Sedatives and Hypnotics Ahmad Al-Tarifi Zahra Khalil 1 P a g e Pharmacology 7
OCD can lead to an anxious behavior and anxiety can be treated with drugs called Sedatives and Hypnotics. What are sedatives? Sedatives are drugs that can produce a calming effect on the patient; they decrease activity and moderate excitement. On the other hand, hypnotics are drugs that put the patient to sleep; they produce drowsiness, facilitate the onset and maintenance of sleep. Anxiolytics are drugs used to decrease hyperactivity or anxiety (simply, the drugs used to manage anxiety.) Anxiety is an unpleasant state, accompanied by nervous behavior. Symptoms of anxiety: Tachycardia/Palpitations Sleep disturbances Breathlessness/ Breathing fast Nausea and vomiting Inability to swallow As you can see in the picture below, most of the symptoms are shared with the sympathetic nervous system activation. 2 P a g e
Anxiety normal Hypnotics sedatives Dose: Sedative s/hypno tics Calm sedation Sleep hypnosis Surgical anesthesia Hyper excitation could be due to an anxiety disorder or to fear issues, (for example, if somebody comes on to the stage for the first time they may have tachycardia, sweating.etc.) but this is normal and we can t call it anxiety or have the person go to a doctor and take anxiolytics. On the other hand, anxiety is a problem for patients and those patients should seek treatment. For example, if somebody our age worries about what he s going to do in the 7 th year after graduating, should he go to this specialty or that, if he s going to find a job, or if the market goes down and he stays at home!! It is too early for him! 3 P a g e
In the other direction, if the smiling face (normal) above is going a little bit down, there will be a sensation of calmness and sedation, so if the patient is not sleeping he can respond, he can function normally. This is sedation but when we continue with the functional inhibition, the patient will go to sleep or hypnosis. During sleep or hypnosis, the motor function is not impaired since we can breathe and move our hands but the cognitive function is impaired since we cannot answer questions and interact with other people. So in this case, we are reserving the motor function but losing the cognitive function. But if we go on with further inhibition, such as in surgical anesthesia, we actually lose the motor function, the cognitive function as well as the general sensation. For example, when you are sleeping, if someone touches you or calls you at a high pitch, you may wake up but when you re under surgical anesthesia, you will not! Finally, if we continue with further inhibition, it may lead to death! We have drugs that are used to return the patient from anxiety back to normal situation called Anxiolytics, drugs that calm the patient called sedatives and finally, drugs that are used to induce sleep called hypnotics. When we increase the dose, we move the patient from the upper left corner to the right lower corner (please refer to the picture in the previous page.) The drugs that we are going to talk about: Benzodiazepines OTC Medications Barbiturates 4 P a g e Buspirone Non- Benzodiazepines
We will start with Benzodiazepines (BDZ): BDZ replaces barbiturates for all indications. The most widely used anxiolytics. They usually end with -zolam or -zepam. They target GABA receptors. A Mechanism of action: We have two types of GABA receptors: GABA A: ionotropic (5 units and a channel in the middle ). GABA B: metabotropic (example of G-Protein coupled receptor ) In this figure you can see GABA A receptor, it consists of multiple subunits (α, β and γ) and if you look at the cross section, you can see a pore in the middle and the binding site for GABA (it binds to the site where α and β subunits connect to each other.) Just ignore GABA B! 5 P a g e
You can also see here the binding site for benzodiazepine, it is not the same active site as the GABA binding site and it is an example of allosteric modulators. The binding of BDZ enhances the function of the GABA receptor, hence called positive allosteric modulator allowing GABA to then bind to the receptor. Positive allosteric modulator means: binding of BDZ increases the frequency of the opening of chloride channels and enhances the affinity of GABA receptor for its ligand. If you look at this picture, (A)this is a normal inactive receptor, (B)once GABA binds, the pore in the middle will open and chloride ions (negative ions) will go inside and that will produce hyperpolarization (inhibition in general). However, (C) if BDZ binds to the receptor first and then comes GABA, there will be an enhancement in the function of GABA and more chloride ions will influx inside the cell and that will produce further hyperpolarization. 6 P a g e
Pharmacokinetics: Lipophilic they are absorbed orally they can cross BBB they can cross Placenta Metabolized by liver microsomal enzymes Have Active metabolites(especially long acting BDZ) Final metabolism through conjugation and then excretion. Indications of BDZ: when do we use BDZ? 1. In anxiety disorders : - For continued severe anxiety. - For short period of times(due to dependence and tolerance issues.) - Diazepam, Clonazepam and Lorazepam are preferred (long-acting BDZ.) 2. Muscle spasms: multiple sclerosis, cerebral palsy. 3. Epilepsy: DOC for grand-mal seizures and status epilepticus. 4. Sleep disorders: - latency to sleep, frequent and early awakening. (Though it s not the first DOC in inducing sleep since it causes anterograde amnesia.) - Increase stage II of non-rem sleep Can produce rebound insomnia (which means when we stop the drug we will have insomnia again and may be worse, so when we want to stop the drug, we should taper down the dose slowly ) and it is seen more in shortacting BDZ. Flurazepam: Long-acting (40-200 hrs). Temazepam: Intermediate acting Triazolam : Short-acting (May produce rebound insomnia) 7 P a g e
This figure shows rebound insomnia: x- axis : reflects time (how long the patient stays awake after stopping the drug) y_axis : different drugs You can see in Triazolam the patient stays awake for the longest period of time after stopping the drug, he stays awake for almost 50 hrs!! On the other hand, if the patient stops taking Flurazepam which is long-acting, he will continue to experience its effect of inducing sleep. So the highest risk of having rebound insomnia is usually associated with short-acting drugs. Side effects of BDZ: Paradoxical effect: that means you prescribe the drug but the patient experiences opposite effects; the patient stays awake or becomes more anxious. This rarely happens. Tolerance and dependence: tolerance develops very quickly so the patient feels the need to take higher doses and that s what makes them dependent on the medication. Symptoms associated with withdrawal of the drug: Confusion, anxiety, agitation, restlessness, insomnia, tension and seizures. For example, if you use them to treat sleep disorders and then you stop them, you will have insomnia. Drowsiness and sedation: so you have to give instructions to the patient regarding safety such as driving and instead of just telling them, you may write it down on a piece of paper or tell their family members. Combination with other sedatives: Alcohol, barbiturates, anesthetics (all of them produce inhibition to the brain) Example: Michael Jackson lost consciousness first and then eventually died due to multiple BDZ (Midazolam and Lorazepam) administered together with an anesthetic, Propofol. 8 P a g e
Anterograde amnesia (disadvantage /advantage ) - Impaired ability to learn new information. Examples of Benzodiazepines (BDZ): Diazepam (Valium): -It is a long acting drug. Other long acting medications like Diazepam are Flurazepam, Clonazepam, Chlordiazepoxide*I took Chlordiazepoxide from pulse slides the doctor didn t read it in the lecture* Uses: 1- Anxiolytic. 2- Anticonvulsant (DOC in status epilepticus.) 3- Sedative/hypnotic. 4-Muscle relaxant S/E: 1- Anterograde amnesia 2-Can produce tolerance, dependence and withdrawal symptoms. Pharmacokinetics: Oral, IM, IV. It has a good oral bioavailability (100%). Protein bound in the plasma. Very lipid soluble and can cross BBB: can accumulate in organs. It has active metabolites (that s why it is long acting). Metabolized (Glucuronidation) in liver and excreted by kidney. Half-life may reach 100hrs (with active metabolites). 9 P a g e
Lorazepam: - Some books say it's long acting but others say it's intermediate acting the doctor considered them intermediate acting drugs. - Intermediate duration of action (9-20 hrs)>>imagine if the patient takes it before he goes to bed, the effect may last to the next day affecting his work or preventing him from attending the pharmacology lecture. - Other examples of intermediate acting drugs are Alprazolam, Temazepam. - Uses: o Anxiety o Epilepsy o Nausea and vomiting o Muscle spasms o Insomnia (since we become closer to short acting drugs) - Moving from long acting drugs to the shorter acting drugs, patients start to develop more tolerance and they will be more prone to dependence. In other words, short acting drugs consumers will develop tolerance and dependence faster than intermediate acting drugs and the same story applies to intermediate and long acting drugs.. Midazolam, Triazolam : - Are short acting drugs. - DOC in short-term treatment for severe insomnia - Uses: o Anticonvulsant o Preoperative sedation o Pre-anesthetic medication o Endoscopic procedures (conscious sedation) o Anterograde amnesia o Recall please>> We have talked about Midazolam and we said it's an example of preanesthetic medications to enhance or produce sedation as well as to decrease anxiety before surgery. - Half-life 2-6 hrs 10 P a g e
Summary Anxiety: (intermediate/long) drugs are preferred like: Alprazolam Status epilepticus (I.V): Diazepam, Lorazepam In anesthesia induction, we usually use short acting drugs like: Midazolam Insomnia: (short/intermediate) Temazepam, Oxazepam(a short acting drug) BDZ Overdose Sgins/Symoptoms: (think like it will inhibit everything) Drowsiness and slurred speech Hypotension and ataxia Respiratory and cardiovascular depression Risk of BDZ overdose is enhanced if combined with other depressants like: Alcohol, opioids, TCAs(Tricyclic antidepressants) and barbiturates. Antidote: - Its usage is still controversial; for example, in long term users, if you give them Flumazenil, it will produce very severe withdrawal symptoms and it may lead to convulsions or seizures but not epilepsy (epilepsy is a wrong description, it s better to say convulsions or seizures) - Re-sedation story now Flumazenil has a short duration of action, maybe for half an hour! So the patient will return to the sedation state or overdose state again What can we do??...we simply administer Flumazenil again whenever the patient returns to sedation, until all the BDZ is cleared from the system. - Flumazenil can lead to arrhythmias as well. 11 P a g e
Barbiturates: - These are older than BDZ and they are replaced by BDZ due to their tremendous and harmful side effects. - They induce liver enzymes which means more drug-drug interactions. - They may produce dependence and maybe worse than BDZ. - They have severe withdrawal effects. - Examples: Thiopental (short acting drug): best one of them, may still be used in the induction of anesthesia. Phenobarbital (long acting): an anticonvulsant and one of the last choices in epilepsy (review the epilepsy lecture if u don t remember please) Pentobarbital (intermediate): Sedative/hypnotic (wasn t mentioned by the doctor at all, I only included it cause I found it in pulse slides) BDZ vs. Barbiturates - If we compare the MOA of BDZ to barbiturates, we notice that barbiturates don t bind to the same binding site as BDZ or GABA. They actually bind close to the channel and enhance the opening of it, and they keep it open for a slightly longer time. They have nothing to do with affinity. They don t enhance the affinity of the GABA receptor for it s ligand, but instead, they keep the channel open for a longer time, which means more chloride ions enter the cell, causing more hyperpolarization. 12 P a g e
This graph shows the difference between BDZ and barbiturates. Now if you look at the X-axis, we have the dose of the drug and on the Y-axis, we have the effect they contribute. The first effect brought about is usually at a low dose and it is anxiolysis, then sedation and then sleep..all the way up to death. You also noticed that barbiturates have a low therapeutic window(low lethal dose/effective dose ratio). Actually, BDZ are very very safe compared to barbiturates. This scheme is from our book showing a comparison between different sedatives and their therapeutic index (lethal dose over effective dose.) If you look at Morphine for example, the therapeutic index is very small compared to Diazepam, which is very high. Same story between Phenobarbital and Diazepam. 13 P a g e
14 P a g e Nonbenzodiazepines: Zolpidem - Most commonly prescribed drug for insomnia in the US and it's replacing BDZ as a sleeping drug. - It is not a BDZ, and it s MOA is still not well known but it has a similar MOA to BDZ. - It has a short half life (2-3 hrs), and a rapid onset of action. - It decreases sleep latency(the time it takes from going to bed to actually sleeping), and it doesn t affect sleep itself but makes the patient sleep faster. - It has multiple routes of administration. - S/E may include impaired performance in the morning such as in driving, and dependence. Buspirone: - It's different from BDZ and has a different MOA. BDZ bind with GABA-a receptors while Buspirone functions as a serotonin 5-HT1A agonist and has some dopamine D2-antagonist activity. - Some theories say that when someone is feeling sleepy or he wants to sleep, serotonin levels will be high in the system and this drug is a partial agonist to serotonin receptors, producing similar effects as serotonin and therefore, putting the patient to sleep. - Effect >> it is usually delayed (sometimes it takes weeks!) while BDZ have an immediate effect..so what we usually do is we prescribe both of them together. BDZ will give us an immediate effect, and is stopped when Buspirone starts working. The patient is then continued on Buspirone only. - Uses>> IT HAS NO hypnotic, sedative, anticonvulsant, or muscle relaxant activity, which is opposite to BDZ. - It may lead to addiction and dependence. Ramelteon: - It is a Melatonin agonist. Melatonin is a hormone in the pineal gland that controls the circadian rhythm. - Indicated for insomnia. - MOA: It decreases sleep latency. - S/E: o Dizziness, fatigue, and somnolence.
OTC medications: Antihistamines: (1st generation drugs are the best since they have the sedative component) Used for insomnia (mild) Examples are Diphenhydramine, Chlorphenamine. Alcohol: - Has sedative effects. Drugs used to treat alcohol dependence: Disulfiram, Naltrexone. Note: there are some points about alcohol, Disulfiram and Naltrexone that the doctor said we should go back to in the book and read them since a question may be asked about them for the make up students but he also may write a question about them in our exam so to stay on the safe side, here they are: 15 P a g e DONE