Week 7-12 pharmocology

Week 7 Contraindications and drug interactions

• This week explores drug interactions, adverse drug reactions, and adverse drug events.

Contraindications

• A contraindication is a condition or factor that increases the risk associated with a particular drug, medical procedure, or activity.

• Two types of contraindications:

  • Absolute contraindication: Completely prohibits the use of a treatment.

  • Relative contraindication: Suggests caution; risks may outweigh benefits.

• Contraindications can be found in MIMS Online, Australian DI, Australian Medicines Handbook, or other medical/pharmacological databases.

• Example: Aspirin contraindications include hypersensitivity to salicylates, rare hereditary problems, and severe renal impairment.

Drug Interactions

• A drug interaction is a measurable modification in a drug’s action caused by another substance.

• Occurs when one drug’s effects are increased or decreased by another.

• Involves prescription and non-prescription drugs, food, alcohol, and smoking.

• Can be beneficial or adverse.

• Patients taking six or more drugs have a 60–80% chance of experiencing a drug interaction.

• The sicker the patient, the greater the risk.

• Particularly important for drugs with a low or narrow therapeutic index.

Figure 7.1 displays mechanisms of drug interactions:
* Pharmacokinetics: Altered drug concentration.
* Pharmacodynamics: Altered drug effects.
* Pharmaceutics: Altered drug properties.

Negative or Adverse Reactions

• Some drug combinations should never be given together.

• Example: NSAIDs should not be combined with ACE inhibitors and diuretics (used to treat high blood pressure).

  • This can lead to the 'triple whammy' effect, impairing blood pressure regulation.

• Narcotic analgesics (e.g., codeine) can interact with MAOIs.

  • MAOIs inhibit the enzyme monoamine oxidase, increasing monoamine levels in the brain.

  • Narcotic analgesics can decrease the metabolism of neurotransmitters, leading to altered drug concentrations.

  • Can also interact with CNS depressants, causing additive effects, potentially shutting down brain function.

Positive Reactions

• Some drug interactions are beneficial.

• Example: Probenecid (for gout) given with penicillin to prevent excretion, increasing penicillin levels for severe bacterial infections.

• Carbidopa and levodopa (for Parkinson’s disease):

  • Carbidopa inhibits the peripheral metabolism of levodopa, allowing more levodopa to reach the brain for therapeutic effect.

Drug and Food Interactions

• Can be pharmacokinetic or pharmacodynamic.

• Some drugs must be taken without food or before food, while certain foods should be avoided.

Limiting Drug Interactions

• Avoid certain drug combinations.

• Knowledge of pharmacology helps avoid adverse interactions.

• Space dosing over time to avoid simultaneous peak concentrations.

• Close monitoring in the laboratory or clinical setting.

• Improve patient education on drug interactions.

Adverse Drug Reactions

• An adverse drug reaction is 'a response to a medicine which is noxious and unintended, and which occurs at doses normally used in man’.

• Individual factors play a role, and the phenomenon is noxious.

Adverse Drug Event

• An adverse drug event is an injury resulting from medical intervention related to a drug.

• Includes overmedication, misuse/malfunction of infusion pumps, and errors in ordering, dispensing, or administration.

• Classified as adverse drug events (ADEs) rather than adverse drug reactions (ADRs).

Types of Adverse Drug Reactions

• Categorized into main types:

  • Type A: Augmented

  • Type B: Bizarre

  • Type C: Chronic

  • Type D: Delayed

  • Type E: End of use

  • Type F: Failure

Type A Reactions

• Most common; ‘A’ stands for augmented.

• Reactions are intrinsic or mechanistic, relating to the known pharmacology of the drug.

• An extension of the drug’s normal therapeutic effect, thus predictable.

• Dose-dependent, predictable, and often preventable.

• Generally, common and mild.

• Example: Warfarin increasing bleeding (anticoagulant effect), hypoglycaemia from insulin, hypertension from beta blockers, constipation from anxiolytics.

Type B Reactions

• Bizarre, not related to the drug’s pharmacology.

• Unrelated to the drug’s intrinsic actions, making them unpredictable.

• No relationship to dose or pharmacology.

• Smaller proportion of adverse drug reactions but associated with more severe effects and high morbidity/mortality rates.

• May have predisposing or risk factors like hypersensitivity, immunological, or allergic responses.

• Atopic individuals are especially predisposed.

• Example: Allergic reaction to penicillin (rash), topically administered drugs causing a rash, aspirin causing bronchoconstriction.

Type C Reactions

• Involve drugs used chronically.

• Dose-related and time-related, occurring due to long-term use.

• Chronic or continuous reactions.

• Include adaptive changes similar to tolerance or dependence with social drugs, leading to desensitization.

• Example: Tardive dyskinesia (movement disorder) from long-term use of neuroleptics or antipsychotics.

• Also involve rebound phenomena, such as rebound tachycardia after stopping beta blockers.

Type D Reactions

• Delayed effects, not noticed until long after stopping the drug.

• Examples: Irreversible infertility in a young cancer patient, carcinogens causing lymphoma or other cancers, teratogens.

• Thalidomide (used in the 1950s for morning sickness) caused phocomelia (missing limbs) in babies, a delayed effect noticed in newborns.

Type E Reactions

• End-of-use reactions related to withdrawal of a drug.

Type F Reactions

• Involve the failure or unexpected failure of therapy.

• Becoming increasingly common and associated with drug interactions.

Prevalence in the Community

• Adverse drug reactions significantly burden the healthcare system.

• One in ten patients visiting a GP has experienced an adverse drug event in the previous six months.

• ADRs affect over 1.5 million people per year, resulting in numerous hospital admissions.

• Important to prevent ADRs and ADEs.

Groups at Greater Risk

• Elderly

Elderly

• Polypharmacy (use of multiple medications) increases the risk of ADRs and drug interactions.

• 25–30% of the elderly take 6-10 medications daily.

• The elderly consume a high proportion of prescribed and over-the-counter drugs.

• Take three times more drugs than younger people and are admitted to hospitals with ADRs more frequently.

• 70-80% of ADRs in the elderly are dose-related and preventable.

Pharmacokinetic Changes of Ageing

Aging affects the liver, fat tissue, renal blood flow and gastric emptying, all of which influence drug processing.
* Absorption: Slower gastric emptying can affect drug absorption.
* Distribution: Increased fat tissue can lead to toxicity of fat-soluble drugs (e.g., benzodiazepines).
* Metabolism: Decreased hepatic blood flow can increase the half-life of drugs (e.g., beta blockers).
* Excretion: Decreased renal blood flow affects drug clearance, leading to drug accumulation and toxicity.

• The elderly are often prescribed drugs with a low therapeutic index, increasing the risk of ADRs.

• Prescribing medications to the elderly should follow the principle of 'start low, go slow'.

Practical Points for Prescribing Medications

• Adopt non-pharmacological approaches (e.g., dietary or lifestyle modifications).

• Review medications frequently.

• Avoid polypharmacy where possible and opt for the simplest drug regimen.

• Discontinue unnecessary drugs.

• Consider new symptoms as potential adverse drug reactions.

• Choose drugs carefully within a drug class.

• Use the lowest effective dose.

• Provide simple written and verbal instructions to improve compliance.

Other Groups at Greater Risk

• Children and infants:

  • More sensitive to ADRs, especially drugs acting on the central nervous system.

  • Immature hepatic enzymes and renal clearance mechanisms can lead to drug accumulation and toxicity.

• Women:

  • Twice as likely to experience ADRs compared to men, possibly due to taking more medications and seeking treatment more often.

  • Women tend to outlive men, making up a significant part of the elderly population.

  • Pregnancy makes women susceptible to teratogens.

• Those with pre-existing liver and kidney disease.

• Individuals with a predisposition to allergies (Type B reactions).

• Those on drugs with a low therapeutic index, high doses, or long-term medication.

Causes and Prevention of Adverse Drug Reactions

• Causes are varied; some preventable, others unpredictable.

• Unpredictable ADRs should be monitored and reported.

• A large proportion, especially ADEs, are preventable.

• Reducing the number of drugs taken concurrently decreases ADRs and drug interactions.

• ADEs often involve prescribing, dispensing, and administration errors.

• Most ADRs result from system problems, not people problems.

• Medication errors can lead to fatal ADEs, so minimizing these errors is crucial.

Prevention Tips

• Use drugs only when necessary.

• Use as few drugs as possible.

• Use the lowest effective doses.

• Check patient family history for sensitivities and allergies.

• Exercise caution with drugs in groups most at risk.

• Monitor drug therapy for likely ADRs.

• Ensure new drugs have been well-tested and widely used before starting them.

• Prevention involves better communication systems and simplifying procedures.

• Changes in labelling or packaging can prevent ADEs.

Monitoring of Adverse Drug Reactions or Effects

• The Therapeutic Goods Administration (TGA) requests reports of all suspected reactions to new medicines or multiple medications interacting adversely.

• They want to know about any unexpected reactions not generally described in product information.

• Reactions causing death, hospital admission, prolonged stay, increased investigations/treatment, or birth defects should be reported.

• Reporting can be done online, and the TGA takes these reports very seriously; enough reports can lead to a medicine being taken off the market.

Quality Use of Medicines (QUM)

• Involves rational prescribing based on the best available evidence to improve health outcomes.

Selecting Management Options

• Treatment duration: acute vs. chronic conditions affect medication choice.

• Weigh the risks and benefits compared to other treatments.

• Consider the cost of the drug relative to others.

• Health documents like the National Medicines Policy provide in-depth guidance.

How to Use the Medicines

• Ensure medicines are used safely and effectively.

• Monitoring outcomes: assess effectiveness, identify adverse effects, and minimize misuse, overuse, and underuse.

• Choose the correct dosage and ensure patients use the drug as intended.

• Provide clear information to patients about how to use their medicines.

• Maintain accurate medical records and access up-to-date, independent information.

Practicing Evidence-Based Medicine (EBM)

• Use the best available evidence to make optimal decisions for treating patients.

Levels of Evidence

• The National Health and Medical Research Council (NHMRC) guides the classification of evidence strength.

• Strongest evidence: systematic reviews of randomized controlled trials (RCTs).

• Controlled studies (potentially involving thousands of patients) provide very strong evidence.

• A single clinical trial offers good evidence.

• Individual experiments or case studies do not provide strong evidence.

• EBM relies on extensive data and high-quality information from numerous well-controlled studies.

Outcomes

• Improve compliance with prescribed therapy by providing good information.

• Reduce ADRs and drug interactions by anticipating potential issues.

• Improve treatment outcomes and symptom control.

• Avoid hospital admissions or reduce length of stay.

• Avoid unnecessary clinical procedures.

• Save money (individual and healthcare system).

Factors Influencing Drug Dose

• Drug dosing (dose and frequency) can vary between patients.

Rational Use of Drugs

• A particular concentration of a drug will have the desired therapeutic effect with minimal adverse effects.

• Aim to achieve a relatively constant or steady-state plasma concentration of the drug that maintains the desired response.

• Keep the drug within a margin of safety (therapeutic index).

• Achieving steady-state involves considering the dose size and dosing frequency (dosing regimen).

• Example: Coversyl (for hypertension) is available in different doses; adjust the dose size and frequency to achieve the desired therapeutic effect.

Compliance and Drug Action

• Compliance means following all aspects of the treatment plan.

• Involves taking the right dose of the drug, at the right time, and for the correct duration of treatment.

• Crucial for the effectiveness of the treatment.

• Challenging for patients taking multiple drugs with different dosage schedules.

Causes of Non-Compliance

• Doctors often cannot predict which patients will adhere to their treatment plans.

• Patients may not be honest about taking medication as prescribed.

• Consequences include under-dosing, overdosing, and toxicity.

• The more complicated a treatment plan is, the more difficult it is to achieve good compliance.

Factors Influencing Drug Action

• Genetic factors:

  • Different forms of enzymes that metabolize a drug.

  • Variations in the drug target protein.

• Body composition:

  • Body weight, muscle mass, and fat composition influence drug action.

  • Obese patients may require a higher dose of general anaesthetic and take longer to recover.

• Smoking:

  • Alters enzyme levels and causes interactions with many other drugs.

• Bioavailability:

  • How a drug enters the body and reaches the bloodstream affects its action.

  • Drug formulation and whether it’s consumed with or without food.

• Pregnancy:

  • Higher blood volume and different body composition can affect drug action.

• Age:

  • Elderly people often have lower kidney and liver function, resulting in slower metabolism and excretion of drugs.

• Oral administration:

  • Hypermotility of the gastrointestinal tract can affect drug absorption.

• Drug response:

  • Idiosyncratic reactions are unpredictable responses to a drug.

• Repeated use:

  • Desensitization, tachyphylaxis, and tolerance.

• Drug interactions:

  • One drug affects the concentration or action of another.

• Health of a patient:

  • Cardiovascular, renal, and liver diseases can alter drug distribution, excretion, and metabolism.

Smoking and Drug Interactions

• Smoking induces cytochrome P450 enzymes CYP1A2 and CYP2B6.

Drugs Affecting the Enzyme CYP1A2

• Antidepressants (amitriptyline, clomipramine, mirtazapine)

• Antipsychotics (clozapine, haloperidol, olanzapine)

• Others (paracetamol, caffeine, estradiol, propranolol, warfarin, naproxen [NSAID], fluvoxamine [SSRI])

  • Inhibitors: St. John's Wort, grapefruit juice

Drugs Affecting the Enzyme CYP2B6

• Antidepressants (bupropion, selegeline)

• Others (meperidine, methadone, ketamine, propofol, valproic acid)

  • Inhibitor: fluoxetine (SSRI)

• Results in faster clearance of drugs metabolised by these enzymes (shorter half-life, lower serum concentrations).

• Smokers might need to consume four times more caffeine than non-smokers to achieve the same serum concentrations!

• If a patient stops smoking, CYP levels decrease, slowing down drug metabolism (longer half-life, higher serum concentrations). Therefore, drug doses need to be adjusted to prevent toxicity.

Somatic

• Somatic conscious control involves a single neuron running from the CNS to the effector organ.

  • The neurotransmitter acetylcholine (ACh) binds to nicotinic receptors (N).

Sympathetic

• The sympathetic and parasympathetic pathways involve two neurons running from the CNS to an autonomic ganglion and then a second neuron that runs directly to the effector organ.

  • Sympathetic pathways involve short preganglionic neurons but long postganglionic neurons.

    • The main neurotransmitter that causes an effect is noradrenaline, binding to alpha and beta adrenoreceptors.

Parasympathetic

• The parasympathetic pathway has an opposite structure from the sympathetic pathway, where you have a long preganglionic neuron and a shorter postganglionic one.

What is happening at the synapse?

• During neurotransmission (see Figure 8.3), precursor molecules (e.g. choline, DOPA) are transported into the presynaptic neuron, where they are converted into active neurotransmitters (e.g. ACh, noradrenaline, dopamine).

  • These neurotransmitters are then packaged into synaptic vesicles.

Sympathetic vs parasympathetic

• The parasympathetic nervous system slows the body down, aiding in digestion and secretions.

Other neurotransmitters

• There are other neurotransmitters in the autonomic nervous system that are non-adrenergic, non-cholinergic (NANC).

  • vasoactive intestinal polypeptide (VIP), which facilitates bronchodilator

  • nitric oxide (NO), a major neurotransmitter of the cardiovascular system that facilitates vasodilation and also promotes gastric emptying

  • neuropeptide Y, which enhances vasoconstriction

  • adenosine triphosphate (ATP)

  • 5-hydroxytryptamine (5-HT), also known as serotonin

  • γ-aminobutyric acid (GABA).

Cholinergic neurotransmission

• We will focus on the parasympathetic arm of the autonomic nervous system, specifically on cholinergic neurotransmission and the drugs that target this system.

Where does cholinergic neurotransmission occur?

• Cholinergic transmission occurs at the somatic neurons and the ganglion, where ACh binds to nicotinic receptors.

• in the parasympathetic nervous system, cholinergic transmission also occurs at the effector organ, where ACh binds to muscarinic receptors.

Steps in cholinergic neurotransmission

• synthesis, storage, release, receptor activation and inactivation.

Cholinergic receptors

• acetylcholine binds to nicotinic receptors and muscarinic receptors.

  • acetylcholine binds to nicotinic receptors, which are located at the neuromuscular junction or autonomic ganglia.

    • These are fast-acting ligand-gated ion channel receptors.

    • acetylcholine binds to muscarinic receptors, which are G protein-coupled receptors.

      • In different organs, including:

        • M1 receptors: Neural (act through the inositol triphosphate IP3 pathway, regulates calcium)

        • M2 receptors: Cardiac (inhibit adenylate cyclase, decreasing cyclic adenosine monophosphate or cAMP)

        • M3 receptors: Glandular (sweat glands are the only sympathetic cholinergic).

Drugs affecting cholinergic neurotransmission: Muscarinic

• muscarinic agonists, muscarinic antagonists, drugs affecting the autonomic ganglia, drugs affecting neuromuscular transmission and drugs that inhibit and enhance ACh.

Muscarinic agonists

• Muscarinic agonists are also known as parasympathomimetic because their action mimics parasympathetic nervous stimulation, similar to the effects of acetylcholine

  • The main effects induced by muscarinic agonists are related to parasympathetic stimulation, and the 'rest and digest' pathways.

  • The side effects of these drugs are associated with the overstimulation of the parasympathetic nervous system.

Mechanism of action

Clinical uses for muscarinic agonists

• Opthalmic

  • Constrict pupils (miosis)

  • Reverse mydriasis and treat glaucoma

• Gastrointestinal

  • Stimulate gastrointestinal motility (such as in impaired peristaltic activity)

• Bladder emptying

  • Treatment for postoperative or postpartum, non-obstructive urinary retention

Side effects for using muscarinic agonists

• abdominal pain and upset, nausea and vomiting, increased salivation and sweating, and blurred or disturbed vision

Muscarinic antagonists

• Muscarinic antagonists are parasympatholytic or anticholinergic because they block the effects of parasympathetic activity.

  • atropine, a muscarinic receptor antagonist.

    • Atropine, derived from the belladonna plant, prevents acetylcholine from binding to muscarinic receptors.

• The effects of muscarinic antagonists essentially block the parasympathetic response

Clinical uses for muscarinic antagonists

• bronchodilation in asthma treatment.

• side effects of these drugs are also the opposite of cholinergic activity and may include dryness of the mouth, impaired vision and urinary retention.

Other drugs affecting cholinergic neurotransmission

Drugs affecting the autonomic ganglia

• the receptors at the ganglion are nicotinic receptors where acetylcholine can bind.

• These are called ganglion stimulants, and an example of that is nicotine

• ganglion-blocking agents are used clinically.

  • act to block the actions of ACh at the ganglia by competing with the ACh at the synapse, or directly block nicotinic receptors, interfering with acetylcholine release or prolonged depolarisation.

Drugs affecting neuromuscular transmission

• acetylcholine can also bind to nicotinic receptors at the neuromuscular junction, leading to smooth muscle contraction

  • non-depolarising blocking agents

  • Depolarising blocking agents

Drugs affecting ACh release

Inhibit ACh transmission

• block the release of ACh from the sympathetic presynaptic terminal.

  • act by preventing calcium entry, which halts ACh release and neurotransmission

  • neurotoxins in snake venom (β-bungarotoxin) and Botox (botulinum toxin), leading to reduced neurotransmission and smooth muscle relaxation.

    • Botox has been used to treat blepharospasm (involuntary blinking) and strabismus (squint in the eye)

      • in cosmetic surgery to relax facial muscles and reduce wrinkles.

Enhance ACh transmission

• inactivation of cholinergic transmission requires acetylcholinesterase, which breaks down acetylcholine in the synaptic cleft.

  • Anticholinesterase are used to enhance acetylcholine activity for skeletal muscle weakness

    • (the drug neostigmine is used for myasthenia gravis, which is characterised by the loss or decrease in ACh nicotinic receptors).

  • used in biowarfare and as pesticides (organophosphates).

Anticholinesterase poisoning

• Anticholinesterase poisoning occurs due to the inhibition of acetylcholinesterase (AChE), which increases ACh levels.

• symptoms of anticholinesterase poisoning reflect parasympathetic overactivity and include classical signs like increased secretions, such as sweating or salivation.

  • slow the heart down or cause respiratory failure.

Adrenergic neurotransmission

• Where does adrenergic neurotransmission occur?

  • Adrenergic neurotransmission occurs only at the effector organ, where noradrenaline binds to alpha and beta adrenoreceptors.

    • main neurotransmitter responsible for the effector organs in adrenergic transmission is the catecholamine noradrenaline

Steps in noradrenergic neurotransmission

synthesis, storage, release, receptor activation and inactivation.

Drugs affecting adrenergic neurotransmission

Adrenoceptor agonists

• known as sympathomimetics

  • noradrenaline, adrenaline and dopamine endogenously.

  • Actions resemble sympathetic nerve stimulation The sympathetic arm of the ANS is involved in the fight-or-flight response.

    • lowers awareness and physical output but also reduces less critical processes, including decreases in gastrointestinal activity.

      • It may not be easy to remember all the functions of each receptor at each organ.
        Still, some are easy to remember, such as the β1 adrenoceptor, which is almost solely expressed in the heart and increases heart rate or contractility.

      • he α1 adrenoceptors are located on smooth muscles, blood vessels, the gastrointestinal tract and the pupils.

      • β2 adrenoceptors are also located on smooth muscle, but they actually cause the opposite effect as they can cause relaxation.

Clinical uses for adrenoceptor agonists

• α1 agonists

  • act as decongestants by causing nasal vasoconstriction.

  • used in emergency situations of hypotension, where large reductions in blood pressure occur, to cause vasoconstriction and increase the patient’s blood pressure.

• α2 agonists

  • clonidine, can be used to treat hypertension by acting as a negative feedback receptor to further inhibit the release of noradrenaline.

• β1 agonists

  • dobutamine, can be used in emergency situations such as cardiac arrest and hypotension to increase cardiac contractility.

• β2 agonists

  • salbutamol, are mainly used in asthma by causing bronchodilation.

• β3 agonists

  • currently not used in the clinical setting, but some agents are being developed for the control of obesity.

Adrenoceptor antagonists

• Adrenoceptor antagonists can vary in selectivity for different adrenoceptor subtypes.

  • block the action of sympathetic nerve activity, but the specific action that is blocked depends largely on the receptor subtype.

    • antagonists that block the various receptors, which will have different effects depending on the targeted receptor.

linical uses of adrenoceptor antagonists

• used clinically to control blood pressure or target the cardiovascular system. act to block the constriction of the sympathetic nervous system

  • non-selective alpha antagonists

    • treat hypertension.

      • not very effective because they block not only the α1 adrenoceptor but also inhibit the α2 effects.

        • α2 receptor is part of the negative feedback loop.

          • Inhibiting this receptor removes the negative feedback, increasing the amount of noradrenaline release (non-selective α1 and α2 antagonists, which target both receptors, are probably not very effective in treating hypertension).

  • Beta-adrenergic antagonists

    • β1antagonists are again cardioselective and can be used to treat hypertension or to slow the heart.

    • Non-selective beta-blockers

      • propranolol, are mainly used to treat cardiovascular diseases such as hypertension, heart failure or arrhythmias.

        • Non-selective beta blockers, such as propranolol, are contraindicated in people with asthma due to their non-selective nature

Drugs that affect noradrenaline release and uptake

What are neurotransmitters?

• Neurons are highly specialised cells in the body that communicate via neurotransmission at synapses.

  • An action potential travels down an axon to the synapse, where the electrical signal is converted into a chemical signal.

• Neurotransmitters, which are specialised signalling molecules, transmit information from one neuron to another cell via the synapse.

• The neurotransmitters remain within the synapse until they are somehow removed.

Stages in neurotransmission

• Neurotransmission is a complex process that allows neurons to communicate with each other.

  • either an enzyme or a transporter (depending on the neurotransmitter) deactivates the signal, removing the neurotransmitter from the synapse. Potential sites for drug action

    • Drugs that affect brain function somehow modify the processes
      We will use the neurotransmitter GABA as an example of how different drugs can modify the different aspects of neurotransmission.

Drug action site

• We can interfere with increasing or decreasing the neurotransmitter molecules

  • inhibiting the GAD will decrease the availability of GABA, reducing its availability released from a neuron and act at its receptors.

• Transmitter storage

  • modify how much neurotransmitter is available for release into the synapse when an action potential arrives.

• Transmitter Release

  • modifying the presynaptic neuron to decrease the sensitivity to action potentials

• Action at receptors

  • modifiers and antagnoists

• Transmitter Reuptake

  • Removing the neurotransmitter from the synapse is essential to how neurotransmitters work. If we decrease the activity of transporters that normally remove the neurotransmitter from the synapse, result in greater activation of the receptors

• Transmitter Degradation

  • enzyme inhibitors would slow down this removal and result in increased activation of the neurotransmitter's receptors.

Neurotransmitter receptors

• Fast neurotransmission

  • ligand-gated ion channels

• slower transmissions

  • G protein-coupled receptors,

Catecholamines

• The first group group of neurotransmitters include dopamine , noradrenaline and adrenaline

  • are derived are formed through successive enzymatic steps from tyrosine, which is present in the diet, neurons contain tyrosine

• Altering catecholamine action

  • the primary mechanism of inactivation is reuptake into the presynaptic terminal by specific transporters.

    • breakdown of neurotransmitters

      • monoamine oxidase (MAOA, MAOB, intracellularly) and catechol O-methyl transferase (COMT, membrane-bound or intracellularly).

Examples of catecholamines

• Dopamine and its receptors

Receptors are G protein-coupled.

• Involved in many functions, but mostly clinically in Parkinson's disease or to address psychiatric effects in disorders such as schizophrenia
  *key functions
  *
  * Behaviour
  * Cognition, working memory, learning
  * Voluntary movement
  * Motivation
  * Mood
  * Punishment / reward
  * Lactation
  * Sleep and attention

• Noradrenaline / adrenaline and their receptors

Receptors for noradrenaline and adrenaline are called alpha and beta adrenoreceptors, are all G protein-coupled receptors.
key function
*
*
* Attention
* Sleep-wake cycle
* Fight-or-flight response
* Fear and anxiety
* Blood pressure
* Memory

• Serotonin (5-HT) and its receptors

7 types of 5-HT receptors, most are G protein-coupled.

• Some effects such as nausea and vomiting, and migraine,antagonists at these receptors can be useful in treating these conditions
  key function
  *
  *
  * Mood
  * Anxiety
  * Arousal
  * Sensory processing
  * Emotion

• SSRIs target the effect of serotonin by inhibiting the transporter that
  removes serotonin from the synapse, these drugs allow serotonin to produce moreactivation of its receptors, which can improve symptoms of depression and anxiety

Amino acid neurotransmitters

• GABA and its receptors

GABA -the brain's major inhibitory neurotransmitter

precursors come from the cellular metabolic pool associated in the Krebs cycle and TCA cycle

*Activativation of GABA receptors reduce neuronal excitability
*GABA-A receptors are ligand-gated ion channels with binding sites for barbiturates and benzodiazepines, which potentiate GABA binding. The binding of these substances affects consciousness and wakefulness.
GABA-B receptors are G protein-coupled receptors
key function
*
*
* Anxiety
* Consciousness
* Muscle tone

• L-Glutamate (Glu) and its receptors receptors

Glutamate (Glu) is an excitatory neurotransmitter.

*Functionally Glumate is balance with the inhibitory actions of GABA in the brain
*Excessive Glutamate Receptors can cause neurons to die.excitotoxicity in Parkinson's disease Huntington's chorea and motor neuron disease
key function
*
*
* Learning and memory
* Cognition
* Pain
* Nociception

Neuropeptides

• very short sequences of amino acids

  • synthesised in the neuronal cell body, not at the terminal

  • inactivated enzymatically, being broken down by enzymes called proteases, so there is no reuptake, and they are not transported back into neurons.

Addiction: An overview

Drugs of abuse

• These include opioids ,CNS depressants, psychomotor stimulants, psychomimetic agents
  Pharmaceutical misuse in Australia

*It has been a massive issue in the US, It’s not just illicit drugs that are a problem;
*prescribed drugs can also lead to addictionthe Most common for pain treatment such as opioids, including oxycodone and CNS depressants such as such as benzodiazepines
There are many reason why people engage in using drug

• Risk factors
  Drugs often start early do to brain development in teens when the prefrontal cortex is still developing making decision making
  Overall, risk factors in addiction are interplay between biology genetics and environment*

Factors:

• Biology/Genes
  *
  * Genetics
  * Gender
  * Mental disorders

• Drug
  *
  * Route of administration
  * Effect of the drug itself

• Environment
  *
  * Chaotic home/abuse
  * Parents’ use and attitude
  * Peer influence
  * Community attitudes
  * Poor school achievements
  In terms of gender, males are more likely than females to take high-dependence drugs
  Route of administration and drug's effectiveness in initial reinforcing effects changes in the neurochemical networks the addiction*

The mechanisms of addiction

Definitions and terminologies

• Dependence
  Psychological is strong urge to take the drug (lifelong event)
  Physical
  *
  * tissue and receptor responses shift from basal physiological function
  * Reversible
  * Withdrawal symdrome(Acute)

• Tolerance (decrease of effedt of drug with repeated administration, due to increased metabolism, decreased sensitivity of receptors
  Sensitisation (There is an increase in drug's effect after administration with locomotor effects)

• Reinforcement
  *
  * positive: reinforcement to experience a desirable stimulus
  * negative: reinforcement to remove an undesirable (e.g. a painful or distressing) stimulus

• Conditioning is where cues cause relapse
  Addiction( compusive drig use, bad outcome) driven by neurochemical ,molecular changes in the brain
  It is importanat to note
  Why do drugs make you feel good(drugs release feel good neurotransmitters)
  *Releases feel good neurotransmitters called Dopamine

Addiction is a brain disease is the dopomeine receptor pathways that go from the ventral tegmental area (VTA) to an area called nucleus accumbens (causes euphoria)
*GLUTAMATERGIC Pathways is also Excitiotory effects *limbic system takes over the over from the prefrontal cortex which leads drug use *
Positive Plasticity*Changes can reverse

*** Cues and relapse