Drugs for Hyperlipidemia and Antiepileptic Drugs PDF

L11 Drugs for Hyperlipidemia and Antiepileptic drugs Drugs for Hyperlipidemia -Hyperlipidemia is an abnormally high level of lipids in the blood which may cause Coronary heart disease (CHD) is positively associated with high total cholesterol and with elevated levels of low-density lipoprotein (LDL)...

L11 Drugs for Hyperlipidemia and Antiepileptic drugs Drugs for Hyperlipidemia -Hyperlipidemia is an abnormally high level of lipids in the blood which may cause Coronary heart disease (CHD) is positively associated with high total cholesterol and with elevated levels of low-density lipoprotein (LDL), triglycerides (TG) and low levels of high-density lipoprotein (HDL). -Other risk factors for CHD include cigarette smoking, hypertension, obesity, and diabetes. Cholesterol levels may be elevated due to lifestyle factors (for example, lack of exercise or diet containing excess saturated fats). Hyperlipidemias can result from a combination of genetic and lifestyle factors. Appropriate lifestyle changes, along with drug therapy, can lead to a 30% to 40% reduction in CHD mortality. -Lipids include: Cholesterol, triglycerides, phospholipids and free fatty acids -Types of hyperlipidemia: primary or secondary due to: Ѳ Hypothyroidism Ѳ Diabetes Ѳ Nephrotic syndrome Ѳ Chronic alcoholism Ѳ Chronic renal failure Ѳ drugs e.g corticosteroids, oral contraceptive, β-blocker - Risk factors for hyperlipidemia Diet, obesity, hypertensions, hereditary, advancing age, women after menopause, lack of exercise, smoking, stress, overuse of alcohol. -Pharmacological management 1. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statin family). Ѳ Atorvastatin, Ѳ Lovastatin, Ѳ Simvastatin Ѳ Pravastatin, Ѳ Fluvastatin, Ѳ Rosuvastatin Mechanism of action -Inhibition of the enzyme HMG-CoA reductase, a key enzyme in cholesterol synthesis in the liver -Decrease in hepatic cholesterol synthesis -Increased synthesis of LDL receptors on the liver cells -Increased clearance of plasma LDL -Reduction in plasma LDL cholesterol levels -Increased plasma HDL level in some patients. Clinical uses -All types of hyperlipidemias -Hypertriglycermia Adverse effects -Increase in serum transaminase and creatine phosphokinase -GIT disturbance -Insomnia -Angioedema -Rash -Severe myopathy -Hepatitis -Contraindication -Pregnancy -Children or teenagers 2-fibrates Gemfibrozil and fenofibrate Are derivatives of fibric acid that lower serum triglycerides and increase HDL levels. Mechanism of action -Increase activity of lipoprotein lipase enzyme that degrades of triglycerides. -Inhibit VLDL synthesis by liver and increases its clearance from circulation. -increases HDL Clinical uses -The fibrates are used in the treatment of Hypertriglyceridemias (elevated level of triglycerides associated with atherosclerosis). -They are particularly useful in treating dysbetalipoproteinemia (high amounts of cholesterol and triglycerides). Adverse effects -Mild gastrointestinal disturbances (nausea, dyspepsia, diarrhea) -lower testosterone levels may lead to impotence -Gall stone formation -Myositis (inflammation of voluntary muscle) 3.Bile acid–binding resins Cholestyramine , colestipol and colesevelam Bile acid resins have significant LDL cholesterol–lowering effects, although the benefits are less than those observed with statins. Mechanism of action: -Are anion-exchange resins that bind negatively charged bile acids and bile salts in the small intestine. The resin/bile acid complex is excreted in the feces, thus lowering the bile acid concentration. -This causes hepatocytes to increase conversion of cholesterol to bile acids, which are essential components of the bile. Consequently, intracellular cholesterol concentrations decrease, which activates an increased hepatic uptake of cholesterol-containing LDL particles, leading to a fall in plasma LDL-C clinical uses: The bile acid–binding resins are useful for treating type IIA (increased LDLand cholesterol). type IIB (elevated LDL, cholesterol and triglyceride. Adverse effects: - Nausea, heart burn, constipation and flatulence - Impaired intestinal absorption of fat-soluble vitamins (A, D, E and K) 4. Niacin (nicotinic acid) Niacin can reduce LDL-C by 10% to 20% and is the most effective agent for increasing HDL-C. It also lowers triglycerides by 20% to 35% at typical doses of 1.5 to 3 grams/day. Niacin can be used in combination with statins, and a fixed -dose combination of lovastatin and long-acting niacin is available. Mechanism of action: -The liver normally uses circulating free fatty acids as a major precursor for triglyceride synthesis. - Niacin reduces liver triglyceride levels decrease hepatic VLDL production, which in turn reduces LDL-C plasma concentrations. Clinical uses: Since niacin lowers plasma levels of both cholesterol and triglycerides, it is useful in the treatment of familial hyperlipidemias. It is also used to treat other severe hypercholesterolemias, Adverse effects: -Intense cutaneous flush (accompanied by an uncomfortable feeling of warmth) and pruritus. Administration of aspirin prior to taking niacin decreases the flush. 5. Cholesterol absorption inhibitor Ezetimibe -Selectively inhibits absorption of dietary and biliary cholesterol in the small intestine, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. Ezetimibe lowers LDL cholesterol by approximately 17%. -Is often used as an adjunct to statin therapy or in statin-intolerant patients. Adverse effects are uncommon with use of ezetimibe. 6.Omega-3 fatty acids Omega-3 polyunsaturated fatty acids are essential fatty acids that are predominately used for triglyceride lowering. Essential fatty acids inhibit VLDL and triglyceride synthesis in the liver. The omega-3 are found in marine sources such as tuna, halibut, and salmon.  Antiepileptic drugs Epilepsy: it is due to an abnormal discharge of neurons in some specific area of the brain. -The discharge may spread to other groups of neurons. The neurons become with hyper-excitability (firing). -The site of the origin of the discharge is called the focus. -It is possible to record the discharge by using EEG. -Normally every neuron has excitatory mediators and inhibitor mediators. -The excitatory mediators include Ach, nor-Ad, and Glutamate. -While the inhibitory mediators include one major neurotransmitter (GABA). -Excitatory mediators: cause influx of Na in the neurons. -Inhibitory mediators: Act either prevents Na influx or increase Cl influx. -Causes of focus: it seems that, it caused by reducing the inhibition on the neurons rather than excessive excitation. -Tumors, injuries or infection may produce focus. -Spread of focus can be enhanced or initiated by predisposing factors are: Hypoglycemia, change in plasma pH and electrolytes, fatigue, physical or mental stress and alcohol. Types of epilepsy: are of two types 1-Partial (focal).The symptoms of each seizure type depend on the neuronal discharge and on the extent to which the electrical activity spreads to other neurons in the brain this some time may be due to e.g infarction, Haematoma. Partial is of two subtypes according to site of lesion. a. Simple partial: These seizures are caused by a group of hyperactive neurons exhibiting abnormal electrical activity a single focus in the brain; the electrical disorder does not spread. The patient does not lose consciousness but only sensation loss and often exhibits abnormal activity of a single limb or muscle group that is controlled by a part of the brain. b.Complex partial: These seizures exhibit complex sensory hallucinations, mental distortion, and loss of consciousness. Motor dysfunction may involve chewing movements, diarrhea, and urination.  2. Generalized: These seizures begin locally, but they rapidly spread producing abnormal electrical discharge. Generalized seizures may be convulsive or nonconvulsive Characterized by loss of consciousness. The discharges of neurons are distributed all over the brain. They are five main subtypes. a. Generalized Tonic-Clonic (Grand mal) seizures. The clinical attacks are characterized by: Tonic stage Clonic stage Relaxation stage 30 seconds 1-2 minutes 0.5-1 hour This type is usually with a maximal tonic spasm of all body muscular. b. Absence (petit mal) seizures. That with transient loss of consciousness lasts for 10-15 seconds. c. Myoclonic seizures. These seizures consist of short episodes of muscle contraction that may reoccur for several minutes. Myoclonic seizures are rare occur at any age and are often a result of permanent damage acquired as a result of hypoxia, uremia, encephalitis or drug poisoning. d. Febrile seizures in children. Young children (3 months to 5 years of age) frequently develop seizures with illness accompanied by high fever. The febrile seizures consist of generalized Tonic-clonic convulsions of short duration. They are benign and don’t cause death, neurologic damage, injury, or learning disorders, and rarely require medication. e.Status epilepticus. Some time the episodes of grand mal occurs without recovery of consciousness. The patient reaches the level of recovery and then he retains back again another time with the episodes. These seizures are fatal unless treated rapidly. Mode of action of antiepleptic drugs: The modes of action of antiepleptic drugs are unknown. But there is a neurophysiological mechanism about the effect of antiepleptic drugs. The spread of seizures is decreased: In case of alteration in neuronal permeability to Na, k, Ca and Cl ions. In case of enhancing the activity of inhibitory neurotransmitter (GABA). Inhibition of excitatory neurotransmitter e.g (glutamate). Antiepleptic drugs 1. Ethosuximide Mechanism of actions: It blocks a particular types of calcium channel that is active in absence seizures. Clinical Use: Drug of choice for petit mal epilepsy. Side effects: Nausea, vomiting, drowsiness, headache, allergic reaction, blood disorder and systemic lupus erythematosus (SLE) 2. Sodium valproate (valproic acid) Mechanism of action: Inhibitions of the GABA transaminase enzyme in the brain, thus increasing levels of GABA. Clinical Use: All types of epilepsy (very effective against absence seizures). Drug interaction: Inhibits the metabolism of other antiepleptic drugs as phenytoin, Phenobarbitone and carbamazepine. Side effects: Stimulate appetite (weight gain), increases alertness, nausea, increase hepatic enzyme, liver failure, pancreatitis, coagulation disorder due to inhibition of platelet aggregation, temporal alopecia (re-grow again). 3.Benzodiazepines Mechanism of action: On GABA receptors. Several of the Benzodiazepines show antiepleptic activity. a.Diazepam Drug of choice for status epilepticus. b.Clonazepam Is used for petit mal and myoclonic attacks (Alternatives). 4.Phenytoin Mechanism of action: It alters fluxes of Na, K and Ca a cross cell membrane. Clinical use: Grand mal, partial and status epilepticus. Pharmacokinetic: Given orally, absorbed well from intestine, but there is a pharmaceutical bioavailability problem in relation to the nature of the diluent in the tablet. Patients should always use the same formulation. Side effects: Osteomalasia and hypocalcemia, megaloblastic anemia, gum hyperplasia, hirsutism in females and skin rash. 5. Carbamazepine Mechanism of action: It is structurally releated to imipramine. Like Phenytoin It blocks sodium channels. Clinical use: Grand mal and partial epilepsy (Drug of choice), Trigeminal neuralgeia (drug of choice) and in manic depressive patients. Adverse effects: Blurred vision, drowsiness, dizzines, diplopia, respiratory depression, ataxia and vertigo. 1. Barbiturates -Phenobarbitone Mechanism of action: It enhances activity of GABA. Clinical Use: As alternative in grand mal and partial epilepsy. -Primidone (mysolin) Is structurally related to phenobarbitone. It is metablized in the body to active substance Phenobarbitone. It is an alternative choice in partial and grand mal epilepsy. 7. Vigabatrin Mechanism of action: It acts as irreversible inhibitor of GABA-transaminase so that GABA accumulates. GABA- transaminase is resynthesised over 6 days. Clinical use: In partial seizures, infantil spasm and types of seizure which are difficult to control with slandered anticonvulsants. 8.GABApentin Mechanism of action: It is an analogue of GABA, but it does not work through the GABA receptors. It may, however, alter GABA metabolism. Clinical use: As alternative in partial epilepsy. 9.Lamotrigin Mechanism of action: Its principal mechanism of action Like that of Phenytoin, concerns sodium channels. Clinical use: The drug is effective as monotherapy for partial seizures. 10. Topiramate Mechanism of action: Blocking of sodium channels and also appears to potentiate the inhibitory effect of GABA. Clinical use: Partial and generalized tonic-clonic seizures.