Department of Pharmacology, DSMA

1. Department of Pharmacology, DSMA Hypnotic Drugs. Anticonvulsants. Drugs used in Parkinson‘s disease.

2. Department of Pharmacology, DSMA Sleep is an active, circadian, physiologycal depression of conciousness It is characteraized by ciclical (4-6 cycles) electroencephalographic (EEG) and eye movement changes: 1. NREM (non-rapid eye movement), orthodox, forebrain or slow-wave EEG sleep (about 90 min.).Heart rate, blood pressure and respiration are steady or decline and muscles are relaxed; growth hormone secretion is maximal. 2. REM (rapid eye movement), paradoxical, hindbrain or fast-wave EEG sleep; awakened subjects state they were “dreaming” (about 20 min.). Heart rate, blood pressure and respiration are increased, muscles are profoundly relaxed.

3. 1. NREM sleep makes up the bulk of your sleep (75% of your night). NREM sleep has been categorized into four distinct sleep stages. These stages are: Stage 1 (transition between wake and sleep) Stage 2 (light sleep) Stages 3 and 4 (deep sleep) Stages 3 and 4 are considered to be the deepest levels of sleep. There is evidence thatstage 3 and 4 play an important role in our mental and physical recuperation. To put it another way, these stages help us recharge our batteries. Depriving ourselves of this sleep can cause us to suffer fatigue and reduced physical and mental performance. 2. REM sleepappears to be responsible for helping us in our ability to learn and make decisions. More studies are needed to understand the function of REM and NREM sleep. When we wake up in the morning remembering a dream, we have usually awakened from REM sleep.

4. Department of Pharmacology, DSMA Sleep disorders (insomnia) • Onset insomnia (difficulty in getting to sleep); • Difficulty in staying asleep, repeated awakenings. • Early waking in which sleep is shorter.

5. The average sleep we need varies among people, but the majority of adults require an average of seven to eight hours of sleep each day. Sleep duration also varies with age. Note that we obtained up to 16 hours of sleep each day when we were babies. Also note that half of that sleep is REM sleep. This is perhaps because babies must learn quickly, and REM sleep promotes learning. Age also affects how much sleep we can manage to get and whether we get most of our sleep in one single sleep period (young adult) or whether we need to nap (infants and elderly). By the time we reach 60, sleep has been reduced by about two hours compared to what we obtained when we were 18. Note that this reduction is mostly due to a reduction in NREM sleep. This explains the impression that as we age our sleep gets lighter. Also, it should be emphasized that the present population of marine pilots is between the ages of 40 and 60.

7. 2. Barbituric acid derivatives (barbiturates) Phenobarbitalum Barbitalum Barbital natrum Amobarbitalum Aethaminalum-natrium Hypnotic drugs • Benzodiazepines Nitrazepamum, Oxazepamum, Phenazepamum, Triazolamum, Lorazepamum, Diazepamum, Tenazepamum, Flurazepamum, Flunitrazepamum 3. Miscellaneous drugs Zolpidemum Zopiclonum Bromisovalum Metaqualonum

8. Department of Pharmacology, DSMA Pharmacological properties of barbiturates The barbiturates reversibly depress the activity of all excitable tissues. The CNS is exquisitely sensitive, and, even when barbiturates are given in anesthetic concentrations, direct effects on peripheral excitable tissues are weak. However, serious deficits in cardiovascular and other peripheral functions occur in acute barbiturate intoxication.

9. Department of Pharmacology, DSMA Barbiturates

10. Department of Pharmacology, DSMA Pharmacological properties of barbiturates 1. Central Nervous System. The barbiturates can produce all degrees of depression of the CNS, ranging from mild sedation to general anesthesia. Certain barbiturates, particularly those containing a 5-phenyl substituent (phenobarbital, mephobarbital), have selective anticonvulsant activity. The antianxiety properties of the barbiturates are not equivalent to those exerted by the benzodiazepines, especially with respect to the degree of sedation that is produced. The barbiturates may have euphoriant effects.

11. Department of Pharmacology, DSMA Pharmacological properties of barbiturates 1.1. Effects on Stages of Sleep. Hypnotic doses of barbiturates increase the total sleep time and alter the stages of sleep in a dose-dependent manner. Like the benzodiazepines, these drugs decrease sleep latency, the number of awakenings, and the durations of REM and slow-wave sleep. During repetitive nightly administration, some tolerance to the effects on sleep occurs within a few days, and the effect on total sleep time may be reduced by as much as 50% after 2 weeks of use.

12. Department of Pharmacology, DSMA Pharmacological properties of barbiturates 1.2. Tolerance. Both pharmacodynamic (functional) and pharmacokinetic tolerance to barbiturates can occur. The former contributes more to the decreased effect than does the latter. With chronic administration of gradually increasing doses, pharmacodynamic tolerance continues to develop over a period of weeks to months, depending on the dosage schedule, whereas pharmacokinetic tolerance reaches its peak in a few days to a week. Tolerance to the effects on mood, sedation, and hypnosis occurs more readily and is greater than that to the anticonvulsant and lethal effects. Pharmacodynamic tolerance to barbiturates confers tolerance to all general CNS-depressant drugs, including ethanol.

13. Department of Pharmacology, DSMA Pharmacological properties of barbiturates 1.3. Abuse and Dependence.Like other CNS-depressant drugs, barbiturates are abused, and some individuals develop a dependence upon them.

14. Department of Pharmacology, DSMA Pharmacological properties of barbiturates Sites and Mechanisms of Action on the CNS.Barbiturates act throughout the CNS; nonanesthetic doses preferentially suppress polysynaptic responses. Facilitation is diminished, and inhibition is usually enhanced. The site of inhibition is either postsynaptic, as at cortical and cerebellar pyramidal cells and in the cuneate nucleus, substantia nigra, and thalamic relay neurons, or presynaptic, as in the spinal cord. Enhancement of inhibition occurs primarily at synapses where neurotransmission is mediated by GABA acting at GABAA receptors. Barbiturates enlarge GABA-induced chloride currents by prolonging periods during which bursts of channel opening occur, rather than by increasing the frequency of these bursts, as benzodiazepines do.

15. Department of Pharmacology, DSMA Pharmacological properties of barbiturates 2. Peripheral Nervous Structures. Barbiturates selectively depress transmission in autonomic ganglia and reduce nicotinic excitation by choline esters. This effect may account, at least in part, for the fall in blood pressure produced by intravenous oxybarbiturates and by severe barbiturate intoxication. At skeletal neuromuscular junctions, the blocking effects of both tubocurarine and decamethonium are enhanced during barbiturate anesthesia. These actions probably result from the capacity of barbiturates at hypnotic or anesthetic concentrations to inhibit the passage of current through nicotinic cholinergic receptors.

16. Department of Pharmacology, DSMA Pharmacological properties of barbiturates 3. Respiration. Barbiturates depress both the respiratory drive and the mechanisms responsible for the rhythmic character of respiration. The neurogenic drive is diminished by hypnotic doses, but usually no more so than during natural sleep. The barbiturates only slightly depress protective reflexes until the degree of intoxication is sufficient to produce severe respiratory depression. Coughing, sneezing, hiccoughing, and laryngospasm may occur when barbiturates are employed as intravenous anesthetic agents. Indeed, laryngospasm is one of the chief complications of barbiturate anesthesia.

17. Department of Pharmacology, DSMA Pharmacological properties of barbiturates 4. Cardiovascular System.When given orally in sedative or hypnotic doses, the barbiturates do not produce significant overt cardiovascular effects, except for a slight decrease in blood pressure and heart rate such as occurs in normal sleep.

18. Department of Pharmacology, DSMA Pharmacological properties of barbiturates 5. Liver. The best-known effects of barbiturates on the liver are those on the microsomal drug-metabolizing system. Acutely, the barbiturates combine with several species of cytochrome P450 and competitively interfere with the biotransformation of a number of other drugs as well as of endogenous substrates, such as steroids. The chronic administration of barbiturates causes a marked increase in the protein and lipid content of the hepatic smooth endoplasmic reticulum, as well as in the activities of glucuronyl transferase and the oxidases containing cytochrome P450. The inducing effect on these enzymes results in an increased rate of metabolism of a number of drugs and endogenous substances, including steroid hormones, cholesterol, bile salts, and vitamins K and D. An increase in the rate of barbiturate metabolism also results, which accounts for part of the tolerance to barbiturates.

19. Department of Pharmacology, DSMA Pharmacological properties of barbiturates 6. Kidney.Severe oliguria or anuria may occur in acute barbiturate poisoning, largely as a result of the marked hypotension.

20. Department of Pharmacology, DSMA Pharmacological properties of barbiturates Untoward Effects • After-effects. Drowsiness may last for only a few hours after a hypnotic dose of barbiturate, but residual depression of the CNS sometimes is evident the following day. • Paradoxical Excitement. In some persons, barbiturates repeatedly produce excitement rather than depression, and the patient may appear to be inebriated. This type of idiosyncrasy is relatively common among geriatric and debilitated patients and occurs most frequently with phenobarbital and N-methylbarbiturates. • Pain. Barbiturates often are prescribed for localized or diffuse myalgic, neuralgic, or arthritic pain but often do not effectively treat these symptoms, especially in psychoneurotic patients with insomnia. Barbiturates may cause restlessness, excitement, and even delirium when given in the presence of pain. • Hypersensitivity. Allergic reactions occur especially in persons who tend to have asthma, urticaria, angioedema, and similar conditions. • Drug Interactions. Barbiturates combine with other CNS depressants to cause severe depression.

21. Department of Pharmacology, DSMA Pharmacological properties of barbiturates Barbiturate Poisoning • In severe intoxication, the patient is comatose; respiration is affected early. Breathing may be either slow or else rapid and shallow. Superficial observation of respiration may be misleading with regard to actual minute volume and to the degree of respiratory acidosis and cerebral hypoxia. Eventually, blood pressure falls owing to the effect of the drug and of hypoxia on medullary vasomotor centers; depression of cardiac contractility and sympathetic ganglia also contribute. Pulmonary complications (atelectasis, edema, and bronchopneumonia) and renal failure are likely to be the fatal complications of severe barbiturate poisoning. • The optimal treatment of acute barbiturate intoxication is based on general supportive measures. Hemodialysis or hemoperfusion is only rarely necessary, and the use of CNS stimulants increases the rate of mortality. The present treatment is applicable in most respects to poisoning by any CNS depressant.

22. Department of Pharmacology, DSMA Benzodiazepines Benzodiazepines are classified according to their duration of action: • Intermediate-acting (Nitrazepamum, Flunitrazepamum, Lorazepamum) – sleep begins in 20-40 min. and prolongs 6-8 hours. • Short-acting (Triazolamum, Midazolamum) - sleep begins in 10-20 min. and prolongs 2-3 hours.

23. Department of Pharmacology, DSMA Pharmacological properties of benzodiazepines The effects of the benzodiazepines virtually all result from actions of these drugs on the CNS. The most prominent of these effects are sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia, and anticonvulsant activity. Only two effects of these drugs appear to result from actions on peripheral tissues: coronary vasodilation, seen after intravenous administration of therapeutic doses of certain benzodiazepines, and neuromuscular blockade, seen only with very high doses.

24. Department of Pharmacology, DSMA Pharmacological properties of benzodiazepines While the benzodiazepines affect activity at all levels of the neuraxis, some structures are affected to a much greater extent than are others. The benzodiazepines are not general neuronal depressants, as are the barbiturates. The major molecular targets of the benzodiazepines are inhibitory neurotransmitter receptors directly activated by the amino acid, gamma-aminobutyric acid (GABA).

25. Department of Pharmacology, DSMA Pharmacological properties of benzodiazepines Effects on EEG and Sleep Stages. Most benzodiazepines decrease sleep latency, especially when first used, and diminish the number of awakenings and the time spent in stage 0 (a stage of wakefulness). Time in stage 1 (descending drowsiness) usually is decreased, and there is a prominent decrease in the time spent in slow-wave sleep (stages 3 and 4). Most benzodiazepines increase the time from onset of spindle sleep to the first burst of rapid-eye-movement (REM) sleep, and the time spent in REM sleep usually is shortened. However, the number of cycles of REM sleep usually is increased, mostly late in the sleep time.

26. Department of Pharmacology, DSMA Pharmacological properties of benzodiazepines • Respiration. Hypnotic doses of benzodiazepines are without effect on respiration in normal subjects. • Cardiovascular System. The cardiovascular effects of benzodiazepines are minor in normal subjects, except in severe intoxication. In preanesthetic doses, all benzodiazepines decrease blood pressure and increase heart rate. • Gastrointestinal Tract. Benzodiazepines are thought by some gastroenterologists to improve a variety of "anxiety-related" gastrointestinal disorders. There is a paucity of evidence for direct actions. Benzodiazepines partially protect against stress ulcers in rats, and diazepam markedly decreases nocturnal gastric secretion in human beings. • Untoward Effects. At the time of peak concentration in plasma, hypnotic doses of benzodiazepines can be expected to cause varying degrees of lightheadedness, lassitude, increased reaction time, motor incoordination, impairment of mental and motor functions, confusion, and anterograde amnesia. Cognition appears to be affected less than motor performance.

27. Department of Pharmacology, DSMA Miscellaneous hypnotic drugs • Zopiclon (Imovan), Zolpidem (Ivadal) – act on a subset of the benzodiazepine receptor family. They have no anticonvulsive or muscle relaxing properties. They show no withdrawal effect, exhibits minimal rebound insomnia and little or no tolerance occurs with prolonged use. They have a rapid onset of action and shot elimination. They have advantage over the benzodiazepines. • Methaqualonum – like barbiturates, but it is not impairs sleep structure. • Bromisovalum – weak hypnotic drug (contains two sedative components – bromide and isovalerianic acid).

28. Department of Pharmacology, DSMA Anticonvulsants The epilepsies are common and frequently devastating disorders. More than 40 distinct forms of epilepsy have been identified. Epileptic seizures often cause transient impairment of consciousness, leaving the individual at risk of bodily harm and often interfering with education and employment. Therapy is symptomatic in that available drugs inhibit seizures, but neither effective prophylaxis nor cure is available. Compliance with medication is a major problem, because of the need for long-term therapy together with unwanted effects of many drugs.

29. Department of Pharmacology, DSMA Etiology of epilepsy

30. Department of Pharmacology, DSMA Classification of epilepsy

31. Department of Pharmacology, DSMA Choice of antiepileptic drugs

32. Department of Pharmacology, DSMA Mechanisms of action of antiseizure drugs The mechanisms of action of antiseizure drugs fall into three major categories. Drugs effective against the most common forms of epileptic seizures, partial and secondarily generalized tonic-clonic seizures, appear to work by one of two mechanisms. One is to limit the sustained repetitive firing of a neuron, an effect mediated by promoting the inactivated state of voltage-activated Na+ channels. A second mechanism appears to involve enhanced gamma-aminobutyric acid (GABA)-mediated synaptic inhibition, an effect mediated by an action presynaptically for some drugs and postsynaptically for others. Drugs effective against a less common form of epileptic seizure, absence seizure, limit activation of a particular voltage-activated Ca2+ channel, known as the T current. Antiseizure drug-enhanced Na+channel inactivation. Some antiseizure drugs (shown in blue text) prolong the inactivation of the Na+ channels, thereby reducing the ability of neurons to fire at high frequencies. Note that the inactivated channel itself appears to remain open, but is blocked by the inactivation gate (I). A, activation gate.

33. Department of Pharmacology, DSMA Drugs used in Parkinson‘s disease Neurodegenerative disorders are characterized by progressive and irreversible loss of neurons from specific regions of the brain. Prototypical neurodegenerative disorders include Parkinson's disease (PD), where loss of neurons from structures of the basal ganglia results in abnormalities in the control of movement. At present the pharmacological therapy of neurodegenerative disorders is limited to symptomatic treatments that do not alter the course of the underlying disease. Symptomatic treatment for PD, where the neurochemical deficit produced by the disease is well defined, is in general relatively successful, and a number of effective agents are available

34. Department of Pharmacology, DSMA Parkinson‘s disease Parkinsonism is a clinical syndrome comprising four cardinal features: bradykinesia (slowness and poverty of movement), muscular rigidity, resting tremor (which usually abates during voluntary movement), and an impairment of postural balance leading to disturbances of gait and falling. The most common cause of parkinsonism is idiopathic PD, first described by James Parkinson in 1817 as paralysis agitans, or the "shaking palsy." The pathological hallmark of PD is a loss of the pigmented, dopaminergic neurons of the substantia nigra pars compacta, with the appearance of intracellular inclusions known as Lewy bodies. Progressive loss of dopamine neurons is a feature of normal aging; however, most people do not lose the 80% to 90% of dopaminergic neurons required to cause symptomatic PD. Without treatment, PD progresses over 5 to 10 years to a rigid, akinetic state in which patients are incapable of caring for themselves. Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism.

35. Dopamine agonists Levodopa Carbidopa Madopar Nacom Midantan (Amantadin) Bromocriptin Cholinergic antogonists Cyclodol (Parkopan) Norakin Akineton Department of Pharmacology, DSMA Strategy of treatment PD

36. The End