Clinical pharmacology   By : Dr. MOHAMMED J AL MANNA PHD – Clinical Pharm. and Toxicology

Pharmacokinetics Pharmacokinetics represent the effects of biologic systems on drugs. The major processes involved in pharmacokinetics are Absorption, Distribution, Metabolism and Elimination. (ADME)

1)Absorption - (oral ,Topical or parenteral) - A drug must be absorbed and achieve adequate concentration at its site of action in order to produce its biological effects. 2)Distribution - The blood, extracellular, lymphatic and cerebrospinal fluids are involved in movement of drug through the body. Depending upon its chemical and physical properties, the drug may be bound to plasma proteins or dissolved in body fat.

Volume of Distribution The volume of distribution (Vd) relates the amount of drug in the body to the plasma concentration according to the following equation:

198 units 2 units

Q/ Describe the pharmacological implication of Vd? Toxicological …… Drugs with Vd less than 1 →( i.e. less distribution ; circulate in blood , so they are accessible for hemodialysis and /or gastric lavage (Within 1st 6 hrs of ingestion ) in case of poisoning) . Drugs with Vd equal or greater than 1 →( i.e. has higher distribution in body , so they are not accessible for hemodialysis in case of poisoning { can be treated with antidote and /or gastric lavage ) 3) Metabolism - How drugs are handled biochemically by the body and includes hydrolysis, conjugation, and oxidation-reduction. The most important organ for drug metabolism is the liver. The kidneys play an important role in the metabolism of some drugs. A few drugs (eg, esters) are metabolized in many tissues (eg, liver, blood, intestinal wall)

Drug – drug interactions 1)Enzyme Induction Induction usually results from increased synthesis of cytochrome P450-dependent drug-oxidizing enzymes in the liver. Several days (7-10 days) are usually required to reach maximum induction. The most common strong inducers of drug metabolism are carbamazepine, phenobarbital, phenytoin, and rifampin. Q/ What is the effect of drugs enzyme inducer?

2) Enzyme Inhibition The most likely inhibitors of drug metabolism to be involved in serious drug interactions are amiodarone, erythromycin , cimetidine, grapefruit juice, azole antifungals, and the HIV protease inhibitor ritonavir. Q/ What is the effect of drugs enzyme inhibitor? Q/ some drugs addict use cimetidine with diazepam ? explain

4) Excretion: Clearance The kidney is the most important organ for excretion of drugs. The lungs and sweat usually play a minor role. Clearance Clearance (CL) relates the rate of elimination to the plasma concentration: .

Half-Life Half-life (t 1/2) is a derived parameter, completely determined by Vd and CL. Like clearance, half-life is a constant for drugs that follow first-order kinetics. Half-life can be determined from the following relationship:

First-Order Elimination The term first-order elimination implies that the rate of elimination is proportional to the concentration (i.e., the higher the concentration, the greater the amount of drug eliminated per unit time). Drugs with first-order elimination have a characteristic half-life of elimination that is constant regardless of the amount of drug in the body. The concentration of such a drug in the blood will decrease by 50% for every half-life. Most drugs in clinical use demonstrate first-order kinetics.

Zero-Order Elimination The term zero-order elimination implies that the rate of elimination is constant regardless of concentration . This occurs with drugs that saturate their elimination mechanisms at concentrations of clinical interest. This is typical of ethanol and of phenytoin and aspirin (at high dose).

Steady state After 5-6 half-life → Steady state ≡ duration of action. For example : Ampicillin has t1/2 =1hr ; so the duration of action is 6 hrs and should be given 4 times daily. Also from half life we can estimate onset of action

Bioavailability The bioavailability of a drug is the fraction (F) of the administered dose that reaches the systemic circulation. Bioavailability is defined as unity (or 100%) in the case of intravenous administration. After administration by other routes, bioavailability is generally reduced by incomplete absorption, first-pass metabolism, and any distribution into other tissues that occurs before the drug enters the systemic circulation.

Adjustment of dosage when elimination is altered by disease Renal disease or reduced cardiac output often reduces the clearance of drugs that depend on renal function. Alteration of clearance by liver disease is less common but may also occur. The dosage in a patient with renal impairment may be corrected by { Normal dose χ CL} using Cockcroft-Gault equation: Normal Scr in SI = 70-120Mmole/l (M) ; 50-90Mmole/l ( F) . If scr was given in mg/dl should be multiplied by 100. The final result is multiplied by 0.85 for females.

Protein Binding: A drug in blood exists in two forms: bound and unbound. Notably, it is the unbound fraction (free) which exhibits pharmacologic effects. It is also the fraction that may be metabolized and/or excreted. For example, the "fraction bound" of the anticoagulant warfarin is 97%. This means that of the amount of warfarin in the blood 97% is bound to plasma proteins. The remaining 3% (the fraction unbound) is the fraction that is actually active and may be excreted.

Clinical application of drug protein binding: Increased the S/E or toxicity: If the amount of plasma protein is decreased (such as in catabolism, malnutrition, liver disease, renal disease), there would also be a higher fraction unbound drug S/E or toxicity. 2) Decreased the efficacy Nephrotic syndrome is a nonspecific kidney disorder characterized by a number of signs of disease: proteinuria, hypoalbuminemia and edema. It is characterized by an increase in permeability of the capillary walls of the glomerulus leading to the presence of high levels of protein passing from the blood into the urine (proteinuria at least 3.5 grams per day)

Because some of the protein albumin has gone from the blood to the urine) but not large enough to allow RBC through (hence no hematuria). By contrast, in nephritic syndrome red blood cells pass through the pores, causing hematuria. Signs and symptoms It is characterized by 1)proteinuria (>3.5g/day). 2) hypoalbuminemia. 3) Hyperlipidaemia {Why?}. 4) edema (which is generalized and pitting type) that begins in the face. 5) predisposition for coagulation and infection {why???????}.

.

Treatment Corticosteroids: the result is a decrease in the proteinuria and the risk of infection as well as a resolution of the edema. Patients are treated with prednisolone 2 mg/kg/day till urine becomes negative for protein. Then, 1.5 mg/kg/day for 4 weeks. Frequent relapses treated by: cyclophosphamide or cyclosporin or levamisole. Note : For the treatment of any condition in patient with nephrotic syndrome we must choose the least protein binding drug to give us full action Ex: Patient with hypertension we use lisinopril (have no binding to plasma protein)

Q /Patient with severe otitis media ; has history of nephrotic syndrome ( or any condition that decreases S albumin) what is antibiotic of choice: Ampicillin 20% Ciprofloxacin 30% Ceftriaxone 90% Amoxiclav 10%

Shelf life or expire date: The expiration date of drugs specifies the date the manufacturer guarantees the full potency and safety of a drug. After the drugs reach the expire date there was still at least 90 percent of the active ingredient left in the drug, while 10% is converted into inert , safe , or toxic compounds. Most medications continue to be effective and safe for a time after the expiration date. A rare exception is a case of renal tubular acidosis {fanconi’s syndrome} purportedly caused by expired tetracycline.

A study conducted by the Food and Drug Administration {FDA} covered over 100 drugs. The study showed that about 90% of them were safe and effective as long as 15 years past their expiration dates. A handful of exceptions {Toxic drugs beyond their expiration}- notably nitroglycerin , digoxin, insulin and some liquid antibiotics

Pharmacodynamics Pharmacodynamics :deals with the effects of drugs on biologic systems, whereas pharmacokinetics deals with actions of the biologic system on the drug. Mechanisms of drug action It is currently believed that most drugs interact with macromolecular component (called receptors) of a cell to begin biochemical and physiological changes that produce drug's response.

Receptor –effector coupling: When a drug binds to a receptor on a cell membrane , the extracellular drug signal must be converted (transduced) to an intracellular message , the process termed signal transduction. In the simplest case Drug (A) binds to 1 receptor coupled to 1 effector (transduction pathway) and produces 1 effect.

While drug (B) binds to 1 receptor coupled to more than 1 effector so it produces more than 1 effect in the same or different cells..

On the other hand , drug (C) have affinity for more than 1 receptor with each receptor coupled to a different effector so it produces more than 1 effect ; effect 2 can be therapeutic or side /adverse effect.

Agonists and Antagonists Agonist is a drug capable of fully activating the effector system when it binds to the receptor. Drugs can activate receptors and thus elicit a biological effect (i.e , have intrinsic activity or efficacy ). The agonist possess high efficacy and can elicit a maximal tissue response.

 

A partial agonist produces less than the full effect, even when it has saturated the receptors . Partial agonists have intermediate levels of efficacy (the tissue response is submaximal even when all receptors are occupied).   Antagonists An antagonist is a drug that has no intrinsic activity but can reduce or abolish the effect of an agonist.e.g atropine (antagonist) which inhibit the effect of acetylcholine (agonist).

In contrast, inverse agonists have a much higher affinity for the inactive Ri state than for Ra and eliminate any constitutive activity.

Efficacy—often called maximal efficacy—is the greatest effect (Emax) - Efficacy versus potency: Efficacy Efficacy—often called maximal efficacy—is the greatest effect (Emax) an agonist can produce if the dose is taken to very high levels. Potency: a comparative measure , refers to the different doses of two drugs that are intended to produce the same effect. .

By definition, partial agonists have lower maximal efficacy than full agonists. 1- Efficacy is the maximum effect of a drug, Emax. 2-Efficacy is independent of the slope or position of the dose –response curve . in figure 1-1 drug A and drug B have equal efficacies{ the same Emax} 3- drugs such as aspirin and morphine produce the same pharmacological effect {analgesia} but have very different levels of efficacy.

2).

potency is independent of efficacy , and efficacy is usually more important than potency in selecting drugs for clinical use. in fig , drug A is more potent than drug B, because of the dose of drug B must be larger than the dose of drug A to produce a given effect.

Enhancement of drug effects: a- Additive drug effects occur if two drugs with same effect , when given together , produce an effect that is equal in magnitude to the sum of the effects . 1+1=2 b- Synergism: occurs if two drugs with same effect , when given together , produce an effect that is greater in magnitude than the sum of the effect when the drugs are given individually . 1+1 >2 c- Potentiation: occurs if a drug lacking an effect of its own increases the effect of a second active drug. 0+1 >1

Thank You