Seminar 9. Histamine & Local anesthetics PDF

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Seminar 9.Pharmacology of histamine.Local anesthetics.I. Histamine Stored in vesicles in different tissues Histamine containing cells: mast cells, basophils Histamine containing tissues: tissues rich in mast cells ➔ more mast cells in tissues that are in direct contact with environment → skin, lungs...

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Seminar 9. Pharmacology of histamine. Local anesthetics. I. Histamine - Stored in vesicles in different tissues# - Histamine containing cells: mast cells, basophils - Histamine containing tissues: tissues rich in mast cells ➔ more mast cells in tissues that are in direct contact with environment → skin, lungs, GIT, mouth, blood vessels

- Non-mastcell histamine: - Found in brain → histamine acts as a neurotransmitter - CNS: histamine is involved in neuroendocrine control, cardiovascular regulation, thermoregulation, sleep cycle#

- Involved in regulation gastric acid: histamine interacts with parietal cells stomach ⇾ trigger release of gastric acid #

- One of the main mediators released during immunological process ➔ histamine release especially triggered by Ig E antibodies#

- ‘Immediate’ / ‘Type 1’ reaction → eg hay fever - IgM antibodies might trigger release of histamine as well# - Histamine can modulate its own release# - When histamine binds H2 receptors → decrease its own release# - When H2 receptors are located on the mast cells#

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4 types of histamine receptors G-protein coupled receptors Types: H1, H2, H3, H4 Important in pharmacology: H1 & H2 receptors

H1

- Gq receptor → stimulate phospholipase# - Mainly located in smooth muscles of various organs: blood vessels, endothelium, brain

- Stimulation of H1 receptors can cause 2 types of effect: local or systemic# - Stimulation of H1 is followed by vasodilation → pain, itching, …

H2

- Gs receptor → activation adenylyl cyclase# - Mainly located in stomach, heart (cardiac muscle), mast cells, brain - Stimulation of H1 receptors can cause 2 types of effect: local or systemic# - Stimulation of H1 is followed by vasodilation → pain, etching, …

H3

- Mainly located in CNS - Responsible for appetite control, …#

H4

- Involved in immune response

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Tissue and organ effect of histamine

Nervous sytem • Histamine is a very powerful stimulant of the sensory nerve endings ⇾ especially in pain and itching sensations ➔ H1 mediated response# • H3 receptors involved in control of the appetite → stimulation of those receptors might lead to weight gain# • CNS: histamine receptors involved in nociception (pain sensation)#

Cardiovascular sytem • Release or injection of histamine causes decrease blood pressure and increase in heart rate • Change in blood pressure: indirect → due to vasodilation ➔ vasodilation produced by histamine causes ‘reflex tachycardia’ (we need large amounts of histamine to produce such dramatic effect)# • Change in heart rate: direct → stimulation histamine causes tachycardia# • Small doses of histamine → trigger H1! ! ! mediated by release NO (nitric oxide) by endothelium#

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• High doses of histamine → trigger H2 → H2 are located in the heart, so cardiac stimulation is produced by H2 mediated mechanisms

Respiratory system • Bronchoconstriction → mainly due to H1 stimulation# • Patient not suffering from asthma or other respiratory deseases → no great effect# • Patients suffering from asthma → are very sensitive to histamine (bronchoconstriction due to histamine in asthma patients is due to overreactivity in their response to histamine) !

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GIT • Histamine causes contraction intestinal smooth muscles (due to activation H1)# • Histamine triggers release of gastric acid (due to activation H2 parietal cells)! Histamine is released by neighbouring cells in gastric mucosa → H2 receptors on parietal cells activated → activation triggers release of gastric acid

Other smooth muscles • Histamine has no significant effect on smooth muscles of the eye or genitourinary tract, but patients suffering from severe allergic reactions might suffer from histamine-induced contractions (Keep in mind: this is very rare)#

Local effect of histamine

If we inject histamine intradermally or subcutaneously → we would observe the socalled “triple response” ➔ a red spot oedema Reddening of the skin appears due to vasodilation small vessels#

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* All of the drugs discussed are histamine antagonist: we are not using histamine as a drug! It was used in the past, but not used anymore Pharmacology: blockage of H1 and H2 receptors

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H1 receptor antagonists (antihistamines) H1 receptor blockers are all involved in the treatment of allergic reactions Not used in treatment of asthma! (blockade of H1 is not enough in treatment of asthma) 1st generation: older drugs, also involved in other treatments (sleeping pill, motion sickness) 2nd generation: only used for the treatment of allergic reactions, we rely only on the H1 blocking effect Pharmacokinetics: Oral administration, very well absorbed

1st generation H1 blockers • Pharmacokinetics: #

- Short plasma half live → 1st generation drugs taken twice a day, duration of action usually between 4 and 6 hours#

- Widely distributed → penetrate easily through blood-brain barrier# - Lipid-soluble # - Could penetrate through placenta# - Intensively metabolised in the liver by cytochromes# • Main mechanism of action is the highly selective blockade of H1 receptors → not involved in any H2 receptor interactions# • Adverse reactions:!

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almost the same as atropine#

• 1st generation drugs are capable of also blocking the muscarinic receptors# • Majority of 1st generation drugs produce sedation (very specific for the 1st generation drugs!)" " " " " " " " " " "" ➟ Supressing effect on CNS " " " " " " "" !!

➟ 1st generation H1 blockers cant be used if a person has to drive ➟ Normally we observe sedation, in children we observe the opposite → we observe excitation #

• Xyrostomia (dry mouth)# • Used to treat drug-induced Parkinson disease → some drug-induced Parkison disease symptoms are due to activation muscarinic receptors

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• Some 1st generation drugs might block α receptors (adrenergic receptors) → connected to orthostatic hypotension (blockade of α receptors cause vasodilation)# • Some can produce local anaesthetic effects → due to blockage voltage gated sodium channels in excitable membranes # • Demihydrinate:# • Used as a sleeping pill (sedation makes falling asleep easier)# • Used to treat motion sickness → blocks H1 receptors in vestibular apparatus • One of the drugs with the strongest anti-muscuranic effect (causes the deepest sedation)# • Can be used in pregnant women to treat morning sickness

2nd generation H1 blockers • Pharmacokinetics second generation: #

- Inactive drugs when taken orally → rely on the liver metabolism to get activated → activated by cytochromes#

- Longer duration of action (up to 10 to 12 hours) → 2nd generation usually taken once a day

- Less lipid soluble compared to 1st generation ➔ 2nd generation drugs can’t cross blood-brain barrier (so no 2nd generation drug should be found in CNS)

- Excreted with the urine • 2nd generation drugs do not interact with muscarinic receptors!# • No sedation, no CNS excitation (specific for the 1st generation drugs) → Safe for people who need to drive • Adverse reactions:# • Cardiac toxicity → 2nd generation drugs might trigger ventricular arrhythmia • Tachycardia#

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H2 receptor antagonists

- Were used to treat stomach ulcers in the past, not anymore# - Mainly used to decrease the secretion of gastric acid# - They bind & block H2 receptors on the parietal cells and thus block the release of gastric acid

- This effect is not enough to treat peptic ulcers# - Work best during night time (histamine has strongest effect on gastric acid production during night) → efficacy the best during the night

- Adverse reactions: # - Not a lot of adverse reactions, pretty safe to use# - It is possible to have reactions like dizziness, headache, … (they penetrate blood-brain barrier)

- Tachycardia (rarely) → only possible if H2 antagonist was injected, can’t produce such severe effects when taken orally

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II. Local anesthetics Loss of sensation in limited region of the body, without the loss of consciousness • Effects: #

- Loss of sensation# - Muscle paralysis# - Suppression of reflexes# • The recovery of the local anaesthesia is usually spontaneous, it's predictable# • Without a lot of adverse effects, pretty safe

• 2 types of local anesthetics: esters and amides # • Chemical structure: 2 Parts → lipid soluble part (aromatic ring) + water-soluble part (easily ionised part)# • Aromatic ring bound to water-soluble part via ester or amide bond#

• Local anesthetics are capable of blocking all nerves • This might be a huge problem ➞ their actions aren't limited to loss of sensation of a painful stimulus ➞ usually there are some additional effects# • Unwanted effects: # • muscle paralysis → not only skeletal, smooth muscle paralysis is also possible# • Local anesthetics affects the CNS → breathing paralysis# • Autonomic nerve blockade → causes hypotension#

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• Use dependence / the difference in susceptibly of the nerve fibers to the local anesthetics# • Local anesthetics block smaller diameter fibers1 first (fast firing fibers)# • Larger fibers are blocked more slowly ➞ they require a higher dose of the local anesthetic to achieve the same effect as in the smaller diameter fibers # • Myelinated nerve fibers tend to be blocked much easier than unmyelinated fibers # • The more frequent the firing of the nerve fibre is, the more frequent the depolarisation of this finer will be ➞ the more affected by local anesthetics (pain fibers are frequent firing)#

• Local anesthetics prefer neutral or basic pH ➞ ionised in acidic pH

• Local anesthetics are weak bases ➞ so will be ionised (needed to enter the cell)#

• Sometimes vasoconstrictor is added to the local anestethic#

• All local anesthetics are vasodilators, except mepivacaine and cocaine 2

• Local anesthetics don’t block open sodium channels, they prolong inactive state of channels → making it impossible for another action potential to stimulate the channel

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Smaller diameter nerve fibers: mainly responsible for pain perception

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Mepivacaine & cocaine are vasoconstrictors

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Mechanism of action of local anesthetic

Whalen, K. (z.d.). Figure 13.12 Mechanism of local anesthetic action. [figure]. Retrieved from Lippincott Illustrated Reviews Pharmacology p. 174

• Local anaesthetic in solution → mainly in the form of a salt → ionised (a must for its solubility)

• Local anaesthetic should be non-ionised in tissues# • Non-ionised form is lipid-soluble → should be capable to penetrate the cell membrane • pH in organism 7.4 and pH in solution much lower → so local anaesthetic will be ionised

• Lipid soluble → Local anaesthetic travels from extracellular to intracellular compartment # • Ionised form of the local anesthetic is the one capable to bind the inactive form of the sodium channel

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Esters - Very easily inactivated → the reason why esters have shorter duration of action

- Are deactivated by plasma enzymes (plasma esterases) - Esters can produce allergic reactions → para-aminobenzoic acid released during enzymatic breakdown → acid causes hypersensitivity #

Cocaine ➔ not due to sodium channels • Significant CNS and cardiac toxicity blockade, but due to its interaction with the monoadrenergic transmission (cocaine increases the release of norepinephrine and dopamine) • Addiction potential (overdose danger) !

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⇾ explains decreased use today

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Amides - Longer duration of action → amides are not metabolised by any tissue enzymes, but in the liver

- Much better tolerated by the patient → Provoke less hypersensitivity reactions → amides do not release Para-Aminobenzoic Acid #

- Amides are preferred during epidural anaesthesia - Higher rate of non-ionised drug ➟ their penetration through membranes is much better than that of esters#

Lidocaine • Lidocaine is one of the most used local anesthetics nowadays, together with mepivacaine# • Lidocaine is the only drug also used outside local anaesthesia → also used for treatment tachycardia arrhythmia's • Only local anesthetic that can be used intravenously • Injected IV → Reaches the heart → reaches sodium channels → decrease phase zero (depolarisation phase) # • used in treatment of tachycardia arrhythmia's

Mepivacaine • Only amide that is a vasoconstrictor • Most simular CNS toxicity as cocaine# • Cardiac toxicity

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