazine's mechanism of action is primarily through its anti-dopaminergic effects, particularly by blocking D2 dopamine receptors in the brain. This blockade inhibits dopaminergic signaling in the mesolimbic system, contributing to its antipsychotic and antiemetic properties. Additionally, it affects serotonin type 3 (5-HT3) receptors at the chemoreceptor trigger zone (CTZ), further aiding in the prevention of nausea and vomiting.

Pharmacodynamics

As an antipsychotic agent, prochlorperazine promotes postsynaptic inhibition of dopaminergic neurons. It has strong antiemetic activity, displaying efficacy similar to ondansetron in preventing nausea and vomiting. Prochlorperazine also exhibits weak anticholinergic effects, moderate sedation, and strong extrapyramidal side effects. It can cause sedation and muscle relaxation through its blockade of alpha-1 adrenergic receptors and displays anti-anxiety effects.

Pharmacokinetics

Prochlorperazine is well absorbed after oral administration, with peak plasma concentrations typically reached in 1 to 2 hours. It has a plasma half-life of approximately 6 to 8 hours, with metabolism occurring primarily in the liver through cytochrome P450 enzymes. The drug is excreted mainly in urine as metabolites, with only a small fraction excreted unchanged. Caution is advised in patients with hepatic or renal impairment, as these conditions can affect drug clearance.

Contra-indications

• CNS depression
• comatose states
• history or family history of congenital QT prolongation
• phaeochromocytoma

Adverse effects

• drowsiness
• extrapyramidal symptoms
• blurred vision
• muscle spasms
• hypotension
• dry mouth
• constipation
• urinary retention
• heatstroke
• confusion
• delirium

Interactions

• pimozide
• other antipsychotics
• tricyclic antidepressants
• drugs prolonging the QT interval
• certain antihistamines
• antiarrhythmics
• drugs causing electrolyte disturbances, especially diuretics

Precautions

• caution in elderly patients
• monitor ECG in patients receiving large doses or co-administered with pimozide
• caution in hepatic impairment
• caution in renal impairment
• monitor for signs of neuroleptic malignant syndrome

Pregnancy

Prochlorperazine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is classified as Category C.

Breast-feeding

Prochlorperazine is excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• oral tablets
• oral suspension
• buccal tablets
• deep intramuscular injection

Indications

• Mild to moderate pain
• Fever
• Headaches
• Muscle aches
• Arthritis
• Backaches
• Toothaches
• Colds

Dosage

Adults: For adults, the typical dosage is 500 mg to 1 g every 4 to 6 hours, with a maximum daily limit of 4 g. In cases of intravenous administration, the dosage is 15 mg/kg every

Mechanism of action

Paracetamol is thought to exert its analgesic effects by inhibiting cyclo-oxygenase (COX) enzymes, specifically COX-1 and COX-2, which are involved in the synthesis of prostaglandins responsible for pain sensation. Unlike most NSAIDs, paracetamol does not exhibit peripheral anti-inflammatory effects. Its antipyretic action is believed to result from direct action on heat-regulating centers in the brain, leading to peripheral vasodilation and sweating.

Pharmacodynamics

Paracetamol has been shown to have both antipyretic and analgesic effects, lacking any significant anti-inflammatory activity. It does not interfere with platelet aggregation or disrupt hemostasis, making it a safer option for individuals at risk of bleeding. Allergic reactions to paracetamol are rare. The drug does not affect uric acid secretion or acid-base balance when used at recommended doses.

Pharmacokinetics

Paracetamol is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations typically occurring within 30 to 60 minutes after oral administration. It is primarily metabolized in the liver via conjugation with glucuronide and sulfate, with a minor pathway involving cytochrome P450 enzymes. The elimination half-life ranges from 1 to 4 hours, with renal excretion of metabolites as the primary route of elimination.

Adverse effects

• Nausea and vomiting
• Liver injury
• Renal damage
• Hypersensitivity reactions
• Flushing
• Hypotension
• Anorectal erythema
• Angioedema
• Agranulocytosis
• Thrombocytopenia
• Leukopenia
• Severe cutaneous adverse reactions (SCARs)

Interactions

• Increased risk of methaemoglobinaemia with topical prilocaine
• Increased risk of methaemoglobinaemia with topical anaesthetics
• Increased anticoagulant effect with coumarins
• Increased risk of hepatotoxicity with imatinib
• Decreased exposure with rifampicin
• Decreased exposure with pitolisant

Precautions

• Monitor patients with liver disease or heavy alcohol use for increased risk of hepatotoxicity
• Adjust doses in patients taking enzyme-inducing antiepileptic medications
• Use caution in patients with renal impairment
• Clinical judgement is required for dose adjustment in weight-based dosing

Pregnancy

Paracetamol is generally considered safe to use during pregnancy for pain and fever relief, but should be used at the lowest effective dose for the shortest duration necessary.

Breast-feeding

Paracetamol is excreted in breast milk in small amounts and is considered safe for use while breastfeeding.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Oral tablets (500 mg)
• Oral suspension (120 mg/5 mL, 500 mg/5 mL)
• Rectal suppositories (various strengths)
• Intravenous infusion (various strengths)

Indications

• Acute treatment of migraine attacks
• Cluster headache (off-label use)

Dosage

Adults: 1 mg taken once daily for 6 nights in 7, occasionally given for 1-2 weeks, dose to be taken at night.

Mechanism of action

Ergotamine tartrate acts as an agonist at serotonin (5-HT) receptors, particularly 5-HT1B and 5-HT1D subtypes, leading to vasoconstriction of cranial blood vessels. It modulates neurotransmitter release and inhibits the release of pro-inflammatory neuropeptides, which are involved in the pathophysiology of migraine.

Pharmacodynamics

The pharmacodynamic effects of ergotamine tartrate include vasoconstriction and a reduction in blood flow within the cranial vasculature, effectively alleviating headache symptoms. Additionally, it can influence dopaminergic pathways, contributing to its efficacy in treating migraine.

Pharmacokinetics

Ergotamine tartrate is well-absorbed from the gastrointestinal tract, with peak plasma concentrations occurring approximately 1-2 hours after oral administration. It undergoes extensive first-pass metabolism in the liver, resulting in a bioavailability of about 3-4%. The drug is primarily excreted via the kidneys, with a half-life of approximately 2 hours.

Contra-indications

• Acute porphyrias
• Coronary heart disease
• Hyperthyroidism
• Inadequately controlled hypertension
• Obliterative vascular disease
• Peripheral vascular disease
• Sepsis

Adverse effects

• Abdominal pain
• Dizziness
• Nausea
• Vomiting
• Cyanosis
• Diarrhoea
• Muscle weakness
• Pain in extremities
• Sensation abnormal
• Arrhythmias
• Cardiac valve fibrosis
• Dyspnoea
• Ergot poisoning
• Myocardial infarction
• Myocardial ischaemia
• Skin reactions
• Anxiety
• Arthralgia
• Blood disorder
• Cerebral ischaemia
• Confusion
• Constipation
• Depression
• Drowsiness
• Dry mouth
• Extrapyramidal symptoms
• Hallucination
• Renal artery spasm
• Seizure
• Sleep disorder
• Thrombosis
• Tremor
• Urinary retention
• Vision blurred

Precautions

• Anaemia
• Cardiac disease
• Dependence
• Elderly
• Risk of peripheral vasospasm

Pregnancy

Avoid; oxytocic effect on the uterus.

Breast-feeding

Avoid; ergotism may occur in infant; repeated doses may inhibit lactation.

Storage

Store in a refrigerator (2-8°C) and protect from light.

Formulations

• Tablets
• Injectable solution

Indications

• Management of apnea of prematurity
• Enhancement of alertness and cognitive performance
• Relief of headaches, particularly when combined with analgesics
• Enhancement of physical performance in sports

Dosage

Children: For infants, particularly for apnea of prematurity

Adults: The usual adult dose for alertness enhancement is 100 to 200 mg, taken as needed. For the management of apnea of prematurity, doses may vary and should be determined by a healthcare professional.

Mechanism of action

Caffeine acts primarily as an antagonist of adenosine receptors, inhibiting the action of adenosine, which normally promotes sleep and relaxation. This antagonism leads to increased neuronal firing and the release of neurotransmitters such as dopamine and norepinephrine. Caffeine also inhibits phosphodiesterase enzymes, enhancing levels of cyclic AMP and cyclic GMP, which are important for various cellular functions. Additionally, in the context of respiratory function, caffeine stimulates the respiratory centers in the central nervous system, enhancing ventilation.

Pharmacodynamics

Caffeine stimulates the central nervous system, increasing alertness and reducing fatigue. It relaxes smooth muscles, increases cardiac muscle contraction, and can enhance physical performance. Caffeine also promotes gastric acid secretion and gastrointestinal motility, and it exhibits mild diuretic properties. Its effects can lead to restlessness and agitation in some individuals, particularly at higher doses.

Pharmacokinetics

Caffeine is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 30 to 120 minutes after ingestion. It is distributed widely throughout body tissues, readily crossing the blood-brain barrier. Caffeine is metabolized primarily in the liver by cytochrome P450 1A2, producing three primary metabolites: paraxanthine, theobromine, and theophylline. The elimination half-life varies significantly among individuals, influenced by factors such as age, liver function, pregnancy, and the use of certain medications. It is primarily excreted in urine.

Adverse effects

• Restlessness
• Agitation
• Insomnia
• Increased heart rate
• Nausea
• Gastrointestinal discomfort
• Headaches

Interactions

• caffeinecitrate+adenosine: Unknown (decreases efficacy)
• caffeinecitrate+antiarrhythmics: Unknown (decreases efficacy)

Precautions

• Use cautiously in patients with a history of anxiety disorders, insomnia, or cardiac arrhythmias.
• Monitor caffeine intake in individuals with certain medical conditions, such as hypertension.

Pregnancy

Caffeine crosses the placenta; excessive intake during pregnancy may be associated with adverse outcomes. It is generally recommended to limit caffeine consumption.

Breast-feeding

Caffeine is excreted in breast milk; moderate consumption is considered safe, but excessive intake may affect the infant's sleep and behavior.

Storage

Store in a cool, dry place away from direct light. Keep out of reach of children.

Formulations

• Tablets
• Oral solutions
• Injectable preparations
• Caffeine citrate

Indications

• Acute migraine attacks
• Cluster headaches

Dosage

Adults: The usual dosage for adults is 1 to 2 mg taken orally at the onset of a migraine attack. Doses may be repeated after 30 minutes if necessary, but should not exceed 6 mg in a 24-hour period or 10 mg per week.

Mechanism of action

Ergotamine acts on migraine through two proposed mechanisms: firstly, it activates 5-HT1D receptors on intracranial blood vessels, leading to vasoconstriction and relief of migraine headache. Secondly, it activates 5-HT1D receptors on sensory nerve endings in the trigeminal system, inhibiting pro-inflammatory neuropeptide release. Moreover, ergotamine stimulates alpha-adrenergic receptors, causing peripheral vasoconstriction, while its competitive alpha-adrenergic blocking effects emerge at higher doses. Additionally, it inhibits norepinephrine reuptake, enhancing its vasoconstrictor action.

Pharmacodynamics

Ergotamine exhibits complex pharmacological properties, acting as a vasoconstrictor and alpha adrenoreceptor antagonist. Its actions are multifaceted, with varying effects on tryptaminergic, dopaminergic, and alpha adrenergic receptors depending on the site of action. It is a potent uterine stimulant and effectively reduces extracranial blood flow, leading to decreased pulsation amplitude in cranial arteries and diminished hyperperfusion in the territory of the basilar artery, while not affecting cerebral hemispheric blood flow.

Pharmacokinetics

Ergotamine is well absorbed after oral administration, with peak plasma concentrations occurring approximately 1 to 2 hours post-dose. It undergoes extensive hepatic metabolism, primarily via cytochrome P450 enzymes, and has a half-life of about 2 hours. The drug is excreted mainly in the urine as metabolites, and its pharmacokinetics can be significantly altered by concomitant medications that affect liver enzymes.

Contra-indications

• Hypersensitivity to ergotamine or any of its components
• Severe renal or hepatic impairment
• Pregnancy
• Peripheral vascular disease
• Ischemic heart disease
• Uncontrolled hypertension
• Severe infections
• Concurrent use with potent CYP3A4 inhibitors

Adverse effects

• Nausea
• Vomiting
• Abdominal pain
• Chest pain
• Ischemia
• Ergotism (characterized by cold, numb extremities, pain, and possibly gangrene)
• Headache
• Dizziness
• Tachycardia
• Hypertension

Interactions

• miconazole: Severe (increases exposure)
• hiv-protease inhibitors: Severe (increases risk of ergotism)
• macrolides: Severe (increases risk of ergotism)
• ribociclib: Severe (increases exposure)
• selpercatinib: Severe (increases exposure)
• clarithromycin: Severe (increases risk of ergotism)
• fedratinib: Moderate (increases exposure)
• larotrectinib: Moderate (increases exposure)
• palbociclib: Moderate (increases exposure)
• rucaparib: Moderate (increases exposure)

Precautions

• Use with caution in patients with a history of cardiovascular disease
• Monitor for signs of ergotism, especially with prolonged use or high doses
• Assess renal and hepatic function before treatment
• Consider alternative treatments for patients with risk factors for ischemic conditions

Pregnancy

Ergotamine is contraindicated in pregnancy due to the risk of uterine contractions and potential harm to the fetus.

Breast-feeding

Ergotamine is excreted in breast milk; caution is advised when administering to nursing mothers.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Tablets
• Suppositories
• Injectable forms

Indications

• Dehydration
• Electrolyte imbalance
• Heat-related illnesses
• Postoperative recovery
• Diarrhea and vomiting
• Chronic illnesses leading to fluid loss

Dosage

Children: Pediatric dosing should be guided by clinical guidelines and the severity of dehydration. For children experiencing mild to moderate dehydration, ORS is recommended, with the amount based on weight and age. For severe dehydration, intravenous fluid therapy is indicated, with specific protocols available in pediatric guidelines.

Adults: Dosage varies based on the degree of dehydration and the underlying clinical condition. For mild dehydration, oral rehydration solutions (ORS) are often sufficient, while severe cases may require intravenous fluids, with specific rates and types determined by clinical judgment.

Mechanism of action

Hydration works by replenishing lost fluids and electrolytes, restoring osmotic balance and cellular function. The primary components of hydration solutions, such as water, electrolytes (sodium, potassium, chloride), and sometimes glucose, promote proper cellular hydration and support metabolic processes.

Pharmacodynamics

The pharmacodynamics of hydration primarily involves the restoration of plasma volume and the maintenance of electrolyte homeostasis. Proper hydration enhances kidney function, improves cardiovascular stability, and supports normal physiological functions, such as thermoregulation and nutrient transport. It also aids in the recovery of tissues and organs affected by dehydration.

Pharmacokinetics

The pharmacokinetics of hydration solutions depend on the composition of the fluid administered. Oral hydration solutions are absorbed primarily in the gastrointestinal tract, with the rate of absorption influenced by the concentration of electrolytes and glucose. Intravenous fluids can distribute rapidly into the extracellular space, with effects seen almost immediately. The elimination of excess fluids occurs mainly through renal excretion.

Pregnancy

Hydration is essential during pregnancy, but fluid intake should be monitored to avoid excessive hydration, which can lead to complications.

Breast-feeding

Adequate hydration is important during breastfeeding, as it supports milk production. However, excessive fluid intake should be avoided.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Oral solutions
• Intravenous fluids
• Electrolyte solutions

Mechanism of action

According to its FDA labeling, acetaminophen's exact mechanism of action has not been fully established - despite this, it is often categorized alongside NSAIDs (non-steroidal anti-inflammatory drugs) due to its ability to inhibit the cyclo-oxygenase (COX) pathways. It is thought to exert central actions which ultimately lead to the alleviation of pain symptoms. One theory is that acetaminophen increases the pain threshold by inhibiting two isoforms of cyclo-oxygenase, COX-1 and COX-2, which are involved in prostaglandin (PG) synthesis. Prostaglandins are responsible for eliciting pain sensations. Acetaminophen does not inhibit cyclooxygenase in peripheral tissues and, therefore, has no peripheral anti-inflammatory effects. Though acetylsalicylic acid (aspirin) is an irreversible inhibitor of COX and directly blocks the active site of this enzyme, studies have shown that acetaminophen (paracetamol) blocks COX indirectly. Studies also suggest that acetaminophen selectively blocks a variant type of the COX enzyme that is unique from the known variants COX-1 and COX-2. This enzyme has been referred to as _COX-3_. The antipyretic actions of acetaminophen are likely attributed to direct action on heat-regulating centers in the brain, resulting in peripheral vasodilation, sweating, and loss of body heat. The exact mechanism of action of this drug is not fully understood at this time, but future research may contribute to deeper knowledge. Although further investigation is warranted, the active metabolite of acetaminophen (AM404) was shown to interact with several molecular targets, including the Ca_v3.2 calcium channel, the cannabinoid CB1 receptors, TRPV1 receptors, and Na_v1.8 and Na_v1.7 channels. Acetaminophen produces analgesia and antipyresis by a mechanism similar to that of salicylates. Unlike salicylates, however, acetaminophen does not have uricosuric activity. There is some evidence that acetaminophen has weak anti-inflammatory activity in some nonrheumatoid conditions (e.g., in patients who have had oral surgery). ... Acetaminophen lowers body temperature in patients with fever but rarely lowers normal body temperature. The drug acts on the hypothalamus to produce antipyresis; heat dissipation is increased as a result of vasodilation and increased peripheral blood flow. The effects of acetaminophen on cyclooxygenase activity have not been fully determined. Acetaminophen is a weak, reversible, isoform-nonspecific cyclooxygenase inhibitor at dosages of 1 g daily. The inhibitory effect of acetaminophen on cyclooxygenase-1 is limited, and the drug does not inhibit platelet function. Therapeutic doses of acetaminophen appear to have little effect on cardiovascular and respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing. Acetaminophen (N-acetyl-p-aminophenol (APAP)) is the most common antipyretic/analgesic medicine worldwide. If APAP is overdosed, its metabolite, N-acetyl-p-benzo-quinoneimine (NAPQI), causes liver damage. However, epidemiological evidence has associated previous use of therapeutic APAP doses with the risk of chronic obstructive pulmonary disease (COPD) and asthma. The transient receptor potential ankyrin-1 (TRPA1) channel is expressed by peptidergic primary sensory neurons. Because NAPQI, like other TRPA1 activators, is an electrophilic molecule, /the researchers/ hypothesized that APAP, via NAPQI, stimulates TRPA1, thus causing airway neurogenic inflammation. NAPQI selectively excites human recombinant and native (neuroblastoma cells) TRPA1. TRPA1 activation by NAPQI releases proinflammatory neuropeptides (substance P and calcitonin gene-related peptide) from sensory nerve terminals in rodent airways, thereby causing neurogenic edema and neutrophilia. Single or repeated administration of therapeutic (15-60 mg/kg) APAP doses to mice produces detectable levels of NAPQI in the lung, and increases neutrophil numbers, myeloperoxidase

Pharmacodynamics

Animal and clinical studies have determined that acetaminophen has both antipyretic and analgesic effects. This drug has been shown to lack anti-inflammatory effects. As opposed to the _salicylate_ drug class, acetaminophen does not disrupt tubular secretion of uric acid and does not affect acid-base balance if taken at the recommended doses. Acetaminophen does not disrupt hemostasis and does not have inhibitory activities against platelet aggregation. Allergic reactions are rare occurrences following acetaminophen use.

Mechanism of action

The mechanism of action of prochlorperazine has not been fully determined, but may be primarily related to its anti-dopaminergic effects. Prochlorperazine blocks the D2 dopamine receptors in the brain, which are somatodendritic autoreceptors. Inhibition of D2 receptor signaling results in the blockade of postsynaptic dopamine receptors in the mesolimbic system and an increased dopamine turnover. Nausea and vomiting are proposed to arise from peripheral or central stimulation of serotonin type 3 (5-HT3) and dopamine type 2 receptors, the predominant receptors expressed at the chemoreceptor trigger zone (CTZ). Prochlorperazine exerts antiemetic effects and was shown to inhibit apomorphine-induced vomiting by blocking D2 dopamine receptors in the CTZ.. The principal pharmacologic effects of prochlorperazine are similar to those of chlorpromazine. Prochlorperazine has weak anticholinergic effects, moderate sedative effects, and strong extrapyramidal effects. Prochlorperazine has strong antiemetic activity. The development of phenothiazine derivatives as psychopharmacologic agents resulted from the observation that certain phenothiazine antihistaminic compounds produced sedation. In an attempt to enhance the sedative effects of these drugs, promethazine and chlorpromazine were synthesized. Chlorpromazine is the pharmacologic prototype of the phenothiazines. The pharmacology of phenothiazines is complex, and because of their actions on the central and autonomic nervous systems, the drugs affect many different sites in the body. Although the actions of the various phenothiazines are generally similar, these drugs differ both quantitatively and qualitatively in the extent to which they produce specific pharmacologic effects. /Phenothiazine General Statement/ In the CNS, phenothiazines act principally at the subcortical levels of the reticular formation, limbic system, and hypothalamus. Phenothiazines generally do not produce substantial cortical depression; however, there is minimal information on the specific effects of phenothiazines at the cortical level. Phenothiazines also act in the basal ganglia, exhibiting extrapyramidal effects. The precise mechanism(s) of action, including antipsychotic action, of phenothiazines has not been determined, but may be principally related to antidopaminergic effects of the drugs. There is evidence to indicate that phenothiazines antagonize dopamine-mediated neurotransmission at the synapses. There is also some evidence that phenothiazines may block postsynaptic dopamine receptor sites. However, it has not been determined whether the antipsychotic effect of the drugs is causally related to their antidopaminergic effects. Phenothiazines also have peripheral and/or central antagonistic activity against alpha-adrenergic, serotonergic, histaminic (H1-receptors), and muscarinic receptors. Phenothiazines also have some adrenergic activity, since they block the reuptake of monoamines at the presynaptic neuronal membrane, which tends to enhance neurotransmission. The effects of phenothiazines on the autonomic nervous system are complex and unpredictable because the drugs exhibit varying degrees of alpha-adrenergic blocking, muscarinic blocking, and adrenergic activity. The antipsychotic activity of phenothiazines may be related to any or all of these effects, but it has been suggested that the drugs' effects on dopamine are probably most important. It has also been suggested that effects of phenothiazines on other amines (eg, gamma-aminobutyric acid [GABA]) or peptides (eg, substance P, endorphins) may contribute to their antipsychotic effect. Further study is needed to determine the role of central neuronal receptor antagonism and of effects on biochemical mediators in the antipsychotic action of the phenothiazines and other antipsychotic agents. /Phenothiazine General Statement/ Although the exact mechanism(s) of action has not been conclusively determined, phenothiazines have an antiemetic effect. The

Pharmacodynamics

Prochlorperazine is an antipsychotic agent that works to promote postsynaptic inhibition of dopaminergic neurons. It also exerts its anti-emetic actions via anti-dopaminergic effects, where it displays similar efficacy as ondansteron, a 5HT-3 receptor antagonist and anti-emetic, in preventing delayed nausea and vomiting. Prochlorperazine was shown to inhibit histaminergic, cholinergic and alpha-1 adrenergic receptors. The blockade of alpha-1 adrenergic receptors may result in sedation, muscle relaxation, and hypotension. It displays anti-anxiety effects as well. Compared to other phenothiazine derivatives, prochlorperazine is less sedating and has a weak propensity for causing hypotension or potentiating the effects of CNS depressants and anesthetics. Other than its primary action on D2 receptors, one study showed that prochlorperazine may inhibit the P2X7 receptor in human macrophages, leading to inhibition of calcium ion influx.

Mechanism of action

The mechanism of action of caffeine is complex, as it impacts several body systems, which are listed below. The effects as they relate to various body systems are described as follows: **General and cellular actions** Caffeine exerts several actions on cells, but the clinical relevance is poorly understood. One probable mechanism is the inhibition of nucleotide phosphodiesterase enzymes, adenosine receptors, regulation of calcium handling in cells, and participates in adenosine receptor antagonism. Phosphodiesterase enzymes regulate cell function via actions on second messengers cAMP and cGMP. This causes lipolysis through activation of hormone-sensitive lipases, releasing fatty acids and glycerol. **Respiratory** The exact mechanism of action of caffeine in treating apnea related to prematurity is unknown, however, there are several proposed mechanisms, including respiratory center stimulation in the central nervous system, a reduced threshold to hypercapnia with increased response, and increased consumption of oxygen, among others. The blocking of the adenosine receptors enhances respiratory drive via an increase in brain medullary response to carbon dioxide, stimulating ventilation and respiratory drive, while increasing contractility of the diaphragm. **Central nervous system** Caffeine demonstrates antagonism of all 4 adenosine receptor subtypes (A1, A2a, A2b, A3) in the central nervous system. Caffeine's effects on alertness and combatting drowsiness are specifically related to the antagonism of the A2a receptor. **Renal system** Caffeine has diuretic effects due to is stimulatory effects on renal blood flow, increase in glomerular filtration, and increase in sodium excretion. **Cardiovascular system** Adenosine receptor antagonism at the A1 receptor by caffeine stimulates inotropic effects in the heart. Blocking of adenosine receptors promotes catecholamine release, leading to stimulatory effects occurring in the heart and the rest of the body. In the blood vessels, caffeine exerts direct antagonism of adenosine receptors, causing vasodilation. It stimulates the endothelial cells in the blood vessel wall to release nitric oxide, potentiating blood vessel relaxation. Catecholamine release, however, antagonizes this and exerts inotropic and chronotropic effects on the heart, ultimately leading to vasoconstriction. Finally, caffeine is shown to raise systolic blood pressure measurements by 5 to 10 mmHg when it is not taken regularly, versus no effect in those who consume it regularly. The vasoconstricting effects of caffeine are beneficial in migraines and other types of headache, which are normally caused by vasodilation in the brain. Caffeine competitively inhibits phosphodiesterase, the enzyme that degrades cyclic 3',5'-adenosine monophosphate (AMP). Increased levels of intracellular cyclic AMP mediate most of caffeine's pharmacologic actions. Caffeine stimulates all levels of the CNS... Caffeine's cortical effects are milder and of shorter duration than those of amphetamines. In slightly larger doses, caffeine stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate. Caffeine constricts cerebral vasculature. In contrast, the drug directly dilates peripheral blood vessels...

Pharmacodynamics

Caffeine stimulates the central nervous system (CNS), heightening alertness, and sometimes causing restlessness and agitation. It relaxes smooth muscle, stimulates the contraction of cardiac muscle, and enhances athletic performance. Caffeine promotes gastric acid secretion and increases gastrointestinal motility. It is often combined in products with analgesics and ergot alkaloids, relieving the symptoms of migraine and other types of headaches. Finally, caffeine acts as a mild diuretic.

Mechanism of action

Ergotamine acts on migraine by one of two proposed mechanisms: 1) activation of 5-HT_1D receptors located on intracranial blood vessels, including those on arterio-venous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache, and 2) activation of 5-HT_1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release. Ergotamine has complex pharmacologic effects. In therapeutic doses, ergotamine causes peripheral vasoconstriction (if the vascular tone is low) primarily by stimulating alpha-adrenergic receptors; however, the drug causes vasodilation in very hypertonic vessels. With higher doses, ergotamine is also a competitive alpha-adrenergic blocker, but this effect is somewhat masked by the drug's alpha-adrenergic agonist activity. With therapeutic doses, ergotamine also inhibits reuptake of norepinephrine, thereby maintaining a high concentration of circulating norepinephrine and increasing ergotamine's vasoconstrictor action. Ergotamine has greater vasoconstrictor activity than the other ergot alkaloids but less alpha-adrenergic blocking activity than dihydroergotamine. Ergotamine is a weaker antagonist of serotonin (5-hydroxytryptamine) than is methysergide, but ergotamine does reduce the increased rate of platelet aggregation induced by serotonin. The mechanism by which ergotamine aborts vascular headaches is probably direct vasoconstriction of the dilated carotid artery bed with a concomitant decrease in the amplitude of pulsations; the drug's effects on catecholamines and serotonin are also at least partly involved. Sumatriptan, dihydroergotamine and methysergide inhibit 1% formalin-induced nociception by activation of peripheral 5-HT1B/1D receptors. This study set out to investigate the pharmacological profile of the antinociception produced by intrathecal and intraplantar administration of ergotamine (a 5-HT1B/1D and 5-HT5A/5B receptor agonist) and valerenic acid (a partial agonist at 5-HT5A receptors). Intraplantar injection of 1% formalin in the right hind paw resulted in spontaneous flinching behavior of the injected hindpaw of female Wistar rats. Intrathecal ergotamine (15 nmol) or valerenic acid (1 nmol) blocked in a dose dependent manner formalin-induced nociception. The antinociception by intrathecal ergotamine (15 nmol) or valerenic acid (1 nmol) was partly or completely blocked by intrathecal administration of the antagonists: (i) methiothepin (non-selective 5-HT5A/5B; 0.01-0.1 nmol); (ii) SB-699551 (selective 5-HT5A; up to 10 nmol); (iii) anti-5-HT5A antibody; (iv) SB-224289 (selective 5-HT1B; 0.1-1 nmol); or (v) BRL-15572 (selective 5-HT1D; 0.1-1 nmol). Likewise, antinociception by intraplantar ergotamine (15 nmol) and valerenic acid (10 nmol) was: (i) partially blocked by methiothepin (1 nmol), SB-699551 (10 nmol) or SB-224289 (1 nmol); and (ii) abolished by BRL-15572 (1 nmol). The above doses of antagonists (which did not affect per se the formalin-induced nociception) were high enough to completely block their respective receptors. Our results suggest that ergotamine and valerenic acid produce antinociception via 5-HT5A and 5-HT1B/1D receptors located at both spinal and peripheral sites. This provides new evidence for understanding the modulation of nociceptive pathways in inflammatory pain. It has previously been suggested that ergotamine produces external carotid vasoconstriction in vagosympathectomised dogs via 5-HT1B/1D receptors and alpha2-adrenoceptors. The present study has reanalyzed this suggestion by using more selective antagonists alone and in combination. Fifty-two anesthetized dogs were prepared for ultrasonic measurements of external carotid blood flow. The animals were divided into thirteen groups (n=4 each) receiving an i.v. bolus injection of, either physiological saline (0.3 mL/kg; control), or the antagonists SB224289 (300 ug/kg; 5-HT1B), BRL15572 (300 ug /kg; 5

Pharmacodynamics

Ergotamine is a vasoconstrictor and alpha adrenoreceptor antagonist. The pharmacological properties of ergotamine are extremely complex; some of its actions are unrelated to each other, and even mutually antagonistic. The drug has partial agonist and/or antagonist activity against tryptaminergic, dopaminergic and alpha adrenergic receptors depending upon their site, and it is a highly active uterine stimulant. It causes constriction of peripheral and cranial blood vessels and produces depression of central vasomotor centers. The pain of a migraine attack is believed to be due to greatly increased amplitude of pulsations in the cranial arteries, especially the meningeal branches of the external carotid artery. Ergotamine reduces extracranial blood flow, causes a decline in the amplitude of pulsation in the cranial arteries, and decreases hyperperfusion of the territory of the basilar artery. It does not reduce cerebral hemispheric blood flow.