Which different groups of hallucinogenic drugs are known?

Classic hallucinogens (LSD)

Dissociative drugs (PCP)

Name a few typical effects of the hallucinogenic drugs and discuss the clinical profile of a patient who had taken them.

Psychosis, lack of judgment which leads to reckless behavior and sensory distortion which is mainly visual.

Patients experience a completely different reality which is due to the hallucinogens psychedelic effects.

Somatic effects include nausea, weakness and paresthesia. Panic reactions are also prone to occur. 

Someone who has taken hallucinogens will present with; 

Tachycardia, hypertension, and hyperthermia. 

Sympathomimetic effects include mydriasis, sweating, ataxia, and vomiting. 

A mental status examination must be done to determine the affect on speech, appearance, presence of auditory/visual hallucinations, delusional thinking, and suicidal/homicidal ideation should be carefully assessed.

Although nystagmus in any direction can occur with PCP use, rotatory nystagmus is a classic sign.

How is an over-dose of LSD dealt with? 

Benzodiazepines (phenobarbital,diazepam) are given to calm them, reduce agitation and normalize the operation of the CNS. 

Anti-epileptics are administered for convulsions. 

Chlorpromazine is given to eliminate the hallucinogen and to bring back consciousness.

For vomiting, and antiemetic, metoclopramide can be given. 

Other sources explain the treatment to be;

• Ergotism therapy: IV administration of anticoagulants, vasodilators and sympatholytics could be useful. 
• Rehabilitation and supportive care (respiratory support)

How is an over-dose of anticholinergic drugs dealt with?

Reversible ACh inhibitor: physostigmine.

Benzodiazepine can also be given. 

Classification of the anti-depressants;  

• Tricyclic antidepressants (TAD)

Secondary Amines	Tertiary Amines
NA selective	5-HT selective (alphalytic and many anti-cholinergic SE thus CI in elderly with prostate hypertrophy)
Nortriptyline	Amitriptyline (Rx for chronic pain)
Desimipramine	Imipramine (Rx for enuresis, acute panic, phobias)
Lofepramine	Trimipramine
Amoxapine	Chlorimipramine (Rx for OCD)
Maprotyline (dose related convulsions)	Dothiepine
	Butriptyline

• Monoamine oxidase inhibitors (MAOI)
  • Tranylcypromine (non-selective, reversible blocking, long blackade)
  • Maclobemide (A selective, reversible blocking)
  • Selegiline & Rasagiline (B selective)
• Selective serotonin re-uptake inhibitors (SSRI)
  • Fluoxetine (Effects glucose levels, Rx for OCD, can immediately be given at a high dose)
  • Paroxetine (Short t_1/2, few CV SE, severe withdrawal reaction is seen, Rx for PTSD)
  • Fluvoxamine (Rx for OCD)
  • Sertraline (Rx for OCD)
  • Citalopram 
  • Escitalopram  
• Serotonin, noradrenaline reuptake inhibitors (SNRI)
  • Duloxetine
  • Venlafaxine (Causes hypertension as a SE while all the others cause hypotension)
• Selective noradrenaline reuptake inhibitors (NARI)
  • Roboxetine (Not cardio toxic, no affinity for any NT receptors)
• Tetracyclic & Unicyclic anti-depressants 
  • Mianserin (Not used due to blood deviations)
  • Mirtazepine (No sexual dysfunction)
  • Bupropione (No sexual dysfunction, lower doses used as Rx for nicotine withdrawal, decreases convulsion threshold)
• Serotonin receptor modulators 
  • Trazodone (Off-label hypnotic)
  • Vortioxetine (MANY MoA’s)
  • Nafazodone (Hepatotoxicity)
• Circadian rhythm regulators 
  • Agomelatine 

What do the existing drugs all have in common regarding their mechanisms of action?

Anti-depressants increase NA and 5-HT at central synapses. This is done by;

Re-uptake inhibition, Degradation inhibition and by blocking presynaptic a2 autoreceptors. 

How long does it take for the anti-depressive effects of these drugs to appear? 

14-21 days since it takes two weeks or longer for the synthesis of neurotropic factors which are needed for neural plasticity, resilience and neurogenesis. 

How do the TADs and the selective serotonin reuptake inhibitors (SSRI’s) differ in respect of;

• • Efficacy

Almost all the anti-depressants have the same efficacy and the drug choice depends on patient response. One factors is that TAD are titrated upwards until the MEC is reached which SSRI can immediately be given as full dosages. 

• • Side Effects

TAD = Weights gain, convulsions, sedation, tremors, insomnia, anticholinergic effects, orthostatic hypotension, dysrhythmias, tachycardia, psychosis, precipitation of mania, sexual dysfunction.

SSRI = GI side effects, headaches, EPS like twitches and muscle cramps, insomnia, tremors, decreased libido, sexual dysfunction, anxiety, withdrawal symptoms, CNS stimulating effects like agitation, anxiety and jitters. 

• • Safety

SSRIs are the preferred Ads along with newer drugs because they have a better side-effect profile, safer in acute overdose and SSRI’s can suppress appetite, overweight patients may lose weight.

TAD have cardiovascular side effects (orthostatic hypotension, dysrhythmias, tachycardia) which make them riskier in people with already existing cardiovascular conditions. 

What is the action of mirtazepine?

Mirtazapine is a NA and specific 5-HT anti-depressant. It also blocks H₁(sedation, weight gain) and a₁(postural hypotension) receptors. There is further blockade of the a₂ receptors which then advances NA (auto) and 5-HT (hetero) release. There is indirect stimulation of 5-HT_1Awhich gives mirtazepine anxiolytic properties. Lastly there is blockade of 5-HT₃ (anxiolytic and antiemetic) and 5-HT₂ receptors. 

What is the action of venlafaxine?

Venlafaxine is a serotonin and noradrenaline reuptake inhibitor. But 5-HT is blocked more potently. 

What is the action of agomelatine?

Agomelatine is a MT₁and an MT₂ agonist (this is why it promotes and benefits sleep). It is also a 5-HT_2Cantagonist (this is why it benefits the anti-depression action and also leads to disinhibition of DA and NA release). 

1. How does the sensitivity for blockade by a LA compare regarding the following types of fibers?

1. myelinated fibers with unmyelinated fibers 

Smaller and myelinated fibers are blocked more easily than when compared to larger and unmyelinated fibers. 

2. pressure/touch nerves with the dorsal nerves that transmit pain impulses?

Activated pain fibers fire faster (activated Na channel has the highest affinity for LA). Fibers in the middle of a thick nerve bundle are blocked slower than those fibers on the outside of the bundle. 

2. Make a list of the effects of LA on other tissues.

Heart; class 1 anti-arrythmic drugs (lidocaine blocks Na channels in the heart tissue causing anti-dysrhythmic effects)

Skeletal muscle; weak blocking action (thus no clinical application)

3. What is the basis for the selection of a LA?

The selection depends on the desired effect and the type of procedure which is going to be performed. It is also dependent on the duration of the procedure as well as the numbing effect required in the specific tissue. 

4. Why are LA solutions sometimes saturated with CO₂?

CO₂acts as a buffer for the LA and potentiates its effects. Furthermore, inhalation anesthetics can produce carbon monoxide (CO). CO binds to hemoglobin with high affinity, reducing oxygen delivery to tissues. CO production can be avoided by using fresh carbon dioxide absorbent and by preventing its complete desiccation.

5. Which of the LA are typically used for surface anesthesia?

Benzocaine (temporary pain relief in throat lozenges), Cocaine (ear, nose and eye surgery), Oxybuprocaine (opthamology)

1. Compile a table, listing the major effects on every system (cardiovascular, CNS, renal, hepatic and uterus) for all the inhalation anesthetics. This table is important when it comes to the selection of drugs in certain individuals.

TABLE 1 

	Halothane	Enflurane	Isoflurane
CVS	Decreased BP, decreased heart rate (bradycardia) Arrhythmias may be precipitated due to sensitization of the myocardium to the effects of catecholamines.	No sensitization of the myocardium. Causes less suppression than halothane.	Less suppression than halothane & enflurane. No sensitization of the myocardium.
CNS	Fast SM induction without Stadium II. Increased cerebral blood flow & increased intracranial pressure (so be careful in pts with head injuries). Repeated exposure increases the risk for liver damage (allow 3mnths between exposures).	Fast SM induction. May cause convulsions thus not used in pts with epilepsy.	Faster induction & recovery than halothane.
RENAL	Reduce glomerular filtration rate and urine output. Contraindicated in pts with renal impairment.	Reduce glomerular filtration rate and urine output. Contraindicated in pts with renal impairment.	Reduce glomerular filtration rate and urine output. Contraindicated in pts with renal impairment.
HEPAT	The extent of metabolism is 20-25%. Although rare, hepatotoxicity can occur since the drug is metabolized in the liver (so be careful in pts with liver problems)	Only 2-5% is metabolized by the liver.
UTER	Decreased muscle contraction, it is also used to promote external twisting if the baby is lying incorrectly		Widely used in caesarean sections.
RESP	No irritations (saliva, bronchial secretions, coughing)	More depression than halothane.	Potent depressing effect due to potent skeletal muscle relaxing effects (so be careful in pts with asthma).
USE	Not often used because of hepatotoxicity. The newer drugs are safer & rather used.	Not often used. Used in maintenance of anesthesia.	More ideal than halothane & Enflurane. Widely used but not for patients who have to breath spontaneously.

TABLE 1 CONTINED 

	Desflurane	Sevoflurane	Nitrous Oxide
CVS	Less suppression than halothane and enflurane.	Similar effects to desflurane.	No effect.
CNS	Even faster induction & recovery than isoflurane. Increased cerebral blood flow & intracranial pressure.	Similar effects to desflurane.	Weak anesthetic, potent analgesic & may cause amnesia as a side effect.
RENAL	Reduce glomerular filtration rate and urine output. Contraindicated in pts with renal impairment.	Reduce glomerular filtration rate and urine output. Contraindicated in pts with renal impairment.	Reduce glomerular filtration rate and urine output. Contraindicated in pts with renal impairment.
HEPAT	Undergoes liver metabolism & chemically unstable (be careful in pts with reduced/ compromised liver function)	Undergoes liver metabolism so must be used with caution in pts with liver problems.
UTER	Not recommended for obstetric operations.	Can be used in caesarean sections.
RESP	Strong smell which irritates airways. Can’t be used as induction drug since it causes coughing, shortness of breath, laryngospasm.	Less irritation of the airways.	Pure N2O will lead to hypoxia so it must be mixed with O2or air.
USE	More ideal than isoflurane & sevoflurane. Can be used for various surgical procedures.	Used for induction & maintenance.	Used as additive drug in anesthesia or as single drug for short dental procedures.

2. Name the major acute toxic effects of the inhalation drugs.
   Nephrotoxicity, Hematoxicity, Malignant hypernatremia and Hepatotoxicity

Anxiolytic 

1. Theanine – amino acid found in green tea and it produces a calming effect on the brain. It crosses the BBB and increased the production of GABA and dopamine.  
2. St. Johns wort (Hypericum perforatum) – works by increasing brain levels of serotonin. 
3. Ginkgo biloba – activates GABA pathways and acts as a Benzodiazepine and can thus reduce anxiety. 
4. Ashwagandha (Withania somnifera) – falls into a group of herbs called adaptogens which regulate a person’s stress response. Although it has an anxiolytic effect it also causes improved quality of sleep. It can be taken as a tablet or in a liquid tincture form. 
5. Galphima glauca – tranquilizer to reduce anxiety. 
6. Cannabidiol – one of the active ingredients of the cannabis plant which has been found to have calming effects on the central nervous system. 
7. Blue Skullcap (Scutellaria Laterifolia) – tasty flower in the mint family which helps to boost mood and reduce anxiety. 
8. Hops (Humulus lupulus) – one of the herbs commonly blended in teas or supplements to produce a calming effect. It is believed that the effect it achieved due to hops binding to serotonin and melatonin receptors. 

Insomnia 

1. Prunus serotina – moderate sedative effect. 
2. Lavender essential oil – lavender is a flowering plant belonging to the mint family. The oil contains chemicals known as terpenes (linalool & linalyl acetate) which have been found to have calming affects on chemical receptors in the brain. 
3. Passionflower (Passiflora Incarnata) – treating restlessness, nervousness and anxiety. It works by increasing GABA levels and naturally lowers brain activity. 
4. Chamomile – flowering herb which almost looks like a daisy. There are 2 types (Roman and German chamomile) which can be used medicinally. It can be used as a tea, extract, tablet or even skin cream. It should be noted that chamomile may react with some blood thinners (warfarin).
5. Lemon Balm (Melissa officinalis) – is antiviral, stomach calming and helps to treat sleep disorders caused by nervousness and tension. 
6. Valerian (Valeriana officinalis) – the root has been used for many years to manage insomnia, anxiety and depression. It works against anxiety and is also sleep inducing. It helps with the onset of sleep and with sleep maintenance. It produces it's effects by naturally increasing GABA levels in the body and decreasing synaptic GABA re-uptake. It is available as a tea, tablet or tincture. Not safe in small children or during pregnancy!!
7. Spices including nutmeg, turmeric and garlic have been shown to promote sleep. 

BEFORE TAKING ANY ALTERNATIVE MEDICINE, CONSULT WITH YOUR DOCTOR OR HEALTH CARE PROVIDER. 

1. What factors may affect the absorption and distribution of sedative-hypnotic drugs? What is the clinical significance thereof?

Pharmacokinetics describes what the body does to a drug (Absorption, Distribution, Metabolism, Elimination). 

Lipophilicity is one of the many properties that influences absorption and distribution. With increased lipid solubility comes increased absorption and so the drug is able to reach the brain faster and thus produce an effect faster (quicker onset of action). 

Highly lipid soluble drugs are redistributed from the brain to other tissues (heart, kidneys, muscles, fats) this then proves to us that lipophilicity also plays an important role in distribution. 

2. What is meant by redistribution and what is the significance thereof?

Redistribution is when highly lipid-soluble drugs are initially distributed to organs with high blood flow (brain, heart, kidneys) and then later on they are distributed to less vascular tissues (muscle and fat). A depo is then formed in these less vascular tissues and the drug is then slowly released from them over time. 

The concept of redistribution prolongs the duration of action of the drug as therapeutic drug levels are maintained for longer. 

3. How are the BDs metabolized? Name the various steps in the process.

Benzodiazepines undergo a three step biotransformation by hepatic microsomal enzymes.

STEP 1: DEALKYLATION 

The active metabolite Desmethyldiazepam is formed (it has an elimination half-life of 40hrs)

STEP 2: OXIDATION 

Desmethyldiazepam undergoes oxidation and becomes a new active metabolite known as Oxazepam. 

STEP 3: CONJUGATION 

Oxazepam undergoes glucuronide conjugation to become an inactive metabolite which is now aqueous soluble and can then be excreted in the urine. 

4. Which BDs are converted to active metabolites? What is the significance thereof?

Diazepam, Chlorazepate, Prazepam, Chlordiazepoxide, Ketazolam 

Active metabolites contribute to the extended duration of action of benzodiazepines and with multiple doses it is important to note that a cumulative effect can occur. 

This is clinically significant in elderly patients, neonates and patients using cytochrome P450 inhibitors. In elderly patients, there is a chance that their hepatic microsomal enzymes no longer work at capacity and thus there is a risk of metabolite accumulation and an extended duration of action which could have negative side effects. In neonates, if the mother was taking benzodiazepines the baby can be born with CNS suppression which must be corrected. In patients using cytochrome P450 inhibitors, they should rather be prescribed other drugs (Oxazepam, Lorazepam, Lormetazepam) which don’t make use of dealkylation/oxidation reactions and which won't form active metabolites because due to their use of the cytochrome P450 inhibitors they won't be able to break down active metabolites that form and thus the metabolism of the drug is delayed and there is prolonged CNS suppression. 

5. Which BDs are not dependent on the cytochrome P450 oxidative enzymes for metabolism? What are the advantages thereof?

Oxazepam, Lorazepam, Lormetazepam

These drugs don’t depend on hepatic microsomal enzymes for metabolism, they only rely on glucuronide conjugation. As a result, these drugs can then be used in situations where people have decreased hepatic microsomal enzyme activity (elderly, neonates, patients using cytochrome P450 inhibitors) since the drug will still be converted to an aqueous soluble product for excretion and there is no dangerous of accumulation. 

6. What is enzyme induction? Which of the sedative hypnotic drugs are known for this? What is the clinical significance of enzyme induction?

Enzyme induction is when a drug increases the production of a certain enzyme and that enzyme then increases the metabolism of the drug. If drug metabolism is increased, then overall drug concentrations will decrease in the bloodstream and so the therapeutic effect is decreased. 

This occurs with certain barbiturates for example phenobarbitone. 

1. What does anterograde amnesia mean and which drugs can cause this effect?

Benzodiazepines can interfere with memory function, an example of when this can occur is in anterograde amnesia. Anterograde amnesia is a subset of amnesia and is the inability to remember events that have occurred while an individual has a certain drug present in their bloodstream. This can happen if for example you are taking benzodiazepines while studying, all the information you process while the drugs mechanism of action is being performed is information that you won’t be able to recall later. 

Benzodiazepines that cause this effect are Midazolam, Flunitrazepam, Lorazepam, Temazepam, Nitrazepam, Triazolam, Clonazepam, Alprazolam, Diazepam and Nimetazepam. 

2. Name the effects of the sedative-hypnotic drugs on the normal sleep pattern and explain their significance to the patient.

• Long term use of benzodiazepines can decrease the amount of time it takes a patient to fall asleep (so the onset of sleep begins faster) and they also increase the total sleep duration (this is only effective in patients which sleep for less than 6hrs per night, so it can help them get the required 8hrs). These two characteristics are why benzodiazepines are effective in the treatment of insomnia. 
• Low doses of benzodiazepines have a small suppressing effect on REM sleep while higher doses cause a bigger suppression. Withdrawal of benzodiazepines often leads to increased periods of REM sleep. 

Benzodiazepines increase the duration of phase 2 NREM (so the body is in a state of deep relaxation for longer) and they decrease the duration of phase 4 NREM. 

3. Which of the sedative-hypnotic drugs are used as a supplementary therapy in anesthesia? Can you explain why?

Both the 1^stgeneration anxiolytic sedative-hypnotic drugs (Barbiturates) and the 2^ndgeneration anxiolytic sedative-hypnotic drugs (Benzodiazepines) are used as supplementary treatments in anesthesia. 

Thiopental (Barbiturate) is ultra short acting and is used in anesthesia. 

Benzodiazepines such as Midazolam, Diazepam and Lorazepam can be used in combination with Barbiturates in anesthesia. These benzodiazepines are the same ones that cause anterograde amnesia and that is why they are drugs of choice because patients don’t recall their procedure (which may be traumatic) when the drugs are in their system. 

4. Which of the sedative-hypnotic drugs are used as anticonvulsants?

Many of the Benzodiazepines as well as the Barbiturates can be used as anticonvulsants. This rests on the fact that both groups of drugs cause potentiation of GABA’s effects and one of GABA’s effects is that it has anticonvulsant properties. 

Thus, Barbiturates such as Phenobarbitone can be used in the treatment of epilepsy. 

Benzodiazepines which have anticonvulsant effects and are used in the treatment of status epilepticus include Lorazepam, Diazepam, Clonazepam and Midazolam. 

5. What is the mechanism of the muscle-relaxing effects of some of the carbamates and the BDs?

Both carbamates and benzodiazepines cause potentiation of GABA’s effects and one of GABA’s effects is that it is a skeletal muscle relaxant. They inhibit polysynaptic reflexes which then result in the relaxing effects. 

6. Discuss the effects of the sedative-hypnotic drugs on the respiratory and cardiovascular systems.

• Benzodiazepines can cause medullar depression. The medulla is the area of the brain containing the Reflex Control Centre as well as the Vital (VMC + Breathing) Centre. If patients are suffering from an underlying pulmonary disease or a cardiovascular disease, then it means that Benzodiazepines can cause even further depression even when given at therapeutic levels. This will mean that they will further worsen the effects already experienced by the patients. 
• The ‘ceiling effect’ further describes the effects of the sedative-hypnotic drugs (Barbiturates & Benzodiazepines) on the respiratory system. 

As the dosage of barbiturates increases (rising above the therapeutic level) it causes maximum respiratory depression which leads to total suppression of the brains vital functions and which then leads to death. This is one of the reasons why they are deemed unsafe. 

As the dosage of benzodiazepines increases (rising above the therapeutic level) it reaches a plateau just below the maximum total respiratory depression (even if the dosage is increased further). This is one of the reasons why benzodiazepines (when used alone) are considered as a safer than Barbiturates. This is because the most harm benzodiazepines will do is cause a coma/anaesthesia in relation to barbiturates that will cause death. 

1. Which types of ion channels are found on the nerve cell membranes? 

There are two types of ion channels found on the nerve cell membranes namely, voltage-gated and ligand-gated ion channels.

1. Name 3 differences between voltage-gated and ligand-gated ion channels.
   • Voltage-gated ion channels react to changes in the membrane potential of a cell. These changes are detected by a voltage sensor component in the protein which then controls the gating (opening and closing) of the channel. In contrast, ligand-gated ion channels control the gating of the channel by reacting to the binding of a ligand or a neurotransmitter to the ionotropic channel receptor. 
   • Voltage-gated ion channels are more readily found through the body than when compared to ligand-gated ion channels. Voltage-gated ion channels are found on the axons of nerve cells and on the outer surface of cell bodies and dendrites. Ligand-gated ion channels are also found on the outer surface of cell bodies as well as on both sides (pre and postsynaptic) of synapses. 
   • Examples of Voltage-gated ion channels include sodium, potassium and calcium channels. In contrast, Ligand-gated ion channels act as ionotropic receptors and so they make use of g-aminobutyric acid, acetylcholine, glutamate and serotonin as their neurotransmitters. 

3. Compare ionotropic and metabotropic receptors.

IONOTROPIC	METABOTROPIC
There is no formation of second messengers.	Second messengers are formed in order for the transduction system to come into working.
They work in the same way as ligand-gated ion channels. The binding of a neurotransmitter or a hormone to the inotropic channel receptor is what causes it to open or close.	They work in the same way as G Protein-coupled receptors. The neurotransmitter or hormone must bind to the extracellular section of the receptor protein this allows intracellular processes to occur and the inactive G-protein is activated and the formation of second messengers occurs.
There are only 4 receptors that we know of; GABAA, Nicotinic, EAA and 5-HT3	All the other receptors found in the body.
Responsible for the opening of ion channels.	Responsible for metabolic changes.
Ionotropic receptor activation involves quick stimulation and a quick, short lasting effect.	Metabotropic receptor activation causes the effect to last longer and it can take longer for stimulation to occur.

4. Classify the CNS receptors into ionotropic and metabotropic and know the transduction mechanism of each receptor.

Ionotropic receptors include GABA_A, Nicotinic, EAA, 5-HT₃, BD. 

Metabotropic receptors are divided into two groups based on their transduction systems; Adenylyl cyclase system & Phospholipase C system. 

In the Adenylyl cyclase system there are receptors which are positively bound (b₁₊₂, D₁) and when they are stimulated the formation of 2^ndmessengers occurs and ATP is converted to c-AMP. In the Adenylyl cyclase system there are also receptors which are negatively bound (D₂, a₂, 5-HT_{IA + B}, M₂, GABA_B) and when they are stimulated the formation of c-AMP is suppressed. 

In the Phospholipase C system there are only receptors that are positively bound (a₁, 5-HT₂, M₁, H₁) and when they are stimulated phospholipase C is involved in the conversion of PIP₂ to DAG and IP₃. 

5. Explain the difference between an EPSP and an IPSP and give examples of each.

EPSP stands for Excitatory/Activating Post Synaptic Potential meaning that when activated it will activate additional action potentials. This occurs when the neuronal membrane is hyper polarized. Examples of receptors that will bring about this effect include Nicotinic, EAA, 5-HT₃, BD. 

IPSP stands for Inhibiting Post Synaptic Potential meaning that when activated it will prevent further action potentials from occurring. This occurs when the neuronal membrane is depolarized. Examples of receptors that will bring about this effect include GABA_A. 

6. What is the role of calcium in the development of a synaptic potential?

When an action potential arrives at the axon terminal it results in the depolarization of the membrane. This then causes an influx of calcium into the presynaptic membrane which causes neurotransmitter release from the synaptic vesicles into the synaptic cleft. The neurotransmitters can then diffuse across the cleft and bind to receptors on the postsynaptic membrane which will in turn produces an effect. Thus calcium is essential for neurotransmitter release which is needed in order to produce an effect.